INTL Journal of Intensive Care Winter 2011

WINTER 2011 | VOLUME 18 | NUMBER 4

Current surgicalstrategies to prevent renal failure

Role of novel biomarkers in acutekidney injury

The correct antibiotic dosesfor septic shock

INTERNATIONAL JOURNAL OF

INTENSIVE CAREINTENSIVE CAREEstimating unmeasured ions in extracellular fluid

Estimating unmeasured ions in extracellular fluid

01_Front cover 16/12/11 12:23 pm Page 89

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REVIEWSurgical and intensive care strategies to prevent renal failureAcute kidney injury (AKI) refers to a sudden decline in kidney function causing disturbances in fluid, electrolyte,and acid–base balance. Its occurrence in surgical and critically ill patients is common and it is associated with a substantial increase in morbidity and mortality. In this review, N Brienza, MT Giglio and L Dalfino discuss theepidemiology and prevention of AKI. Currently, excellent supportive care and avoidance of clinical conditions known to cause or worsen AKI remain the cornerstones of management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

COVER FEATURESignificance and estimation of unmeasured ions in extracellular fluid – a brief reviewDuring critical illness, anionic species may leak from the intracellular environment to the extracellular fluid.While these ions may not directly contribute to mortality, they do reflect underlying pathology and their ultimatedisappearance from the extracellular fluid is associated with a return to health. In this review, CM Anstey focuses on the physiological rationale behind measurements in the extracellular fluid and on the shortfalls of the current models for detecting unmeasured ions. A new parameter is introduced. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

REVIEWThe diagnostic role of novel biomarkers in acute kidney injury in critically ill patientsAcute kidney injury (AKI) is a common and serious condition, in particular in critically ill patients. In this review,N Lameire first discusses the drawbacks of serum creatinine and oliguria in the early diagnosis of AKI, and then reviews novel biomarkers – specifically serum cystatin C and plasma and urine neutrophil gelatinase-associated lipocalin – that may allow the early detection, risk stratification and prognostication of patients with AKI. . . . . . . . . . 118

REGULARSComment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Clinical news . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .96Industry news . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98Instructions to authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108Product news . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Editor Dr J Denis EdwardsSub Editor Catherine BoothArt Editor Bettina BrüxIllustrator Marion TaskerAdvertisement Manager Robert SloanEditorial Director Guy Wallis

Editorial Advisory BoardProfessor Rinaldo Bellomo, Melbourne, Australia Dr Martina Brückmann, Mannheim, GermanyProfessor Pierre Carli, Paris, FranceDr Daniel De Backer, Brussels, BelgiumProfessor Guillermo Gutierrez, Washington DC, USADr Klaus Hankeln, Bremen, GermanyProfessor Hiroyuki Hirasawa, Chiba, JapanProfessor Claus-Georg Krenn, Vienna, AustriaProfessor H Matsuda, Tokyo, JapanProfessor Paolo Pelosi, Varese, ItalyProfessor Azriel Perel, Tel Aviv, IsraelDr Kees Polderman, Amsterdam, The NetherlandsDr Jerome Pugin, Geneva, SwitzerlandProfessor Konrad Reinhart, Jena, GermanyDr Thomas Stewart, Toronto, CanadaDr Robert Tasker, Cambridge, UKDr Antonio Torres, Barcelona, SpainProfessor Jean-Louis Vincent, Brussels, BelgiumDr Julia Wendon, London, UKDr Duncan Wyncoll, London, UK

Publishing Director Ashley Wallis

The International Journal of Intensive Care isindexed in EMBASE/Excerpta Medica and in theCumulative Index to Nursing and Allied HealthLiterature (CINAHL). It is published quarterly andcirculated on a controlled basis to practitionerswho specialise in critical and emergency care,coronary and neonatal care. All others are invitedto subscribe.

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© Greycoat Publishing Ltd, 2011.

All rights reserved. No part of this publication maybe reproduced, stored in a retrieval system ortransmitted in any form or by any other means,electronic, mechanical, photocopying, recording,or otherwise, without prior permission, in writingfrom the publisher.

ISSN 1350–2794The publishers, editor and editorial board wish tomake it clear that the data, opinions andstatements appearing in the articles herein arethose of the contributor(s) concerned; suchopinions are not necessarily shared by the editoror the editorial board. Accordingly, the publishers,editor and editorial board and their respectiveemployees, officers and agents accept no liabilityfor the consequences of any such inaccurate ormisleading data, opinions or statements.

COVER PHOTOGRAPH

Blood sample being pipetted into a samplebottle. Blood samples are used to evaluateoxygen levels and search for contaminatingorganisms and toxins in the blood. Duringcritical illness, anionic species may leak fromthe intracellular environment to theextracellular fluid.

© Tek Image/Science Photo Library

CONTENTS WINTER 2011

INTERNATIONAL JOURNAL OF

INTENSIVE CARE

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93WINTER 2011 | INTERNATIONAL JOURNAL OF INTENSIVE CARE

Antibiotics in patients withseptic shock: are we using theright doses?

Fabio Taccone MD

COMMENT

Sepsis is one of the most common reasons foradmission to an intensive care unit (ICU),and results in high morbidity and mortali-

ty.1 In this setting, antibiotic treatment of critical-ly ill patients remains a significant challenge. Anearly and appropriate antimicrobial therapy ismandatory in the management of septic patients;however, an antibiotic is appropriate not onlybecause it is active in vitro against the isolatedpathogens, but also because the selected regimenoptimizes the killing drug activity.2 There are twomajor reasons why ICU patients are exposed tosubtherapeutic antibiotic concentrations duringsepsis. First, antimicrobial dosages used in sepsisare derived from pharmacokinetic (PK) dataobtained from healthy volunteers or less severelyill patients, without taking into account the PKchanges that occur during sepsis, which reduce theefficacy of antibiotics. In sepsis, increased cardiacoutput associated with increased capillary leakageand peripheral effusions induces a larger volumeof distribution (Vd), which may decrease plasmalevels of antibiotic. This hyperdynamic state canalso increase renal blood flow and creatinine clear-ance, resulting in elevated antibiotic elimination.In addition, organ (i.e., renal or hepatic) dysfunc-tion can alter drug metabolism and clearance,leading to drug accumulation and possible sideeffects.3 Second, infections, especially whenacquired in the ICU, are often caused by moreresistant pathogens, which require higher drugconcentrations to be killed.4

To treat these pathogens, the combination ofbroad-spectrum β-lactams with aminoglycosidesand/or glycopeptides (especially vancomycin) isrecommended.5 However, these drugs, which arehydrophilic compounds, have a small Vd (limit-ed to extracellular fluids) and are more likely tobe excreted unchanged by the kidney. Thus, PKalterations occurring in sepsis may profoundlyaffect drug concentrations and modification ofthe drug regimen should be considered.

Using PK principles, different strategies areused to improve antibiotic concentrations in rela-tion to the minimal inhibitory concentration(MIC) of the pathogen to the drug. The MIC rep-resents the threshold of antibiotic levels resultingin inhibition of bacterial growth under standardconditions.3 Experimental studies have demon-

strated that β-lactams have a slow continuous killcharacteristic that is almost entirely related to thetime during which serum concentrations exceedthe MIC (T > MIC) for the infecting organism.6,7

The PK parameter that better drives the efficacyof aminoglycosides is the ratio between the max-imal concentrations obtained after an intra-venous administration (Cmax) and the MIC. ACmax/MIC ratio between 8 and 10 has been report-ed to be the major determinant for optimalantibacterial activity and clinical response.8,9 Forvancomycin, the area under the serum concen-tration time curve (AUC) is generally calculatedto determine the adequacy of drug levels. As itmay be difficult to obtain multiple serum van-comycin concentrations to determine the AUC,trough concentration (Cmin) monitoring has beenrecommended as the most accurate and practicalmethod to adjust vancomycin regimens. A Cmin

above 15 µg/mL should be achieved to optimizedrug activity against Gram-positive bacteria suchas methicillin-resistant Staphylococcus aureus(MRSA) and Enterococcus species.10

Studies on serum concentrations of broad-spectrum β-lactams, including cefepime, cef-tazidime and piperacillin, have reported that druglevels were insufficient to treat less susceptiblestrains in patients with severe infections.11–13 Onthe other hand, serum drug concentrations ofmeropenem were adequate in most studies in crit-ically ill patients, including patients with bacter-aemia and ventilator-associated pneumonia.14,15

Furthermore, these reports excluded severely illpatients with septic shock and those with multi-ple organ failure, limiting the generalizability ofthe results to other populations of critically illpatients. In a prospective multicentre study,serum levels obtained after the first dose ofpiperacillin–tazobactam, ceftazidime or cefepimewere insufficient to empirically treat less suscep-tible pathogens in the early phase of severe sepsisand septic shock.16 Only meropenem achieved anadequate serum concentration in 75% of treatedpatients. In another recent prospective study,monitoring of β-lactams levels was routinelyapplied in the management of 236 critically illpatients; dose increases were required in 50% ofpatients during the early phase of infection ther-apy.17 Dose increases were more frequently

required for difficult-to-treat pathogens such asPseudomonas aeruginosa, Enterobacter andKlebsiella species or MRSA, suggesting again thatthese represent the target pathogens for which β-lactam dose adjustment is necessary to improveblood drug concentrations. In view of theseresults, broad-spectrum β-lactams should beadministered in doses larger than suggested fornon-septic patients. According to PK modelling,continuous or extended β-lactam infusions arerequired to optimize pathogen exposure to bac-tericidal concentrations of these drugs.3However,clinical data that have shown better outcomesusing this strategy are only from retrospectivestudies in critically ill populations of patients withpneumonia.18,19 Further studies are needed toassess the influence of continuous infusion (CI)strategy on morbidity and mortality, especially inpatients with sepsis and infections caused by mul-tidrug-resistant pathogens.

For aminoglycosides, Cmax is determined bythe administered dose and the Vd.3 The Vd ofaminoglycosides is largely increased in criticallyill patients when compared with healthy volun-teers and patients with mild infections, suggest-ing that higher than recommended doses of thesedrugs should be administered to achieve optimalCmax.20 In a recent study, a loading dose of 25mg/kg amikacin was necessary to achieve opti-mal Cmax concentrations in a prospective cohortof septic patients with multiple organ failure.21

Simulation with a standard regimen (15 mg/kg)of amikacin resulted in insufficient peak con-centrations in more than 90% of patients, thusconfirming the need to increase the dosing ofaminoglycosides to optimize Cmax in septicpatients. In another study, an even higheramikacin regimen (30 mg/kg) was required toobtain adequate Cmax levels in septic patients.22

Assuming the three to four-fold factor for con-verting doses of amikacin to gentamicin andtobramycin, higher doses (8–9 mg/kg) were sug-gested to optimize the efficacy of these two drugsin patients with septic shock.23,24

Higher than recommended doses (15 mg/kgevery 12 hours) of vancomycin have been pro-posed to optimize drug concentrations inpatients with septic shock or with trauma andMRSA pneumonia.25,26 As alternative, a CI

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94 INTERNATIONAL JOURNAL OF INTENSIVE CARE | WINTER 2011

COMMENTadministration (15 mg/kg loading dose followedby 30 mg/kg/day) has been proposed to optimizethe effectiveness of vancomycin.3 However, thequestion whether intermittent dosing or CI isbetter to improve vancomycin efficacy remainsunanswered. Wysocki et al. compared CI andintermittent dosing of vancomycin in 160patients with severe MRSA infection and foundno significant differences in clinical efficacy.27

However, a faster time to achieve target drug con-centrations, lower daily dose and reduced thera-py costs were reported for the CI strategy. Relloet al. suggested clinical superiority of vancomycinCI in a subgroup of patients with ventilator-asso-ciated pneumonia due to MRSA.28 Nevertheless,data on the optimal regimen of vancomycinwhen given by CI in patients with sepsis arescarce. Using a Monte Carlo simulation, higherthan recommended loading (35 mg/kg) and daily(30–40 mg/kg if normal renal function) doses ofCI vancomycin have been suggested to rapidlyachieve therapeutic serum concentrations in theearly phase of sepsis.29 However, this strategyneeds to be prospectively validated and its impacton drug-related toxicity further determined.

If higher than recommended doses for all ofthese antibiotics should be considered when treat-ing patients with severe sepsis and septic shock,routine drug monitoring is also required to avoidoverdosing with related toxicity. In 10% of ICUpatients with renal dysfunction receiving cefepime,serum drug accumulation occurred despite dosageadjustments and resulted in non-convulsiveseizures, disappearing after drug discontinua-tion.30 Roberts et al. reported that a β-lactams dosereduction was applied in 24% of ICU patients whenmonitoring was routinely performed.17 Potentialrenal, vestibular and neuromuscular toxicity canoccur in the early or late phases of aminoglycosidetherapy, with a wide spectrum of severity.17 Therisk of renal dysfunction increases with concomi-tant hypovolaemia, pre-existing renal disease,nephrotoxics and advanced age. Cumulative dose,especially where there are persistent elevatedtrough concentrations, is also associated with anincreased risk of renal toxicity so that Cmin moni-toring is advocated to minimize drug side effects.31

Finally, toxicity may occur when increasing thedose of vancomycin, and some studies have shownthat drug levels above 28 µg/mL are associated witha greater risk of renal dysfunction, especially if otherpotential nephrotoxics, such as aminoglycosides oramphotericin, are co-administered.32 Although aslower onset of nephrotoxicity was observed inpatients receiving vancomycin by CI,27 the impactof higher than recommended CI regimens on renalfunction has not been evaluated.

In conclusion, high or CI regimens of antibioticsare necessary to rapidly achieve therapeutic druglevels for difficult-to-treat pathogens in patientswith severe sepsis and septic shock. Monitoringserum antibiotic concentrations is important in

critically ill patients to detect underdosing, whichis frequent in the early phase of therapy, and avoidoverdosing and associated side effects, includingneurological disturbances and renal failure. Otherconditions found in ICU patients, such as the useof continuous renal replacement therapy, obesity,burns or liver cirrhosis, may also alter the PKs ofantibiotics and should be considered for drug reg-imen adjustments. Systematic clinical PK/phar-macodynamic studies are required to evaluate thebeneficial effects of these dosing strategies on theoutcomes for septic patients.

REFERENCES1. Vincent JL, Sakr Y, Sprung C, et al. Sepsis in European inten-

sive care units: results of the SOAP study. Crit Care Med 2006;34: 344–353.

2. Khollef MH. Inadequate antimicrobial treatment: an importantdeterminant of outcome for hospitalized patients. Clin Infect Dis2000; 31(Suppl. 4): S131–S138.

3. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics inthe critically ill patients. Crit Care Med 2009; 37: 840–851.

4. Van Eldere J. Multicentre surveillance of Pseudomonas aerug-inosa susceptibility patterns in nosocomial infections. JAntimicrob Chemother 2003; 51: 347–352.

5. Dellinger P, Levy M, Carlet J, et al. Surviving sepsis campaign:international guidelines for management of severe sepsis andseptic shock. Crit Care Med 2008; 36: 296–327.

6. Andes D, Craig WA. In vivo activities of amoxicillin and amoxi-cillin–clavulanate against Streptococcus pneumoniae: applica-tion to breakpoint determinations. Antimicrob AgentsChemother 1998; 42: 2375–2379.

7. Mouton JW, Punt N. Use of the t > MIC to choose between dif-ferent dosing regimens of beta-lactam antibiotics. J AntimicrobChemother 2001; 47: 500–501.

8. Moore RD, Lietman PS, Smith CR. Clinical response to aminogly-coside therapy: importance of the ratio of peak concentration tominimal inhibitory concentration. J Infect Dis 1987; 155: 93–99.

9. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizingaminoglycoside therapy for nosocomial pneumonia caused byGram-negative bacteria. Antimicrob Agents Chemother 1999;43: 623–629.

10. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin ther-apeutic guidelines: a summary of consensus recommendationsfrom the infectious diseases Society of America, the AmericanSociety of Health-System Pharmacists, and the Society ofInfectious Diseases Pharmacists.Clin Infect Dis 2009; 49: 325–7.

11. Ambrose PG, Owens RC Jr, Garvey MJ, et al. Pharmacodynamicconsiderations in the treatment of moderate to severe pseu-domonal infections with cefepime. J Antimicrob Chemother2002; 49: 445–453.

12. Ikawa K, Morikawa N, Hayato S, et al. Pharmacokinetic andpharmacodynamic profiling of cefepime in plasma and peri-toneal fluid of abdominal surgery patients. Int J AntimicrobAgents 2007; 30: 270–273.

13. Roberts JA, Kirkpatrick CM, Roberts MS, et al. First-dose andsteady-state population pharmacokinetics and pharmacody-namics of piperacillin by continuous or intermittent dosing incritically ill patients with sepsis. Int J Antimicrob Agents 2010;35: 156–163.

14. Kitzes-Cohen R, Farin D, Piva G, et al. Pharmacokinetics andpharmacodynamics of meropenem in critically ill patients. Int JAntimicrob Agents 2002; 19: 105–110.

15. de Stoppelaar F, Stolk L, van Tiel F, et al. Meropenem pharma-cokinetics and pharmacodynamics in patients with ventilator-associated pneumonia. J Antimicrob Chemother 2000; 46:150–151.

16. Taccone FS, Laterre PF, Durgernier T et al. Insufficient b-lac-tam concentrations in the early phase of severe sepsis and sep-tic shock. Crit Care 2010; 14: R126.

17. Roberts JA, Ulldemolins M, Roberts MS, et al. Therapeutic drugmonitoring of beta-lactams in critically ill patients: proof of con-cept. Int J Antimicrob Agents 2010; 36: 332–339.

18. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobac-tam for Pseudomonas aeruginosa infection: clinical implicationsof an extended-infusion dosing strategy. Clin Infect Dis 2007;44: 357–363.

19. Lorente L, Jimenez A, Palmero S, et al. Comparison of clinicalcure rates in adults with ventilator-associated pneumonia treat-ed with intravenous ceftazidime administered by continuous orintermittent infusion: a retrospective, nonrandomized, open-label, historical chart review. Clin Ther 2007; 29: 2433–2439.

20. Marik PE, Havlik I, Monteagudo FS, et al. The pharmacokineticof amikacin in critically ill adult and paediatric patients: com-parison of once-versus twice-daily dosing regimens. JAntimicrob Chemother 1991; 27(Suppl. C): 81–89.

21. Taccone FS, Laterre PF, Spapen H et al. Revisiting the loadingdose of amikacin for patients with severe sepsis and septicshock. Crit Care 2010; 14: R53.

22. Gálvez R, Luengo C, Cornejo R, et al. Higher than recommend-ed amikacin loading doses achieve pharmacokinetic targetswithout associated toxicity. Int J Antimicrob Agents 2011; 38:146–151.

23. Rea RS, Capitano B, Bies R, et al. Suboptimal aminoglycosidedosing in critically ill patients. Ther Drug Monit 2008; 30:674–681.

24. Buijk SE, Mouton JW, Gyssens IC, et al. Experience with a once-daily dosing program of aminoglycosides in critically ill patients.Intensive Care Med 2002; 28: 936–942.

25. Vázquez M, Fagiolino P, Boronat A, et al. Therapeutic drug mon-itoring of vancomycin in severe sepsis and septic shock. Int JClin Pharmacol Ther 2008; 46: 140–145.

26. Patanwala AE, Norris CJ, Nix DE, et al. Vancomycin dosing forpneumonia in critically ill trauma patients. J Trauma 2009; 67:802–804.

27. Wysocki M, Delatour F, Faurisson F, et al. Continuous versusintermittent infusion of vancomycin in severe staphylococcalinfections: prospective multicenter randomized study.Antimicrob Agents Chemother 2001; 45: 2460–7.

28. Rello J, Sole-Violan J, Sa-Borges M, et al. Pneumonia causedby methicillin-resistant Staphylococcus aureus treated with gly-copeptides. Crit Care Med 2005; 33: 1983–1987.

29. Roberts JA, Taccone FS, Udy AA, et al. Vancomycin dosing incritically ill patients – robust methods for improved continuousinfusion regimens. Antimicrob Agents Chemother 2011; 55:2704–2709.

30. Chapuis TM, Giannoni E, Majcherczyk PA, et al. Prospectivemonitoring of cefepime in intensive care unit adult patients. CritCare 2010; 14: R51.

31. Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation ofthe effect of an aminoglycoside dosing regimen on rates ofobserved nephrotoxicity and ototoxicity. Antimicrob AgentsChemother 1999; 43: 1549–1555

32. Vandecasteele SJ, De Vriese AS. Recent changes in vancomycinuse in renal failure. Kidney Int 2010; 77: 760–764. ■

CORRESPONDENCE TO:Fabio Silvio Taccone MDDepartment of Intensive CareHôpital Erasme, Université Libre deBruxelles (ULB)Route de Lennik, 8081070 BrusselsBelgiumE-mail: [email protected]

03_Comment.qxp 16/12/11 9:06 am Page 94

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CLINICAL NEWS From the cutting edge of research

Calorific intake essentialfor ICU patientsThe amount of calories that intensive care patientsreceive is essential for improving their chances ofrecovery, according to Canadian research.1

Patients who receive more calories while in inten-sive care have lower mortality rates than those whoreceive less of their daily-prescribed calories, con-clude the researchers.“Our finding is significant as there have been anumber of previous studies in the area of criticalcare nutrition that have produced conflicting clinicalrecommendations and policy implications,” saidstudy lead author Dr Daren Heyland of Queen’sUniversity and Kingston General Hospital. “Sincecaloric delivery is essential for improving thechances of these critically ill patients, it’s vital thatwe know what the optimal level is.”The research team examined the records of 7872mechanically ventilated, artificially fed patients in352 ICUs in 33 countries. They found that patientsreceiving at least two-thirds of their prescribed calo-rie intake had reduced mortality rates when com-pared with patients receiving less than one-third oftheir prescribed calorie intake. The optimal caloricintake was identified to be about 80 to 85% of totalprescribed calorie intake.

1. Heyland D, Cahill N, Day AG. Optimal amount of calories for criti-cally ill patients: depends on how you slice the cake! Crit Care Med2011; Epub June 23: DOI:10.1097/CCM.0b013e318226641d.

Interactive video games appear to safely enhancephysical therapy for patients in intensive care units,new US research suggests.1

“Patients admitted to our medical intensive careunit are very sick and, despite early physical thera-py, still experience problems with muscle weak-ness, balance and coordination as they recover,”said lead researcher Dr Michelle E. Kho of JohnsHopkins University. “Our study suggests that inter-active video games may be a helpful addition.”

Over a one-year period, the researchers identi-fied a select group of 22 critically ill adult patientswho received video games as part of routine physi-cal therapy. They were mostly males aged 32 to 64years old.

The 42, 20-minute physical therapy sessionsincluded use of the Nintendo Wii and Wii Fit videogames under supervision of a physical therapist.Almost half the sessions included patients whowere mechanically ventilated. The most common

games included boxing, bowling and use of thebalance board, which were chosen to improve thepatients’ stamina and balance.“As always, patient safety was a top priority …when properly selected and supervised by experi-enced ICU physical therapists, patients enjoyed thechallenge of the video games and welcomed thechange from their physical therapy routines,” saidstudy author Dr Dale M. Needham.The video game therapy activities are short in dura-tion, which is ideal for severely deconditioned patients,Dr Needham said. They are also very low cost com-pared to most ICU medical equipment, he added. More research is needed into whether the videogame therapy helps patients to improve their abili-ties to do tasks that are most important to then, theresearchers caution.“Our study had limitations because the patients werenot randomly selected, the video game sessions wereinfrequent and the number of patients was small,”

Kho noted. “Our next step is to study what physicaltherapy goals best benefit from video games.”

1. Kho ME, Damluji A, Zanni JM, Needham DM. Feasibility andobserved safety of interactive video games for physical reha-bilitation in the intensive care unit: a case series. J Crit Care2011; Epub Sept 26: DOI:10.1016/j.jcrc.2011.08.017.

The time at which organ donation in brain deaddonors is first discussed with family members couldaffect whether or not they consent to donation,according to a Dutch study.

Discussing the issue of donation with relatives ofvictims of catastrophic brain injury earlier on in theprocess may have a negative effect on the consentrate, the authors conclude.

In the study, the researchers analysed data col-

lected retrospectively from 228 patients declaredbrain dead between 1987 and 2009 in the ErasmusMC University Medical Centre.

The Donor Register was introduced in theNetherlands in 1998, which increased patient-con-sent rates more than seven-fold, from 5.7% to 41%,the researchers found.

They also observed that over the past 15 yearsthere was a decline in donation after brain deathfrom 89% to 58%; in contrast, donation after circu-latory death increased from 11% to 42%.

The timing of discussion about organ donationwith relatives changed after 1998 from first beingmentioned after the completion of all tests, to afterdetermination of loss of consciousness and theabsence of brainstem reflexes but before completionof confirmatory tests. Lead author Dr Erwin Kompanje said, “It is unclearwhether the observed shift contributed to the highrefusal rate in the Netherlands and the increase infamily refusal in our hospital after 1998 … it is pos-sible that this may have a counterproductive effect.”

1. de Groot YJ, Lingsma HF, van der Jagt M, et al. Remarkablechanges in the choice of timing to discuss organ donation withthe relatives of a patient: a study in 228 organ donations in 20years. Crit Care 2011; 15: R235.

Timing crucial for familyconsent in organ donation

When to discuss organ donation with relatives iscrucial.

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INDUSTRY NEWS An update on recent industry initiatives

The winner of the Swiss Technology Award 2011 hasbeen announced as the INTELLIVENT®-ASV introducedby Hamilton Medical. It is the first complete closed loopventilation solution, that offers automated adjustmentof oxygenation and ventilation. Today, conventionalmechanical ventilation still requires a great deal ofexpertise and the manual adjustment of ventilator set-tings. This can be challenging, as it is impossible for arespiratory clinician to be at the bedside all the time.

Now there is a solution to the problem as the deviceprovides guidance when complex decisions are made.Equally important it not only gives recommendations,but also adjusts ventilation settings automatically. TheINTELLIVENT-ASV even applies comprehensive lungprotective strategies automatically and reduces the riskof operator errors while encouraging early weaning.

The device is based on innovative ASV technology

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The award was in recognition of only one aspect ofHamilton Medical's programme of innovation. It does notend at the hospital doors, but responds to the require-ment for ready access to appropriate modes of therapyfor ventilated patients outside the hospital environment.

The HAMILTON-T1 delivers a cost-effective solutionthat is appropriate for all patients from paediatric toadult. It is suitable for mobile ICU ambulances, heli-copters and long distance jets. The device also includes

advanced lung protective strategies and patient adap-tive modes. The device is the ideal choice for extremeenvironments, where ICU ventilation is essential andreliable data.

Medication data fliesover the airwavesMedication errors remain a continuing hazard in hos-pitals and there are a variety of products available toaddress it. This creates the problem of how to choosethe most suitable infusion system for a particular appli-cation. The latest system to make its appearance isthe new Medfusion® 400 wireless syringe infusionpump with the PharmGuard® infusion managementsoftware suite introduced by Smiths Medical. In com-mon with other infusion devices it is designed to helpprevent errors. The difference is that at the same timeit facilitates the forwarding and receipt of medicationdelivery information more efficiently. This is achievedvia the wireless Ethernet connectivity.

Financial and other considerations are making thechallenge of improved patient outcomes more difficultto achieve. The easy access to medication data canhelp clinicians to make these improvements. This sys-tem with its wireless connectivity allows hospitals tocapture many types of infusion data and facilitates easyreporting for evidence based practice improvements.It also smoothes the update of drug libraries andimproves both patient safety and clinical care by thequick and easy update of pumps.

A certain percentage of patients invariably have tomove around the hospital for a variety of reasons.Monitoring is required during their transport or withinthe hospital, in a progressive care area or during super-vised recovery from an acute event or surgical proce-dure. Recognising this need Philips has introduced theIntelliVue MX40 patient monitor. It is a wearable mon-itor which combines the benefit of the IntelliVue X2 andPhilips Telemetry into a single, compact wearablemonitor. The benefits it brings are considerable. Itallows the clinician to better manage patient alerts andis designed to support effective infection control.

There is easy access to such important data as ECG,SpO2 and non-invasive blood pressure. Patient alertsare highlighted at both the bedside and the centralmonitoring station. The clinician is alerted to changesin the patient conditions based on real-time surveil-lance. In total the monitor makes an important contri-bution to a streamlined data flow. The IntellivueInformation Centre is an integral part of the MX40 solu-tion as it facilitates interfacing with the hospital EMR(electronic medical record).

The development of the system was the result of aresearch initiative that took two different technologiesand combined them into a single innovative device thatcould speed vital patient data around the key points of

the hospital information loop. This has meant greatermobility for patients and more time available for clin-ical and nursing procedures.

Compact monitorgives instant access

PLEASE SEND YOUR NEWS ITEMS TO:Guy WallisEditorial [email protected]

Value of closed loop ventilationrecognised by major award

The Hamilton Medical team receives the SwissTechnology Award for 2011.

Alerts are highlighted at the bedside and the centralmonitoring station as well.

05_Industry news 16/12/11 9:07 am Page 98

p99_ISICEM_2012 16/12/11 9:40 am Page 99

REVIEW


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Surgical and intensive care strategiesto prevent renal failure

meta-analysis established the usefulness of NGAL as a diag-nostic and prognostic tool in cardiac surgical and critical-ly ill patients, as well as in patients with contrast-relatedrenal damage, while no conclusions can be drawn for non-cardiac surgical patients.8 In a large multicentre analysis,the same group confirmed that a positive NGAL findingidentified approximately 40% more AKI cases than creati-nine alone and that these patients were at greater risk ofdeath compared with control subjects.9 Very recent tri-als10,11 suggest that a single NGAL measurement at ICUadmission can predict later-onset AKI as well as ICU mor-tality, both alone or in combination with other AKIbiomarkers.

EPIDEMIOLOGYTraditionally, AKI has been extensively studied in cardiacsurgery, where it has a high occurrence (1–30%) and ishighly predictive of other complications.12 In general sur-gical patients, AKI – defined as a creatinine increase of atleast 2 mg/dL or need for dialysis – occurs in 1% of patientsand is associated with an eight-fold increase in mortality,independent of underlying comorbidities.13 Althoughsmall as an absolute number, the rate of AKI is similar tothat of other ominous perioperative complications, suchas adverse cardiac events or venous thromboembolism.14

In patients admitted to the ICU after non-cardiac surgery,the AKI rate is 7.5% and AKI is an independent risk factorfor mortality at 6 months’ follow-up.15 More interesting-ly, the occurrence of postoperative AKI, independent of itsevolution, seems to affect outcomes.15 Knowing the exacttiming of kidney insult (i.e., surgery) would make preven-tion of postoperative kidney injury easier than in other set-tings. However, one major problem is that we do not knowexactly which patients will really obtain a benefit. Whereasin cardiac surgery preoperative renal risk is carefully strat-ified,12 this evaluation is lacking in non-cardiac surgery,although a specific risk index for AKI including congestiveheart failure, emergency surgery or the complexity ofsurgery, mild or moderate chronic renal insufficiency anddiabetes mellitus under therapy has recently been pro-posed.13

AKI often complicates the course of critical illness and,although previously considered as a marker rather than acause of adverse outcomes, it is independently associatedwith an increase in both morbidity and mortality.16 Themajor causes of AKI in the ICU include renal hypoperfu-sion, sepsis/systemic inflammatory response syndrome anddirect nephrotoxicity, although in most cases the aetiologyis multifactorial.17,18 In a recent multicentre study, 42% of33,375 septic patients developed concomitant AKI.19 Riskfactors for the development of septic AKI included age,comorbidities and a higher severity of illness. Since most ofthese factors are not modifiable, AKI prevention shouldmostly benefit from the avoidance of potential nephrotox-ic conditions and prompt recognition.

Acute kidney injury (AKI) refers to a sudden decline in kidneyfunction causing disturbances in fluid, electrolyte, andacid–base balance due to a loss in small solute clearance anddecreased glomerular filtration rate. Its occurrence in surgicaland critically ill patients is common and it is associated with asubstantial increase in morbidity and mortality. Although thepathophysiology of AKI is complex, subsequent injuryresponses are likely to involve similar mechanisms. Majorcontributors that precede renal injury are hypotension,ischaemia/reperfusion, inflammation and toxins. Appropriateand early identification of patients at risk for AKI provides anopportunity to prevent subsequent renal insults and impactoverall intensive care unit morbidity and mortality; strategiesto prevent AKI are therefore of pivotal importance. Keycomponents of optimal prevention and management of theintensive care unit patient with AKI include maintenance ofrenal perfusion and avoidance of precipitating factors.Whereas management of AKI remains limited primarily tosupportive care, many potential therapies and interventionsare on the horizon. For now, recognition of risk factors,excellent supportive care and avoidance of clinical conditionsknown to cause or worsen AKI remain the cornerstones ofmanagement of AKI.

Acute kidney injury (AKI) is a serious complication insurgical and critical care patients, accounting for18–47% of all hospital-acquired AKI,1,2 augmenting

hospitalisation costs3 and increasing mortality.4

Clinical manifestations of acute renal involvement rangefrom short periods of oliguria to the need for renal replace-ment therapy (RRT). However, these manifestations havedifferent clinical impacts, since a common transient post-operative oliguria may not be synonymous of abnormalrenal function but the appropriate response to hypoperfu-sion of a kidney that is ‘doing its job’. The need for RRT,5

on the other hand, as well as subtle increases in serum cre-atinine, usually perceived as fluctuations within the ‘nor-mal range’,4 are both associated with increased mortalityand morbidity. On the basis of glomerular filtration rate,creatinine level and urine output, the RIFLE (Risk, Injury,Failure, Loss and Endstage Kidney Disease) classificationdefines three grades of increasing severity and two outcomeclasses, all associated with increased hospital mortality.6 TheAKI Network has modified RIFLE by adopting the term‘AKI’ to cover the entire spectrum of acute renal failure7 andby including only three stages representing an increasingdegree of renal impairment, from small increases in creati-nine to the need for RRT.

However, the rise in creatinine lags behind the processleading to AKI, since it is revealed only after a substantialfall in glomerular filtration rate has occurred. Therefore,new biomarkers for AKI early diagnosis have been pro-posed with the aim of identifying an ongoing kidney insultbefore creatinine variation. The most promising is neu-trophil gelatinase-associated lipocalin (NGAL). A recent

N Brienza MD, PhD,MT Giglio MD, L Dalfino MD,Emergency and OrganTransplantation Department,Anesthesia and Intensive CareUnit, University of Bari, Bari, Italy

06_Brienza.qxp 16/12/11 9:08 am Page 100

STRATEGIES TO PREVENT RENAL FAILURE


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PREVENTIVE STRATEGIES A major problem in AKI prevention is the lack of evidence-based strategies. In 2005, a systematic review did not findany reliable evidence from the available literature to suggestthat dopamine, diuretics, calcium-channel blockers orangiotensin-converting enzyme inhibitors can protect thekidneys.20 Recent recommendations for the protection andprevention of AKI in ICU patients are all ‘negative’ 1A rec-ommendations (strong recommendation with a highdegree of evidence), and the few ‘positive’ clinical indica-tions have been downgraded to suggestions with a low gradeof evidence.21,22

How many and which fluids?Both relative and overt hypovolaemia are significant riskfactors for the development of AKI. Consequently, timelyfluid administration is a preventive measure that should beeffective through restoring the circulating volume and min-imising drug-induced nephrotoxicity. In ICU patients,however, AKI commonly involves multiple mechanisms,including hypovolaemia and various types of shock. Forexample, sepsis and trauma can cause AKI through a com-bination of renal hypoperfusion and the release of endoge-nous nephrotoxins. Thus, correction of fluid deficit, whileessential, will not always prevent renal failure. Moreover, itis often difficult for clinicians to determine the amount offluids to administer to a given patient. From a kidney stand-point, on one side failure to prescribe adequate intravenousfluid can place a patient at risk of hypovolaemia, while onthe other side excessive fluid infusion may promote third-space loss and intra-abdominal hypertension (IAH), a well-known risk factor for AKI (see below). Currently, anindividualised, timely fluid ‘replacement’ therapy by titrat-ing volume to physiologic flow-related endpoints withappropriate monitoring23 may be a rational choice.

The question of fluid infusion concerns not only thequantity of fluids, but also their quality. Aggressive crystal-loid resuscitation may increase intra-abdominal pressureand impair renal function, and colloids, while maintainingthe plasma volume more efficiently, may per se impair renalfunction. Recent randomised controlled trials (RCTs) havereported fewer marked changes in postoperative kidneyfunction with 6% hydroxyethyl starch (HES) 130/0.4 com-pared with gelatine in both cardiac and vascular surgerypatients24,25 The most update-to-date evaluation of the rela-tionship between colloids and kidney function shows that,more than the quality, it is the mean colloid cumulative dosethat is associated with AKI.26 A recent Cochrane review stat-ed that colloids carry an increased risk of AKI in septicpatients compared to non-septic surgical and traumapatients.27 However, the small number of studies and thelow event-rate claims for larger studies in non-septic set-ting may have hampered the statistical power of these find-ings.

Recently, a pilot RCT performed in cardiac surgicalpatients undergoing cardiopulmonary bypass suggestedthat intravenous sodium bicarbonate is associated with alower incidence of acute renal dysfunction.28 This resultwarrants further investigation with adequately poweredRCTs and in other surgical settings. The benefit of sodiumbicarbonate has been extensively studied in contrast-induced nephropathy, and recent inconclusive evidenceconfirms a benefit of sodium bicarbonate over normalsaline.29

Haemodynamic optimisationThe kidney normally receives 20–25% of total cardiac output. However, the medullary portion of the nephrons is at risk of hypoperfusion because of low blood flow and high oxygen demand and extraction. In the perioper-ative setting, the increase in oxygen demand may put thekidney at further risk of hypoxia.30 Haemodynamic optimi-sation or goal-directed therapy (GDT) is the perioperativemonitoring and manipulation of physiological haemody-namic parameters by means of fluids and inotropic drugs,with the aim of achieving adequate oxygen delivery to cope with the increase in oxygen demand and prevent organfailure.31

A recent meta-analysis demonstrated that GDT decreas-es the risk of postoperative renal impairment (Table 1).32

Interestingly, this nephroprotective strategy was reportedto be effective in high-risk surgical patients and when start-ed preoperatively to the first hours postoperatively.Moreover, targeting the optimisation to physiological val-ues of cardiac output revealed as much nephroprotectionas adopting supranormal goals of cardiac output. Becauseof potential complications of fluid overload, myocardialischaemia and excessive use of catecholamine, which are notdevoid of risks in terms of renal function,33 aggressive useof fluids and catecholamines in an attempt to increase car-diac output to supranormal values can be avoided. Despitethe obvious limitations of all the meta-analysis regardingmethodological differences among studies, publication biasor suboptimal methodological quality of the studies, peri-operative GDT is, at the moment, the only evidence-basedstrategy able to reduce kidney injury in postoperativepatients. Moreover, evidence suggests that in surgicalpatients, perioperative GDT with epinephrine, dopexam-ine or dobutamine may improve renal outcome,32,34 callingfor further trials to better clarify this issue.

In patients with persistent hypotension despite volumeoptimisation, vasopressors are often employed to increasemean arterial pressure and/or cardiac output, with the goalof ensuring optimal renal perfusion. In septic patients, nore-pinephrine has been traditionally used to increase bloodpressure with improvement of creatinine clearance.35 AnRCT comparing dopamine with norepinephrine as the ini-tial vasopressor in septic shock showed no significant dif-ferences between groups with regard to renal function ormortality, even if the use of norepinephrine was associatedwith a lower incidence of arrhythmias.36 The results ofVASST (Vasopressin and Septic Shock Trial) suggest that,compared with norepinephrine, vasopressin may reducethe progression to severe AKI only in a subgroup of patientswith less severe septic shock.37 The use of norepinephrineto improve renal oxygen delivery and renal oxygenation hasbeen tested in other kinds of vasodilatory shock (i.e., post-cardiac surgery patients) with convincing results.38

VasodilatorsIn recent years, a role for specific vasodilating drugs on kid-ney function has emerged. Fenoldopam mesylate is a selec-tive DA-1 agonist that increases both medullary and corticalblood flow and reduces oxygen demand.39 A meta-analysisincluding 1,290 patients found that fenoldopam significant-ly reduced the need for RRT and in-hospital mortality40 anda later review41 confirmed a beneficial effect in cardiac sur-gical patients, but no conclusion can be drawn regardingnon-cardiac surgery.




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Atrial natriuretic peptide (ANP) is another ideal substanceto counteract the initiation phase of AKI by causing vasodi-latation of the preglomerular artery, inhibition of therenin–angiotensin axis and prostaglandin release.42 A recentCochrane review showed that low-dose ANP after majorsurgery significantly reduced the requirement for RRT inprevention studies, but not in treatment studies.43 However,this result was mostly driven by the efficacy of low-dose ANPin patients undergoing cardiovascular surgery.

Metabolic controlIn 2001, an RCT in surgical ICU patients compared tightblood glucose control with insulin (blood glucose 80–110mg/dL) versus standard care (blood glucose 150–160mg/dL), demonstrating an improved survival rate and a41% reduction in AKI requiring RRT in the intensively con-trolled group.44 These positive findings have recently beenquestioned by the NICE-SUGAR trial,45 which includedsurgical patients but was not limited to them. This trialfound that a blood glucose target of 180 mg/dL or less result-ed in lower mortality than an intensive target of 81–108mg/dL, with no effect on RRT. A recent meta-analysis,which included the NICE-SUGAR trial, tried to put the con-troversial results in a different perspective by analysing sub-groups of mixed, medical and surgical ICU patients.46 Theanalysis concluded that a beneficial effect, if any, on mor-tality of this therapy may be restricted to patients in the sur-gical ICU.

Intra-abdominal hypertensionShock and IAH, by reducing abdominal perfusion pressure,are the strongest independent predictors of AKI.47 ‘Third-space’ losses from compromised bowel capillary endotheli-

um by reperfusion (e.g., after haemorrhagic shock) or byinflammatory mediators of injury (e.g., during sepsis/sys-temic inflammatory response syndrome or major surgery)associated with a positive fluid balance can lead to gut oede-ma and IAH. IAH, by impairing systemic haemodynamicsand renal function, may foster a fluid-overload condition,leading to a vicious cycle that perpetuates IAH itself and renalinjury.47 Therefore, when IAH is present in an oliguricpatient, intra-abdominal pressure should be monitoredcarefully and crystalloid use should be avoided or limited.Specific medical treatments and surgical options should beconsidered to decrease intra-abdominal pressure.48

DrugsThe contribution of treatment-induced renal injury as apreventable cause of AKI is frequently underestimated. Insevere AKI, nephrotoxic drugs are contributing factors inup to 19–25% of cases.2,49 In surgical and critically illpatients, drug-induced AKI is mediated by inherent drugnephrotoxic potential, disease states and impaired drugpharmacokinetics, leading to overdosing.

Drugs may exert a direct nephrotoxic effect by severalmechanisms. Most commonly, renally excreted drugs canexert direct toxic effects on renal tubules, inducing cellularinjury and death in acute tubular necrosis, or can inducerenal interstitium inflammation in acute interstitial nephri-tis. Moreover, hypertonic solutions may cause osmoticnephrosis and tubular obstruction by drug precipitation.Drugs may also be indirectly nephrotoxic by impairingintrarenal blood flow, thus making the kidneys vulnerableto ischaemia and injury in low-flow states such as sepsis,volume depletion, major surgery, trauma and acute decom-pensated heart failure.50

Table 1. Subgroup analyses of pooled odds ratios of renal injury in perioperative haemodynamic goal-directed studies32

Treatment (n/N)

Control (n/N) OR (95% CI) p-value

Q statistic p-value I2 (%)

Statisticalpower (%)

High-quality RCTs (Jadadscore �3)

102/1,741 150/1,699 0.66 (0.50–0.87) 0.003 0.75 0 99.7

Renal injury according toAKIN

97/1,893 145/1,839 0.66 (0.50–0.86) 0.002 0.76 0 99.8

Preoperative optimisation 94/1,347 117/1,289 0.70 (0.53–0.94) 0.02 0.41 0 75.6

Intraoperative orpostoperative optimisation

21/770 58/814 0.47 (0.27–0.81) 0.006 0.80 0 100

High-risk patients 102/1,393 158/998 0.64 (0.49–0.84) 0.001 0.53 0 99.8

Non-high-risk patients 13/724 17/686 0.69 (0.31–1.54) 0.37 0.61 0 19.1

Pulmonary artery cathetermonitoring

103/1,640 151/1,629 0.62 (0.43–0.90 0.01 0.35 10.3 98

Other monitoring devices 12/477 24/474 0.52 (0.25–1.07) 0.07 0.87 0 73

Fluids only 6/334 12/333 0.55 (0.20–1.47) 0.23 0.74 0 31

Fluids + inotropes 109/1,783 163/1,770 0.65 (0.50–0.85) 0.002 0.50 0 100

Fluids + dobutamine 12/511 42/518 0.36 (0.18–0.75) 0.006 0.57 0 100

Supranormal targets 30/354 55/353 0.49 (0.29–0.83) 0.008 0.54 0 98.2

Normal targets 85/1,763 120/1,750 0.70 (0.52–0.94) 0.02 0.71 0 94.5

AKIN = Acute Kidney Injury Network; CI = confidence interval; OR = odds ratio; RCT = randomised controlled trial




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Table 2. Primary pathogenetic mechanisms, specific clinical features and risk factors, preventive measures in high-risk patients and management ofdrug-induced AKI22,26,50,51

Primarymechanism

Drug Clinical features Specific risk factors AKI prevention in high-risk patients/managementRadiocontrast dye

Haemodynamicallymediated

Radiocontrast dye Onset: 24 hours Advanced age, diabetesmellitus, multiple mieloma,nephrotic syndrome,haemodynamic instability

High osmolality and/or highvolume (� twice the baselineGFR in mL) of radiocontrast dye

Number of risk factors

Address the issue of whether contrast exposure ismandatory

Discontinue all other nephrotoxics if possible

Use the smallest volume of iso-osmolar agents

Perform preprocedural hydration with crystalloidsolutions (sodium chloride or sodium bicarbonateinfused at 3 mL/kg/hr for 1 hour), plus high-dose NAC(1,200 mg) administration, followed by postproceduralhydration (1 mL/kg/hr for the subsequent 6 hours)

Monitor renal function at 24–72 hours

ACE inhibitors,angiotensin-receptorblockers

Usually reversible upondiscontinuation

Bilateral renal artery stenosis Consider drug requirement carefully

Discontinue if SCr >30% from baseline orhyperkalemia develops

NSAIDs, COX-2inhibitors

Onset after a few doses

Usually oliguric


Severe cardiovascular orhepatic failure

Type (aspirin the least toxic,indomethacin the most toxic),dose and duration of therapy

Concomitant nephrotoxics

Consider drug requirement carefully (preferacetominophen and/or narcotics)

Begin with a low-dose of short half-lifes NSAIDs(salycilates, sulindac)

Use half doses or avoid ketorolac, avoid indomethacin

Immediatly stop NSAID therapy

Correct volume depletion

Calcineurin inhibitors(cyclosporine,tacrolimus)

Onset: few weeks ormonths

Usually oliguric

Reversible after dosereduction ordiscontinuation

Dose and serum levels


Perform TDM

Avoid other nephrotoxins

Perform dose reduction or drug discontinuation

Acute tubularnecrosis

Aminoglycosides Onset: 5–10 days

Non-oliguric

From mild and rapidlyreversible to severeforms requiring RRT anda prolonged recoverytime

Usually reversible uponearly discontinuation

Advanced age

Type of aminoglycoside(streptomycin the least toxic,neomycin the most toxic)

Persistently high trough serumlevels

Frequency of administration,large cumulative doses, longand/or repeated courses oftherapy


Consider alternative antimicrobials

Use extended-interval dosing (i.e., once-daily dosing)

Perform TDM, and titrate dose basing on trough levelsand renal function

Avoid concomitant nephrotoxins

Discontinue and choose alternative antimicrobials ifpossible, when severe AKI ensues

High-dose vancomicin(daily dose �4 g or�30 mg/kg, or targettrough concentrationsof 15–20 mg/L)

Onset: 4–8 days


Advanced age

Obesity

High APACHE II score

Trough levels >15 mg/L

Duration of therapy

Concomitant aminoglycosidetherapy

Perform TDM and titrate dose based on renal functionand ideal body weight

Discontinue and choose alternative antimicrobials ifpossible, when severe AKI ensues

Amphotericin B Frequency: 80%

Usually oliguric

Hypokalemia

Large single and cumulativedoses


Consider alternative antifungals

Prefer lipid-based formulations

Perform sodium loading with intravenous hydrationbefore each dose

Prescribe prolonged infusion times and daily renalfunction monitoring

Avoid concomitant nephrotoxins

06_Brienza.qxp 16/12/11 12:13 pm Page 104

The Dangerous Progression ofIntra-Abdominal Hypertension

Patient Signs and Symptoms Physiologic Effects of IAH

Very subtle clinical findings:

� Occult ischemia is occurring with little clinical evidence beyond IAP level

� Clinicians cannot feel abdomen or measure its circumference and gain any meaningful insight into the patient’s IAP level

� Difficult to mobilize excess fluid

� Difficult to wean from the ventilator

� Sedation

� Pain control

� Avoid prone position

� Reposition bed: reverse Trendelenburg without flexion at the hips

� Remove all constrictive bandages

� Carefully assess fluid administration:� Do not over resuscitate – use goal

directed volumes and reassess� Avoid unneeded fluid boluses� Concentrate all drips� Aim for neutral to negative fluid balance

by day 3

� Nasogastric tube

� Rectal tube

� Enemas

� Bowel prokinetic agents such as erythromycin, metoclopramide

Increasing Physiologic CompromiseIAP 12 – 15 mmHg

Increased Systemic Vascular Resistance (SVR)

IAP against diaphragm makes breathing difficult

Decreased gut perfusion Increased Ischemia

Decreased wound perfusion(poor healing)

Increased SIRS/Cytokine release

Decreased Urinary Output (UOP)

Vena caval compression

Decreased preload

Decreased Cardiac Output

Lower extremity Venous Pooling (DVT risk)

ALL OF THE ABOVE PLUS:

� Unexplained acidosis

� CVP and Wedge pressure measurements are often falsely elevated (due to IAP transmission to CVP catheter)

� Cardiac output decreasing

� Urine output decreased

� Peak and plateau pressures increasing on the ventilator

� Hypoxemia, hypercarbia, atelectasis

� Abdominal distention MIGHT be visible; not reliable in today’s obese population


� Enteral nutrition at trophic levels only

� Colloids plus diuretics

� Hemofiltration / dialysis to remove excess fluid

� Ultrasound or CT the abdomen to identify free fluid, space occupying lesions amenable to drainage

� Paracentesis catheter to drain any free fluid

� CT or ultrasound guided drainage of abscesses, hematomas

Occult Organ IschemiaIAP 16 – 20 mmHg

Increased bowel edema and ischemia

Worsening vena caval compression

Decreased perfusion, oliguria, difficulty mobilizing fluids

Increased CVP, Increased Wedge pressure (falsely elevated)

Increased ICPDecreased CPP

Further decrease in Cardiac Output

Increased acidosis

Increased lung dysfunction

Rising IAP pushes diaphragm further into chest


� Neuromuscular blockade and infusion

� Colonoscopy to decompress distended colon

� Stop enteral nutrition

� Surgical evacuation of any tumors, masses

� Surgical consultation to plan decompressive laparotomy if the above interventions fail, IAP exceeds 25 mmHg or organ failure ensues


� Intractable acidosis

� Abdomen tense (exam not reliable in today’s obese population)

� Renal insufficiency / failure

� Pulmonary failure with significant difficulty ventilating

� Cardiovascular instability

� Rising intracranial pressure

Onset of Multiple Organ Dysfunction Syndrome (MODS)IAP > 20 mmHg

Increased gut ischemia, Impending necrosis

Anuria/Acute Renal Failure (ARF)

Further worsening of acidosis

Vena caval flattening

Brain swelling and ischemia

Cardiovascular instability

Increased peak pressure,difficult ventilation and oxygenation; VILI /ARDS

This educational poster sponsored by:Posters available upon request

Interventions are based upon WSACS.org international guidelines.References on file 1-801-281-3000 www.abviser.com

Free Posters at Booth 1.17 at ISICEMPatients undergoing resuscitation, especially in the setting of systemic inflammation, will “leak” intravascular fluid into their tissue. Large amounts of

this fluid can accumulate in the abdomen as both free fluid and interstitial edema. As this fluid accumulates the pressure in the abdomen begins to rise.

Once the intra-abdominal pressure (IAP) exceeds 12 mmHg it is defined as intra-abdominal hypertension (IAH), a syndrome found in as many as 50% of

critically ill patients. Left unnoticed IAH may progress to multiple organ dysfunction, the abdominal compartment syndrome and death. Unfortunately,

IAH cannot be identified through physical examination. Therefore proper detection and management of IAH requires screening of all patients at risk for

IAH by monitoring their IAP. The optimal method of measuring IAP is via transduction of the pressure through the bladder using a Foley catheter. The

diagrams below illustrate what happens to the patient’s body as the severity of the illness increases. It highlights the patient’s signs and symptoms, physi-

ologic effects along with what can be done (interventions) to manage IAH.

What Can Be Done (Interventions)




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Another major contributor to drug-induced toxicity isimpaired drugs pharmacokinetics, which frequently occursin critically ill and major surgical patients. Drug distribu-tion, metabolism and excretion are significantly altered dueprimarily to changes in blood delivery, tissue permeability,microenvironment pH, drug characteristics (lipid solubil-ity, pKa and protein binding) and hepatic and renal func-tions. Drug therapy that does not account for this will leadto over-dosing and end-organ toxicity.50,51

In view of these issues, it is crucial that clinicians useappropriate drug dosing based on the knowledge of alteredpharmacokinetics, vigilant monitoring of drug efficacy andtoxicity, recognition of drugs with nephrotoxic potentialand early identification of drug-induced AKI when it devel-ops. Besides pre-existing renal impairment, low-flow orprerenal states represent the leading predisposing factors todrug-induced AKI. Therefore, adequate renal blood flowmaintenance must be the first strategy in preventing renalinjury associated with almost all nephrotoxic drugs. Table2 displays the primary pathogenetic mechanisms, clinicalcharacteristics, specific risk factors, preventive strategies inhigh-risk patients and management of drug-induced AKIin surgical and critically ill patients.

Mechanical ventilationPositive pressure ventilation has several physiological andimmunological consequences for kidney function, includ-ing relative intravascular volume depletion, sympatheticactivation with vasoconstriction of the renal afferent arte-

riole and release of systemic inflammatory mediators thatpromote end-organ cell injury and apoptosis.52 The resultis an increased risk for AKI in mechanically ventilatedpatients. Lung-protective ventilatory strategies appear tomitigate the effect of mechanical ventilation on renal func-tion in patients with acute respiratory distress syndrome.53

These attenuate local and systemic cytokine release,54 bothreducing lung stretch and allowing hypercapnia. Theseresults, however, seem to contrast with those from a recentstudy that showed no reduction in AKI development witha lower tidal-volume strategy.55 This study was limited by apost hoc analysis and a population that included patientswithout lung injury, and further trials are required to elu-cidate the role of mechanical ventilation.

Extracorporeal techniquesPolymyxin B (PMX) haemoperfusion seems to carry a sub-stantial benefit for renal function in patients with severe sep-sis who have had emergency major abdominal surgery forintra-abdominal infection.56 Three days after treatment, therenal SOFA score had increased significantly more in thecontrol group compared with the PMX group. This resultwas associated with an improvement in cardiovascularfunction and, therefore, no conclusion can be drawn aboutany specific PMX effect on renal function. However, somestudies have suggested that PMX improves proximal renaltubular cell damage57 and reduces the proapoptotic activi-ty of plasma on cultured renal tubular cells with improve-ment in AKI severity.58

Table 2. Primary pathogenetic mechanisms, specific clinical features and risk factors, preventive measures in high-risk patients and management ofdrug-induced AKI22,26,50,51 (continued)

Primarymechanism

Drug Clinical features Specific risk factors AKI prevention in high-risk patients/management

Acute interstitialnephritis

Antibiotics (penicillins,cephalosporins,rifampin, co-trimoxazole,ciprofloxacin,vancomycin), proton-pump inhibitors(omeprazole,lansoprazole),diuretics (furosemide)

Idiosyncrasic

Onset: 7–14 days(sooner in thosepreviously sensitised)

Fever, eosinophilia, rash

Self-limited and usuallyreversible upondiscontinuation

None Remove suspected causative agent

Administer prednisone (0.5–1 mg/kg/day for up to 4 weeks)

Tubular obstruction Acyclovir Onset: 24–48 hours

RRT may be required


High doses Titrate dose according to renal function

Adequately hydrate before each dose

Prescribe prolonged infusion times

Avoid concomitant nephrotoxics

Osmotic nephrosis Intravenousimmunoglobulins

Onset: 2–4 days

Oliguric

Usually reversible

RRT may be required

Advanced age


Prescribe prolonged infusion times

Hydroxyethyl starches From mild and rapidlyreversible to severeforms requiring RRT

High molecular weight

High C2–C6 molar substitutionratio

Use cautiously in patients with pre-existing renalimpairment

Prefer lower-molar substitution and low molecularweight starches

Do not exceed daily dosages of up to 33 mL/kg/day

ACE = angiotensin-converting enzyme; COX = cyclooxygenase; GFR = glomerular filtration rate; NAC = N-acetylcysteine; NSAID = non-steroidal anti-inflammatory drug; RRT = renal replacement therapy; SCr = serum creatinine; TDM =therapeutic drug monitoring




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CONCLUSIONImproving the renal outcome of specific high-risk popula-tions is highly desirable from a clinical standpoint and interms of resource allocation; efforts should be focused onthis often-underestimated complication. Whereas preven-tion of post cardiac surgery AKI has been extensively stud-ied, even if with no conclusive results, it is difficult to translatethese measures to other areas. Interventions useful in reduc-ing the incidence of AKI in the cardiac surgery setting maynot be equally effective in other groups of ICU patients.

The advantage of postoperative AKI is that we know themoment of the actual insult to the kidney, and this shouldmake it easy to adopt adequate strategies. Nevertheless, toomany areas of uncertainty still exist due to the lack of renalrisk stratification, adequately powered studies, a uniformAKI definition and appropriate sample compositions. Theonly recommendation for renal protection consists ofmaintaining an optimal blood volume and adequate car-diac output, and avoiding nephrotoxic drugs.

ACKNOWLEDGMENTSThe authors do not have any potential conflict of interestto disclose.

REFERENCES 1. Carmichael P, Carmichael AR. Acute renal failure in the surgical setting. ANZ

J Surg 2003; 73: 144–153. 2. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients:

a multinational, multicenter study. JAMA 2005; 294: 813–818. 3. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA. Complications and costs after

high-risk surgery: where should we focus quality improvement initiatives? JAm Coll Surg 2003; 196: 671–678.

4. Lassnigg A, Schmid ER, Hiesmayr M, et al. Impact of minimal increases inserum creatinine on outcome in patients after cardiothoracic surgery: do wehave to revise current definitions of acute renal failure? Crit Care Med 2008;36: 1129–1137.

5. Conlon P, Stafford-Smith M, White W, et al. Acute renal failure following car-diac surgery. Nephrol Dial Transplant 1999; 14: 1158–1162.

6. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injuryare associated with hospital mortality in critically ill patients: A cohort analy-sis. Crit Care 2006; 10: R73.

7. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network. Report of aninitiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31.

8. Haase M, Bellomo R, Devarajan P, et al. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury:a systematic review and meta-analysis. Am J Kidney Dis 2009; 54:1012–1024.

9. Haase M, Devarajan P, Haase-Fielitz A, et al. The outcome of neutrophil gelati-nase-associated lipocalin-positive subclinical acute kidney injury. A multicen-ter pooled analysis of prospective studies. J Am Coll Cardiol 2011; 57:1752–1761.

10. Doi K, Negishi K, Ishizu T, et al. Evaluation of new acute kidney injury biomark-ers in a mixed intensive care unit. Crit Care Med 2011; 39: 1–6.

11. de Geus H, Bakker J, Lesaffre E, le Noble J. Neutrophil gelatinase-associatedlipocalin at ICU admission predicts for acute kidney injury in adult patients. AmJ Respir Crit Care Med 2011; 183: 907–914.

12. Chertow GM, Lazarus JM, Christiansen CL, et al. Preoperative renal risk strat-ification. Circulation 1997; 95: 878–884.

13. Kheterpal S, Tremper K K. , Heung M, et al. Development and validation of anacute kidney injury risk index for patients undergoing general surgery. Resultsfrom a national data set. Anesthesiology 2009; 110: 505–515.

14. Abelha FJ, Botelho M, Fernandes V, Barros H. Determinants of postoperativeacute kidney injury. Critical Care 2009; 13: R79.

15. Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and acute kid-ney injury during hospitalization after major surgery. Ann Surg 2009; 249:851–858.

16. Cruz DN, Ronco C. Acute kidney injury in the intensive care unit: current trendsin incidence and outcome. Crit Care 2007; 11: 149.

17. Kellum JA. Acute kidney injury. Crit Care Med 2008; 36: S141–S145.

18. Lameire N, Van BW, Vanholder R. Acute kidney injury. Lancet 2008; 372:1863–1865.

19. Bagshaw SM, George C, Bellomo R. Early acute kidney injury and sepsis: amulticentre evaluation. Crit Care 2008; 12: R47.

20. Zacharias M, Gilmore IC, Herbison GP, et al. Interventions for protecting renalfunction in the perioperative period. Cochrane Database Syst Rev 2005; (3):CD003590.

21. Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury andprotection of renal function in the intensive care unit Expert opinion of the work-ing group for nephrology, ESICM. Intensive Care Med 2010, 36: 392–411.

22. Brochard L, Abroug F, Brenner M, et al. An official ATS/ERS/ESICM/SCCM/SRLFstatement: prevention and management of acute renal failure in the ICU patient.An international consensus conference in intensive care medicine. Am J RespirCrit Care Med 2010; 181: 1128–1155.

23. Chappell D, Jacob M, Hofmann-Kiefer K, et al. A rational approach to periop-erative fluid management. Anesthesiology 2008; 109: 723–740.

24. Boldt J, Brosch C, Rohm K, et al. Comparison of the effects of gelatin and amodern hydroxyethyl starch solution on renal function and inflammatoryresponse in elderly cardiac surgery patients. Br J Anaesth 2008; 100:457–464.

25. Mahmood A, Gosling P, Vohra RK. Randomized clinical trial comparing theeffects on renal function of hydroxyethyl starch or gelatine during aorticaneurysm surgery. Br J Surg 2007; 94: 427–433.

26. Groeneveld AB, Navickis RJ, Wilkse MM. Update on the comparative safety ofcolloids: a systematic review of clinical studies. Ann Surg 2011; 253: 470–483.

27. Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethyl starch (HES) versusother fluid therapies: effects on kidney function. Cochrane Database Syst Rev2010; (1): CD007594.

28. Haase M, Haase-Fielitz A, Bellomo R, et al. Sodium bicarbonate to preventincreases in serum creatinine after cardiac surgery: a pilot double-blind, ran-domized controlled trial. Crit Care Med 2009; 37: 39–47.

29. Kanbay M, Covic A, Coca SG, et al. . Sodium bicarbonate for the prevention ofcontrast-induced nephropathy: a metaanalysis of 17 randomized trials. Int UrolNephrol 2009; 41: 617–627.

30. Redfors B, Bragadottir G, Sellgren J, Sward K, Ricksten SE. Acute renal failure isNOT an ‘acute renal success’ – a clinical study on the renal oxygen supply/demandrelationship in acute kidney injury. Crit Care Med 2010; 38: 1695–1701.

31. Shoemaker WC, Appel PL, Kram HB. Haemodynamic and oxygen transportresponses in survivors and nonsurvivors of high-risk surgery. Crit Care Med1993; 21: 977–990.

32. Brienza N, Giglio MT, Marucci M, Fiore T. Does perioperative hemodynamicoptimization protect renal function in surgical patients? A meta-analytic study.Crit Care Med 2009; 37: 2079–2090.

33. Heringlake M, Wernerus M, Grunefeld J, et al. The metabolic and renal effectsof adrenaline and milrinone in patients with myocardial dysfunction after coro-nary artery bypass grafting. Crit Care 2007; 11: R51.

34. Wilson J, Woods I, Fawcett J, et al. . Reducing the risk of major elective surgery:randomised controlled trial of preoperative optimisation of oxygen delivery. BMJ1999, 318: 1099–1103.

35. Albanese J, Leone M, Garnier F, et al. Renal effects of norepinephrine in sep-tic and nonseptic patients. Chest 2004; 126: 534–539.

36. Patel GP, Grahe JS, Sperry M, et al. Efficacy and safety of dopamine versusnorepinephrine in the management of septic shock. SHOCK2010; 33: 375–380.

37. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infu-sion in patients with septic shock. N Engl J Med 2008; 358: 877–887.

38. Redfors B, Bragadottir G, Sellgren J, Sward K, Ricksten SE. Effects of nore-pinephrine on renal perfusion, filtration and oxygenation in vasodilatory shockand acute kidney injury. Intensive Care Med 2011; 37: 60–67.

39. Brogden RN, Markham A. Fenoldopam. A review of its pharmacodynamic andpharmacokinetic properties and intravenous clinical potential in the manage-ment of hypertensive urgencies and emergencies. Drugs 1997; 54: 634–650.

40. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopamin critically ill patients with or at risk for acute renal failure: a meta-analysis ofrandomized clinical trials. Am J Kidney Dis 2007; 49: 56–68.

41. Landoni G, Biondi-Zoccai GG, Marino G, et al. Fenoldopam reduces the needfor renal replacement therapy and in-hospital death in cardiovascular surgery:a meta-analysis. J Cardiothorac VascAnesth 2008; 22: 27–33.

42. Edelstein CL, Ling H, Wangsiripaisan A, Schrier RW. Emerging therapies foracute renal failure. Am J Kidney Dis 1997; 30: 89–95.

43. Nigwekar SU, Navaneethan SD, Parikh CR, Hix JK. Atrial natriuretic peptide forpreventing and treating acute kidney injury. Cochrane Database Syst Rev 2009;(4): CD006028.

44. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy inthe critically ill patients. N Engl J Med 2001; 345: 1359–1367.


45. The NICE-SUGAR Study Investigators. Intensive versus conventional glucosecontrol in critically ill patients. N Engl J Med 2009; 360: 1283–1297.

46. Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy andmortality among critically ill patients: a meta-analysis including NICESUGARstudy data. CMAJ 2009; 180: 821–827.

47. Dalfino L, Tullo L, Donadio I, et al. Intra-abdominal hypertension and acuterenal failure in critically ill patients. Intensive Care Med 2008; 34: 707–713.

48. De Waele JJ, De Laet I, Kirkpatrick AW, Hoste E. Intra-abdominal hyperten-sion and abdominal compartment syndrome. Am J Kidney Dis 2010; 57:159–169.

49. Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in theintensive care unit: the PICARD experience. Kidney Int 2004; 66: 1613–1621.

50. Perazella MA. Drug use and nephrotoxicity in the intensive care unit. KidneyInt 2010, December 1 (epub ahead of print).

51. Pannu N, Nadim MK. An overview of drug-induced acute kidney injury. CritCare Med 2008; 36: S216–S223.

52. Koyner JL, Murray PT. Mechanical ventilation and the kidney. Blood Purif 2010;29: 52–68.

53. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidalvolumes as compared with traditional tidal volumes for acute lung injury andthe acute respiratory distress syndrome. N Engl J Med 2000; 342: 1301–1308.

54. Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation oninflammatory mediators in patients with acute respiratory distress syndrome:a randomized controlled trial. JAMA 1999; 282: 54–61.

55. Cortjens B, Royakkers A, Determann RG, et al. Lung-protective mechanicalventilation does not protect against acute kidney injury in patients without lunginjury at onset of mechanical ventilation. J Crit Care 2011, in press.

56. Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfu-sion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA2009; 301: 2445–52.

57. Nakamura T, Kawagoe Y, Matsuda T, et al. Effects of polymyxin B-immobilizedfiber on urinary N-acetyl-B-glucosaminidase in patients with severe sepsis.ASAIO J 2004; 50: 563–567.

58. Cantaluppi V, Assenzio B, Pasero D, et al. Polymyxin-B hemoperfusion inacti-vates circulating proapoptotic factors. Intensive Care Med 2008; 34:1638–1645. ■

CORRESPONDENCE TO:Nicola Brienza MD, PhDEmergency and Organ Transplantation Department Anesthesia and Intensive Care Unit University of BariP. zza G. Cesare 1170124 Bari, Italy E-mail: [email protected]



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COVER FEATURE


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Significance and estimation ofunmeasured ions in extracellular fluid – a brief review

present, however, clinicians rely on derived parameters touncover their presence and estimate their effect.

Because the majority of the physiologically importantunmeasured ions are generated within the cells, the focusof this short review is on the effect of endogenous distur-bances within the intracellular milieu and the measurementor estimation of those ions in the various extracellular com-partments. The arguments can easily be extended to exoge-nous insults occurring within the context of a generalacid–base disturbance (e.g., poisoning with formate,oxalate, pyroglutamate).

In this context, two questions are important. First, inwhich space should we measure and why? And second, howdo we get an accurate estimate of something that we can-not directly measure?

A note regarding measurement units:Where possible throughout, measurements are expressedin SI units, for example mmol/l or meq/l. Occasionally, thepublished literature dictates the presentation of alternatenon-SI units, notably, the plasma concentration of albuminis expressed in g/l and the partial pressure of carbon diox-ide in mmHg (Torr). Because it is the concepts rather thanthe fine details that are important, no attempt has beenmade to convert these units. They are noted wherever theyoccur throughout the manuscript.

Furthermore, because strong ion theory permeates thebulk of the discussion to follow, the partial pressure of car-bon dioxide is taken to represent the carbon dioxide pre-sent in solution in any non-gaseous, fluid compartmentunder investigation. For example, in the arterial circulationit can be the PaCO2, in the venous circulation it can be thePvCO2 and so on for the capillary circulation, the intersti-tial, intracellular compartments etc. It is denoted by the gen-eral term, PCO2.

During critical illness, particularly if associated with‘metabolic’ acidosis, anionic species may leak from theintracellular environment to be present in the extracellularfluid. While these ions may not directly contribute to mortality,they do reflect underlying pathology and their ultimatedisappearance from the extracellular fluid is associated with areturn to health. A classic example is the presence of excessquantities of L-lactate during periods of organ hypoperfusion.Monitoring of these ions is an important tool in the clinicalarmamentarium. At present, many possibly important ionscannot be directly measured and are assessed by examiningvarious calculated ‘gaps’. To compound this issue, all currenttools used to assess the presence and effect of unmeasuredions are either inaccurate (insensitive) because they onlyexamine the plasma compartment (e.g., anion gap) or limitedby being too general (non-specific) (e.g., standard baseexcess). This short review focuses on the physiologicalrationale behind measurements in the extracellular fluidrather than in plasma or whole blood, and on the shortfalls ofthe current models for detecting unmeasured ions. Finally, anew parameter is introduced, which, in theory, is both highlysensitive and highly specific for the presence of unmeasuredions in the extracellular fluid.

On admission to a critical care area within any mod-ern hospital, a patient will usually undergo arterialblood sampling with part of the sample injected into

a modern benchtop or hand-held device designed foracid–base analysis. The printed output contains anacid–base assessment based on measured and calculatedparameters and will be used by the attending clinician todifferentiate the possible diagnoses.

Significantly, the clinician will attempt to separate respi-ratory and non-respiratory (‘metabolic’) causes of illness.The respiratory causes concern the excretion of carbondioxide, whereas the non-respiratory causes focus on thedetection of circulating anionic species. Over time, estima-tion of these anions has assumed greater importance as weappreciate their association with disease states – for exam-ple, elevated levels of L-lactate in states of poor tissue per-fusion and elevated levels of �-hydroxy butyrate in diabeticketoacidosis. Even though the presence of these anions is apoor predictor of mortality, measurement leads to moni-toring and appropriate treatment with the ultimate goal ofreversing the pathology and returning the patient to health.1

With each new model, acid–base analysers have becomemore sophisticated, although there remains a heteroge-neous group of unmeasured, usually anionic species thatmay have clinical importance (e.g., citrate, acetate, D-lac-tate). With time, this group will become smaller as reliableelectrodes are designed to measure individual species. At

CM Anstey MB, BS, BSc, MSc,FANZCA, FCICM,Department of Critical CareMedicine,Sunshine Coast (Nambour)Hospital,Queensland, Australia

H+

Cl-

H+

Cl-

H+ H+

Cl-

Intersitial fluid IntracellularfluidPlasma

Figure 1. Schematicrepresentation of theredistribution of non-carbonicacid during in vivo CO2

equilibration (adapted fromSiggaard-Andersen, 19632).Hypercarbia causes an increasein and movement of protons withaccompanying chloride. This‘addition’ of non-carbonic acidcauses the whole blood baseexcess concentration to fall, whilethe extracellular fluid base excessconcentration remains constant.As indicated by the heights of thearrows, transfer of protons acrossthe cell membranes is minimal.

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UNMEASURED IONS IN EXTRACELLULAR FLUID


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WHY EXTRACELLULAR FLUID?The non-respiratory disturbances of acid–base balance thatconcern clinicians generally arise initially within the intracel-lular compartment. As a result of these disturbances, sec-ondary changes occur over time in the interstitial fluid, plasmaand erythrocyte fluid. Using the nomenclature convention ofSiggaard-Andersen, these three compartments will be referredto collectively as the extracellular fluid.2 Ultimately, the sumof effects in the general extracellular fluid compartment rep-resents important intracellular disturbances.

According to traditional acid–base theory, the key deter-minant of the overall acid–base status of the organism is thehydrogen ion or, more specifically, the concentration oftitratable hydrogen ion.2 Classically, in fluids where the par-tial pressure of CO2 (pCO2) is an independent variable, theconcentration of titratable hydrogen ion is determined bytitrating the fluid sample to a pH of 7.40 at a pCO2 of 40mmHg and a temperature of 37°C. The resulting quantity,with the opposite sign, is designated the base excess.Practically, because clinicians do not perform titration exper-iments on their patients, the net base excess is calculated eitherfrom published nomograms (e.g., Davenport diagram3) ormathematical models (e.g., Van Slyke equation4). In addi-tion, for any parameter to accurately reflect the non-respira-tory acid–base status, it must be CO2 invariant.5,6

From experimentation, we know that whole blood (plas-ma plus red cell) base excess remains constant when thepCO2 is altered in vitro. When the pCO2 is varied in vivo,however, the whole blood base excess also varies.7 Thisoccurs because CO2 equilibrates across the extracellularfluid compartment, resulting in the movement of protonsand, for example, chloride between the compartments(Figure 1). Thus, whilst the extracellular fluid base excessremains constant, the whole blood base excess will vary.

This difference between plasma or whole blood and theextracellular fluid space is experimentally demonstratedwhen the CO2 titration curves are examined. When healthyvolunteers are exposed to rising concentrations of CO2 andtheir plasma bicarbonate concentrations are measured, theresults are in stark contrast to in vitro titrations of bloodfrom the same volunteers (Figure 2).8–10 This is becausewhole blood is normally in equilibrium with the interstitial

fluid and, therefore, models that only examine either theplasma or the whole blood will not accurately reflect thetrue in vivo situation.

As it is not possible to obtain a representative sample ofextracellular fluid for analysis, researchers have approachedthis problem by adjusting the whole blood mathematicalmodels to incorporate the effect of interstitial fluid.Empirically and mathematically, this is achieved by dilut-ing whole blood 2:1 in its own plasma, so that the resultingbuffer value is similar to the average buffer value of the totalextracellular fluid.11–13 As a result, even though modernacid–base laboratories analyse the in vitrowhole blood com-partment, the results are used to predict changes in the invivo extracellular fluid. Admittedly, it is an imperfect sys-tem with many assumptions along the way, but at presentit is the best system we have for assessing the important non-respiratory disturbances of acid–base status.14

STRONG ION/WEAK ACID THEORY – A SYNOPSISIn 1981, following on from the work of Van Slyke, Singerand Hastings, and Stewart published a book and follow-uppaper describing a different perspective on acid–base theo-ry.15–18 He theorised that in any compartment, the mainthree drivers of acid–base status are pCO2, the net chargedifference between completely ionised species (the strongions) and the total weak acid concentration. Any change inthese independent variables resulted in changes in the twomain dependent variables, pH and [HCO3

–], in accordancewith the general principle of compartment electroneutral-ity and the law of mass action. Further work by Figge et al.in 1991 defined the pH-dependent charge contribution ofboth albumin and inorganic phosphate in the plasma com-partment.19,20 In 2003, Wooten drew important correla-tions between strong ion theory and classical base excesstheory, thus putting strong ion theory on a very firm theo-retical basis. Most recently, Wooten expanded the originalconcept to encompass the extracellular fluid.21–23

Possibly the simplest method of conceptualising strongion theory is to use the Gamblegram (Figure 3).24 In thisvertical bar chart, the cations and anions are separated intotwo vertical bars of the same height signifying electroneu-trality, with each bar divided according to its constituentcharged species. According to strong ion theory, if, forexample, albumin is removed from the plasma leaving theother independent variables constant, the only change thatcan occur is a rise in the concentration of bicarbonate to fillthe gap. This results in a rise in pH and an apparent‘metabolic’ alkalemia. Conversely, the addition of a reason-able volume of normal saline to plasma will raise the rela-tive concentration of chloride, which will act to decrease thebicarbonate concentration and pH, resulting in an appar-ent ‘metabolic’ acidaemia. By extension, when an apprecia-ble amount of unmeasured anion (XA) is present, all elsebeing equal, the effect is seen as a decrease in the concen-tration of bicarbonate with a commensurate fall in pH.Traditionally, this appearance is interpreted as a metabolicacidosis and detection of both the presence and magnitudeof these ions may have wide-ranging clinical ramifications.

CURRENT INDICES OF NON-RESPIRATORYACID–BASE STATUSFrom the days of early physiology research, we have believedthat when non-respiratory disturbances occur in the intra-cellular compartment, the result is the generation of protons

Figure 2. Comparison of the invivo and in vitro CO2 titrationcurves of human blood.8 The invivo response of the intactorganism will provide the mostappropriate reference point forassessing mixed acid–basedisorders. Other approaches thatassume equivalence between thein vivo and in vitro CO2 titrationcurves, and based on the in vitrotitration of either plasma or wholeblood, will give an incorrectimpression of the acid–basedisturbance. This difference hasbeen the basis of a longstandingdebate between various endusers of these methods.5,6

40 60 80 100pCO2 (mmHg)

In vivoIn vitro

32

30

28

26

24

Bica

rbon

ate

(meq

/L)




and their anionic base pairs.25 Much of the proton load gen-erated by these processes is buffered by the imidazole groupsof histidine groups present in intracellular proteins and alsocontained in dipeptides such as carnosine while the associ-ated anions equilibrate across cell membranes using variousexchange mechanisms.26 As we have seen above, with someexceptions (e.g., L-lactate) these anions are generally notmeasured and become apparent as a declining plasma bicar-bonate concentration. This results in the generation of a clas-sical ‘anion gap’ (AG), the time-honoured method ofestimating their presence in plasma (Equation 1).

AG (mEq/L) = ([Na+] + [K+]) – ([Cl–] + [HCO3–]) (Eq 1)

The AG may also be expressed as Equation 2, that is, thesum of the charge present on calcium, magnesium, lactateand the major plasma weak acids, albumin and inorganicphosphate.

AG (mEq/L) = ([A–] + [L – lactate]) – ([Ca2+] + [Mg2+])(Eq 2)

where [A–] is

[A–](mEq/L) = [alb](0.123pH – 0.631) + PO43–](0.309pH –

0.469) (Eq 3)

with [alb] expressed in g/L and PO43– in mmol/L.18

Furthermore, both Figure 3 and Equation 2 give an insightinto the dependence of the AG on the mass concentrationof serum albumin. The criticisms of the AG can now beappreciated. First, it does not include all of the measuredionised species (e.g., calcium, magnesium and L-lactate).Second it does not include the important effects of serumalbumin. Finally, it is purely a plasma estimate.27,28 In health,the potassium-inclusive AG has a reference range of 14.0 ±5.0 mEq/L.

Inclusion of the other measured species results in thestrong ion gap (SIG) (Equations 4, 5 and 6).

SIG (mEq/L) = ∑cations – ∑anions (Eq 4)

where

∑cations (mEq/L) = [Na+] + [K+] + [Ca2+] + [Mg2+] (Eq 5)

and

∑anions (mEq/L) = [HCO3–] + [Cl–] + [A–] + [L – lactate]

(Eq 6)

For practical purposes, it is noted that the concentrationsof hydrogen and hydroxyl ions are too small to have anyeffect on the value of the SIG.29

In general, the fully ionised species (the ‘strong ions’) arelumped together under the banner of the apparent strongion difference or SIDa (Equation 7), while the weak acidscomprise the effective strong ion difference or SIDe

(Equation 8). The difference between the two being the SIG.

SIDa(mEq/L) = ([Na+] + [K+] + [Ca2+] + [Mg2+]) – ([Cl–]+ [L – lactate]) (Eq 7)

and

SIDe (mEq/L) = [HCO3–] + [A–] (Eq 8)

In health, the normal value for SIDa/e is approximately 42.0mEq/L. The SIG has a mean reference range of 0.0 ± 6.5mEq/L.30

The increased complexity of the SIG is offset by a poten-tially increased sensitivity as an index of unmeasured species– it is assumed that a high value for SIG indicates the presence of unmeasured anions in the plasma as a cause of the non-respiratory acidaemia. However, like the AG, the SIG possesses a wide reference range that limits its utility. It is also a plasma estimate and therefore not CO2-invariant.

Currently, the only popular extracellular fluid estimateof the non-respiratory acid–base status is the standard baseexcess (SBE), devised by Ole Siggaard-Andersen. His mostrecent equation, called the Van Slyke equation and namedin honour of Donald D Van Slyke, sums the non-respira-tory disturbance in both the carbonate and non-carbonatespecies present in the extracellular fluid to give an index ofthe overall CO2-independent acid–base status measured inmillimoles per litre.4,7 The general form of the Van Slykeequation is given in equation 9.

SBE= �1 –ctHbecf ��((cHCO3

–pl– 24.50) +�ecf �(pHpl– 7.40))

(Eq 9)

where

ctHbecf Extracellular fluid concentration ofhaemoglobin monomer (mmol/L).

cHCO3–

pl Plasma concentration of bicarbonate calculat-ed from the Henderson-Hasselbalch equation,cHCO3

–pl = 0.0307 � pCO2 x 10(pHpl – pK), where

and pCO2 is expressed in mmHg.

�ecf Represents the non-carbonate buffer value ofthe extracellular fluid.

pHpl Measured plasma pH.

➟

43.0

Figure 3. SimplifiedGamblegrams for plasmashowing the major constituents.24

The four panels demonstrate: (a)the normal situation, (b) relativehyperchloraemia with a resultantdecrease in bicarbonateconcentration, (c)hypoalbuminaemia with anincreased bicarbonateconcentration and (d) addition ofunmeasured anions (XA) resultingin a decrease in bicarbonateconcentration. If the partialpressure of carbon dioxide is heldconstant throughout, the plasmapH will track the changes inbicarbonate concentration.

a b

c d

Sodium Chloride

Sodium Chloride

Sodium Chloride

Sodium Chloride

Albumin

Albumin

Bicarbonate

Bicarbonate

Bicarbonate

XA

Bicarbonate

Albumin

Albumin

PotassiumPotassium

PotassiumPotassium




➟

The Van Slyke equation is usually simplified and sum-marised as Equation 10.

SBE = 0.93 � ((cHCO3–

pl – 24.50) + 14.83 � (pHpl – 7.40))(Eq 10)

Initially designed as a whole blood parameter to estimatethe titratable base and subsequently adapted to model theextracellular fluid, SBE is clinically used as a general CO2-invariant index of the extracellular acid–base status; that is,as an indicator of the presence or absence of non-respira-tory acid–base disturbances. A negative SBE is taken to indi-cate the presence of a non-respiratory acidaemia, while apositive SBE indicates a non-respiratory alkalemia. The ref-erence range for SBE is 0.0 ± 3.0 mmol/L.

It should be noted that because the SBE uses normal base-line values in its calculation (i.e., pH = 7.40 and HCO3

– =24.5mmol/L), any process that disturbs these values will berecorded as an offset from zero.31,32 This includes not onlythe effect of the movement of unmeasured endogenousanions into the extracellular fluid, but also the removal ofextracellular weak acids (e.g., hypoalbuminaemia) or theaddition of exogenous electrolytes (e.g., sodium chloride).

WHAT ARE THE UNMEASURED CHARGED SPECIES?Non-respiratory acidosis is the most frequently occurringacid–base disorder in the critically ill patient. Much of theintracellularly generated anion load finds its way out of thecells and is detectable in the extracellular fluid, as we haveseen, for example, with lactate and β-hydroxy butyrate.Many other anions remain currently undetectable and maysignificantly contribute to the indices of non-respiratoryacid–base status. At least two recent papers have examinedthis issue.

In 2007, using capillary electrophoresis in a canine haem-orrhagic model, Bruegger at al. demonstrated the presenceof significant concentrations of acetate (2.2 mEq/L) and cit-rate (2.2 mEq/L) contributing to an average SIG of 7.1 mEq/L,thus illustrating the potential for currently unmeasured ionicspecies to contribute to major system perturbations.33

In 2008, Moviat et al. used the Stewart physicochemicalapproach outlined above to stratify 31 intensive care unitpatients into high and low SIG groups.34 They examined the‘unmeasured’ anions using various forms of chromatogra-phy and spectroscopy, specifically measuring concentra-tions of amino acids, uric acid and organic acids in the twogroups. They found that only approximately 8% of the SIGelevation was caused by this group of anions, with uric acidresponsible for the largest relative contribution by a singlecompound (2.2%). Even though the sample size was small,the authors were confident that their study ‘excluded manypotent unmeasured anions as major contributors of the SIG’.Furthermore, they noted that ‘the variety in significantly ele-vated anions in the presence of a high SIG may be indicativeof several concomitant causes of SIG metabolic acidosis’.

Currently, the identity of these unmeasured anionsremains a mystery and ‘a largely unclarified portion of theSIG remains to be explored’.35 At best, we should aim atquantifying the sum total effect in the extracellular fluid,even though the individual constituents remain unidenti-fied.

A NEW INDEX OF NON-RESPIRATORY ACID–BASESTATUSStewart, Figge and Wooten have given us a very solid andpowerful foundation upon which to build models to explorethe issue of unmeasured ions in extracellular fluid.18–23 Bysubstituting the surface charge data for albumin and inor-ganic phosphate into Stewart’s basic model, the result is arather complex fourth-order polynomial with [H+] as thedependent variable. This relationship is given in function-al notation in Equation 11 and it relates the dependence ofplasma pH, calculated from [H+] using the usual method,on pCO2, the plasma apparent SID and the pH-dependentcharge contributions of the major plasma weak acids.Because pH is given implicitly, Equation 11 must be solvedusing iterative techniques.17,36

pHpl = ƒ (pCO2, SIDa,[A–]pH) (Eq 11)

Note that the term [A–]pH describes the pH dependence ofthe weak acid charge.

Given then that pH can be both calculated (expected) andmeasured (actual), and that both of these techniques areaccurate, any discrepancy between the two must be due tounaccounted charged species. A subsequent similar calcu-lation can be made for the expected and actual bicarbonateusing the Henderson-Hasselbalch equation.

Subtracting the expected and actual values gives a pair ofΔpH and Δ[HCO3

–] values. These can be inserted into amodified Van Slyke-type equation to give a plasma indexreflecting the unmeasured ion excess (UIXpl) (Equation 12).

UIXpl = ΔHCO3–

pl + �pl � ΔpHpl (Eq 12)

This basic single compartment (plasma) model can beexpanded to represent the whole blood (plasma plus redcell) by applying the multicompartment modelling tech-niques described by Wooten, and further expanded usingSiggaard-Andersen’s ‘haemoglobin dilution’ technique tomodel the extracellular fluid.23

This final multicompartment equation will quantify, inmilliequivalent terms, a value for the unmeasured chargedspecies present. Simplistically, UIX is an electrolyte and weak

Table 1. Biochemical and acid–base data

Admission At 24 hours

pH pCO2 [HCO3–]mmHg mmol/L

7.13 12 4.0

pH pCO2 [HCO3–]mmHg mmol/L

7.32 28 14.1

Cations Cations

[Na+] [K+] [Ca2+] [Mg2+]mmol/L mmol/L mmol/L mmol/L130 4.1 2.66 0.73

[Na+] [K+] [Ca2+] [Mg2+]mmol/L mmol/L mmol/L mmol/L135 3.8 2.56 0.80

Anions Anions

[Cl–] [L-lactate] [Albumin] [PO4–3]

mmol/L mmol/L g/L mmol/L114 0.5 38 0.99

[Cl–] [L-lactate] [Albumin] [PO4–3]

mmol/L mmol/L g/L mmol/L117 0.5 25 0.82

Calculations Calculations

SBE UIX AG SIGmmol/L mEq/L mEq/L mEq/L–22.7 –6.4 16.1 7.9

SBE UIX AG SIGmmol/L mEq/L mEq/L mEq/L–10.6 –0.3 7.7 2.4

Initial blood glucose was 28 mmol/L and β-hydroxy butyrate was 4.5 mmol/L.At 24 hours, blood glucose was 12 mmol/L and β-hydroxy butyrate was <0.1 mmol/L.


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acid-corrected version of the SBE and has a normal range of0.0 ± 2.5 mEq/L.37 If required, the UIX model can be strat-ified to reflect the relative contributions of the componentstrong ion and weak acid species to the overall acid–base dis-turbance described by the SBE. As an index of unmeasuredions, the UIX should be robust, sensitive and specific.

CONCLUSIONThe simple plasma estimates (AG, SIG) have the disadvan-tages of wide reference ranges and lack of CO2 invariance.The more complex extracellular fluid estimates (SBE, UIX)possess both narrow reference ranges and are CO2 invari-ant, so are more reflective of the non-respiratory acid–basestatus. Of the two, only the UIX is a parameter specificallyconstructed to estimate the unmeasured charged species,whereas the SBE is a general measure of the non-respirato-ry acid–base status. The SBE will vary with changes in theelectrolyte and weak acid composition of the extracellularfluid as well as with the presence of unmeasured ions, where-as the UIX will only reflect the unmeasured charged species.If the SIG is seen as the ‘AG on steroids’ then the UIX mightpossibly be the ‘salt-free base excess’.38,39

END NOTEIt is not the intention of the author to critique either theclassical bicarbonate model of acid–base or the newer strongion model, but rather to use the general assumptions implic-it in both to examine questions surrounding unmeasuredcharged species: their presence, their importance and, ulti-mately, their estimation in the physiological milieu.

Finally, the albumin-corrected AG was not examined asa parameter because it is not commonly used in clinicalpractice. It will suffer many of the problems associated withboth the AG and the SIG.

APPENDIXClinical vignette – acute diabetic ketoacidosisThis case concerns an 18-year-old woman presenting withdiabetic ketoacidosis.

After resuscitation with 0.9% normal saline and intra-venous insulin, the patient began taking an oral diet on day2 and was discharged from the intensive care unit on day 3.Her admission and day 2 blood results are shown in Table 1.

On admission, the patient had a significant non-respira-tory acidaemia supported by the SBE of –22.7 mmol/L,although once corrected for electrolyte and weak acidchanges, this is recorded as a UIX of –6.4 mEq/L. As themain ketone bodies, �-hydroxy butyrate and acetoacetate,are virtually fully ionised at physiological pH (pKs of 4.8and 3.6, respectively) and are present in a molar ratio ofapproximately 3:1 in diabetic ketoacidosis without circula-tory shock, as in this case, they account for the bulk of theunmeasured charged species (4.5 + 1.5 = 6.0 mEq/L). Bycontrast, the major component of the SBE disturbance is aresult of a decrease in the apparent strong ion difference ofapproximately 19.0 mEq/L (~23.0 mEq/L as opposed to anormal value of ~42.0 mEq/L).

Twenty-four hours after presentation, the patient wasclinically well with a stable blood sugar concentration anda normal (low) serum �-hydroxy butyrate concentration.At this stage the SBE was still registering non-respiratoryacidaemia, no doubt due to the relative hyperchloraemia.The UIX was near zero in keeping with the lack of clinicalsuspicion for a significant load of unmeasured ions.

Of note, the AG was normal initially and low eventually.This was most likely due to the presence of hypocarbia,hyperchloraemia and hypoalbuminaemia.

Lastly, except for the sign inversion, the SIG roughlytracks the UIX but will ultimately suffer because of its lackof CO2 invariance.

Even though this is a single example, it highlights theimportant issues surrounding the use of the current indicesof non-respiratory acid–base status.

REFERENCES 1. Rocktaeschel J, Morimatsu H, Uchino S, Bellomo R. Unmeasured anions in

critically ill patients: can they predict mortality? Crit Care Med 2003; 31:2131–2136.

2. Siggaard-Andersen O. The acid–base status of the blood. Scand J Clin LabInvest 1963; 15: 19–20.

3. Davenport HW. The ABC of Acid–Base Chemistry. 6th Ed. Chicago: TheUniversity of Chicago Press, 1974.

4. Siggaard-Anderson O. The Van Slyke equation. Scand J Clin Lab Invest 1977;37: 15–19.

5. Bunker J. Great trans-Atlantic acid–base debate. Anesthesiol1976; 25: 591–594.6. Severinghaus JW. Siggaard-Andersen and the “Great Trans-Atlantic

Acid–Base Debate”. Scand J Clin Lab Invest 1993; 53: 99–104. 7. Siggaard-Andersen O, Fogh-Andersen N. Base excess or buffer base (strong

ion difference) as a measure of a non-respiratory acid–base disturbance. ActaAnaesthesiol Scand 1995; 39: 123–128.

8. Brackett NC Jr, Cohen JJ, Schwartz WB. Carbon dioxide titration curve of nor-mal man. N Engl J Med 1965; 272: 6–12.

9. Prys-Roberts C, Kelman GR, Nunn JF. Determination of the in vivo carbon diox-ide titration curve of anaesthetized man. Br J Anaesth 1966; 38: 500–509.

10. Despas PJ, Leigh J. The in vivo carbon dioxide titration curve in man duringrebreathing. Aust J Exp Biol Med Sci 1970; 48: 657–661.

11. Schwartz WB, Relman AS. A critique of the parameters used in the evaluationof acid–base disorders. N Engl J Med 1963; 268: 1383–1388.

12. Siggaard-Andersen O. Titratable acid or base of body fluids. Ann NY Acad Sci1966; 133: 48–51.

13. Fogh-Andersen N, Altura BM, Altura BT, Siggaard-Andersen O. Compositionof the interstitial fluid. Clin Chem 1995; 41: 1522–1525.

14. Schlichtig R, Grogono AW, Severinghaus JW. Human PaCO2 and standard baseexcess compensation for acid–base imbalance. Crit Care Med 1998; 26:1173–1179.

15. Van Slyke DD. On the measurement of buffer values and on the relationshipof buffer values to the dissociation constant of the buffer and the concentra-tion and reaction of the buffer solution. J Biol Chem 1922; 52: 525–570.

16. Singer RB, Hastings AB. An improved clinical method for the estimation of distur-bances of the acid–base balance of human blood. Medicine 1948; 27: 223–242.

17. Stewart PA. How to Understand Acid–Base. A Quantitative Acid–Base Primerfor Biology and Medicine. New York: Elsevier; 1981.

18. Stewart PA. Modern quantitative acid–base chemistry. Can J Physiol Pharmacol1983; 61: 1444–1461.

19. Figge J, Rossing TH, Fencl V. The role of serum proteins in acid–base equilib-ria. J Lab Clin Med 1991; 117: 453–467.

20. Figge J, Mydosh T, Fencl V. Serum proteins and acid–base equilibria: a fol-low-up. J Lab Clin Med 1992; 120: 713–719.

21. Wooten EW. Analytic calculation of physiological acid–base parameters in plas-ma. J Appl Physiol 1999; 86: 326–334.

22. Wooten EW. Calculation of physiological acid–base parameters in multicom-partment systems with application to human blood. J Appl Physiol 2003; 95:2333–2344.

23. Wooten EW. The standard strong ion difference, standard total titratable base,and their relationship to the Boston compensation rules and the Van Slykeequation for extracellular fluid. J Clin Monit Comput 2010; 24: 177–188.

24. Gamble JL. Chemical Anatomy, Physiology and Pathology of Extracellular Fluid.A Lecture Syllabus. Cambridge, Massachusetts: Harvard University Press; 1949.

25. Henderson LJ. Concerning the relationship between the strength of acids andtheir capacity to preserve neutrality. Am J Physiol 1908; 21: 173–179.

26. Abe H. Role of histidine-related compounds as intracellular proton bufferingconstituents in vertebrate muscle. Biochemistry 2000; 65: 757–765

27. Sirker AA, Rhodes A, Grounds RM, Bennett ED. Acid–base physiology: the ‘tra-ditional’ and the ‘modern’ approaches. Anaesthesia 2002; 57: 348–356.

28. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Crit CareMed 1998; 26: 1807–1810.


29. Constable PD. A simplified strong ion model for acid–base equilibria: applica-tion to horse plasma. J Appl Physiol 1997; 83: 297–311.

30. Anstey CM. An assessment of the population variance of the strong ion gapusing Monte Carlo simulation. Anaesth Intensive Care 2009; 37: 983–991.

31. Story DA, Morimatsu H, Bellomo R. Strong ions, weak acids and base excess:a simplified Figge-Fencl approach to clinical acid–base disorders. Br J Anaesth2004; 92: 1–7.

32. Anstey CM. Estimating the net effect of unmeasured ions in human extracel-lular fluid using a new mathematical model. Part I: theoretical considerations.Anaesth Intensive Care 2010; 38: 862–869.

33. Bruegger D, Kemming GI, Jacob M, et al. Causes of metabolic acidosis incanine hemorrhagic shock: role of unmeasured ions. Crit Care 2007; 11: R130.

34. Moviat MAM, Terpstra AM, Ruitenbeek W, et al. Contribution of various metabo-lites to the “unmeasured” anions in critically ill patients with metabolic acido-sis. Crit Care Med 2008; 36: 752–758.

35. Moviat MAM, Pickkers P, Ruitenbeek W, van der Hoeven JG. The nature ofunmeasured anions in critically ill patients. Crit Care Med 2008; 12: 416.

36. Anstey CM. Comparison of three strong ion models used for quantifying theacid–base status of human plasma with special emphasis on the plasma weakacids. J Appl Physiol 2005; 98: 2119–2125.

37. Anstey CM. Estimating the net effect of unmeasured ions in human extracel-lular fluid using a new mathematical model. Part II: practical issues. AnaesthIntensive Care 2010; 38: 870–875.

38. Kellum JA, Kramer DJ, Pinsky MR. Strong ion gap: a methodology for explor-ing unexplained anions. J Crit Care 1995; 10: 51–55.

39. Story DA, Poustie S, Bellomo R. Estimating unmeasured anions in critically illpatients: anion-gap, base-deficit and strong ion gap. Anaesthesia 2002; 57: 1109–1114. ■

CORRESPONDENCE TO:Chris M Anstey MB, BS, BSc, MSc, FANZCA, FCICMDirectorDepartment of Critical Care MedicineSunshine Coast (Nambour) HospitalNambour, Queensland 4560AustraliaE-mail: [email protected]


REVIEW


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The diagnostic role of novelbiomarkers in acute kidney injury in critically ill patients

onset. This delay is most notably in critically ill patients, inwhom the increased volume of distribution and decreasedmuscle mass limit the rise in SCr.

A number of well-known non-renal factors affect SCr,including age, sex, race and, notably, non-uniform assaymethods in different laboratories, fluid overload and vari-able production rates of creatinine in different groups ofpatients (including those with sepsis). Furthermore, basalpremorbid creatinine levels are unavailable for manypatients admitted with AKI. Various studies have used dif-ferent ways to define the basal SCr level, such as level at thetime of hospital admission, the minimum value during hos-pital stay, an estimate from the modified diet of renal dis-ease formula or the lowest value among these.10 The choiceof measure for basal SCr has a marked effect on findingswith regard to the prevalence of AKI, the severity (or stages)of AKI and the mortality associated with AKI in its variousstages (for discussion, see10).

OliguriaThe second parameter in the definition of AKI is oliguria,which is often used as a biomarker of AKI during critical ill-ness. However, its relationship with the subsequent devel-opment of AKI defined by the SCr criteria has been onlyrarely investigated. Recently, Prowle et al. found that olig-uria of longer than 1 hour was significantly associated withAKI, as defined by an elevated SCr level the next day.11 Thepresence of oliguria for 4 hours or longer provided the bestdiscrimination; however, episodes of oliguria were not fol-lowed by renal injury.

In contrast, Macedo et al. found that the incidence of AKIin ICU patients increased from 24%, based solely on SCr, to52% by adding the urine output as a diagnostic criterion.12

Oliguric patients without a change in SCr had an ICU mor-tality rate significantly higher than those without AKI (8.8%vs. 1.3%, respectively), and similar to oliguric patients with anincrease in SCr (10.4%). The diagnosis of AKI occurred ear-lier in oliguric than in non-oliguric patients. One of the mainlimitations of the diuresis parameter is that, at least in mod-ern ICU settings, most AKI patients are not oliguric, partlybecause many of them have received diuretics; as such, theappearance of oliguria is not a very sensitive marker of AKI.

Mainly because of the time lag between the inciting acuteinsult and the diagnostic elevation of SCr and low sensitiv-ity of oliguria, the delay in diagnosing AKI is probably oneof the reasons why it is still associated with dismal clinicaloutcomes.

AKI BIOMARKERSAs a consequence of these shortcomings, the developmentof AKI biomarkers is a top research priority of the American

Acute kidney injury (AKI) is a common and serious condition,in particular in critically ill patients. The diagnosis of AKIdepends on high serum creatinine levels or the presence ofoliguria, both of which are delayed and unreliable indicatorsof AKI. Innovative areas of research such as functionalgenomics and proteomics have led to the detection of severalnovel early biomarkers, which may allow the early detection,risk stratification and prognostication of patients with AKI.The first part of this review briefly discusses the drawbacks ofserum creatinine and oliguria in the early diagnosis of AKI.The second part focuses on the use of two biomarkers, serumcystatin C and plasma and urine neutrophil gelatinase-associated lipocalin, in the early diagnosis of AKI in criticallyill patients. Review of the most recent clinical studies withthese biomarkers reveals that, although they may be promis-ing in future clinical practice, optimism about their use in theapproach to clinical AKI currently appears to be tempered. Sofar, neither of these biomarkers has demonstrated a clearadditional value in the clinical decision-making process andtheir routine use in the intensive care unit is certainly not yetcost-effective.

DEFINITIONS OF ACUTE KIDNEY INJURYSeveral definitions have been used over the years to describeacute kidney injury (AKI).1 Because of the lack of a consen-sus, the Acute Dialysis Quality Initiative Group first definedAKI as a 1.5-fold increase in serum creatinine (SCr), adecrease in estimated glomerular filtration rate (eGFR) ofmore than 25% or a decline in the urine output to less than0.5 mL/kg/hour over 6 hours.2 This definition was used inthe so-called RIFLE (Risk, Injury, Failure, Loss and EndstageKidney Disease) classification.3 The AKI Network group fur-ther modified this definition by adding an increase in SCrby 0.3 mg/dL (26.4 µg/L) or more.4 This criterion was addedon the basis of findings from two large, single-centre stud-ies demonstrating an independent association between anincrease in SCr of 0.3 mg/dL (>26.4 µg/L) or more and in-hospital mortality.5,6 A single definition for practice, researchand public health in AKI has recently been proposed by theKidney Diseases Improving Global Outcomes WorkingGuideline Group and will be published soon.

Serum creatinineTwo studies, one in the USA7 and one in Europe,8 foundthat, compared with the RIFLE criteria, the AKI Networkcriteria do not materially improve the definition and clas-sification of AKI, at least in the first 24 hours after admis-sion to an intensive care unit (ICU).9 Unfortunately, thereare number of important limitations to the use of SCr inthe definition and classification of AKI; chief among themis the delay of several hours before SCr increases after AKI

N Lameire MD, PhD,University Hospital,Gent, Belgium

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Society of Nephrology.13 Based on studies in experimentalmodels of AKI and humans, a number of biomarkers havebeen proposed: cystatin C (CysC), soluble tumour necro-sis factor receptors, N-acetyl-beta-D-glucosaminidase, kid-ney injury molecule 1 (KIM-1), isoform 3 of thesodium-hydrogen exchanger, interleukin (IL)-16, IL-18,matrix metalloproteinase-9, liver-type fatty acid bindingprotein (L-FABP) and neutrophil gelatinase-associatedlipocalin (NGAL).14–26

Most of the investigations have focused on the ability ofthese potential biomarkers to detect either established orincipient AKI. Other studies have prospectively investigat-ed their prognostic performance in predicting either theneed for renal replacement therapy (RRT) or ICU or hos-pital mortality. A few studies have also explored their poten-tial in differentiating between ‘transient AKI’, formerlycalled prerenal AKI, and established intrinsic AKI, mostlyacute tubular necrosis.

This review focuses on the role of biomarkers in the ear-lier diagnosis of AKI, including selected studies on the twomost studied biomarkers: plasma and urinary NGAL, andserum CysC.

Cystatin C CysC is synthesised and released into plasma by all nucle-ated cells at a constant rate, and is freely filtered at theglomerulus. While plasma CysC is a more reliable markerthan SCr for eGFR, urine CysC is a biomarker of tubularcell integrity. Although CysC is less subject to the non-renalvariables that impact SCr, its levels may be affected byanthropometric measures as well as inflammatory process-es, use of corticosteroids and changes in thyroid function.27

In human studies, plasma CysC can predict the develop-ment of AKI28 and the requirement for RRT,29 although itssuperiority over SCr has not been universally found.30

Serum CysC has also been analysed versus plasma NGALand more conventional markers in patients undergoing car-diac surgery.31 Compared with ICU admission postopera-tive SCr levels, contemporaneous plasma NGAL and serumCysC levels were found to have good predictive value forthe subsequent development of AKI. Koyner et al. foundurinary CysC, together with urinary NGAL, to be a verypromising early (within 6 hours of surgery) biomarker forAKI in adult cardiac surgery patients.32

In addition, Nejat et al. found that CysC is superior toSCr for the early diagnosis of AKI developing de novo in theICU.33 A prospective cohort study of patients presenting toa tertiary care emergency department found that bothserum CysC and SCr (at presentation and 6 hours later)showed high discriminatory ability for the diagnosis ofAKI.34 However, only serum CysC demonstrated a signifi-cant early predictive power and could differentiate betweenAKI and prerenal azotemia.

Finally, a systematic review and meta-analysis of the pre-dictive performance of serum CysC for the early diagnosisof AKI looked at patients in different settings, including postcardiac surgery and mixed ICU populations.35 Across allthese settings, the diagnostic odds ratio for serum CysC topredict AKI was 23.5 (95% confidence interval [CI]14.2–38.9), with sensitivity and specificity of 0.84 and 0.82,respectively. The diagnostic odds ratio for urinary CysCexcretion was much lower at 2.60 (95% CI 2.01–3.35), withlow sensitivity and specificity of 0.52 and 0.70, respective-ly. Serum CysC thus appears to be a good biomarker for the

prediction of AKI, whereas urinary CysC excretion has onlymoderate diagnostic value.

Neutrophil gelatinase-associated lipocalin NGAL is a ubiquitous 25 KDa protein that is covalentlybound to gelatinase from human neutrophils. It is expressedat very low concentrations in various human tissues, includ-ing the kidney, and its renal expression increases greatly inthe presence of inflammation and after ischemia–reperfu-sion injury and nephrotoxicity.36 Plasma and urine NGALlevels have been shown to predict AKI in populations asdiverse as patients undergoing percutaneous coronary inter-vention,37 children and adults undergoing cardiacsurgery,38,39 and septic and non-septic critically ill chil-dren.40,41 Several recent and comprehensive reviews areavailable in the literature.42 For detecting AKI in the emer-gency room, the sensitivity and specificity of urinary NGALat a cut-off value of 130 µ/g creatinine have been reportedto be superior to those for other urinary proteins, fraction-al excretion of sodium and SCr. Urinary NGAL was highlypredictive of clinical outcomes, including nephrology con-sultation, RRT and admission to the ICU ; however its diag-nostic performance was not much higher that of SCr alone.43

Two relatively large studies of NGAL in critically illpatients have been published: one evaluating urine NGAL,44

the other plasma NGAL.45 Siew et al. studied the predictivevalue of urine NGAL for the early diagnosis and outcomeof AKI in 451 critically ill adults during their initial 48 hoursin the ICU.44 Median urine NGAL at enrolment was high-er among patients who developed AKI within 48 hours com-pared with those who did not. The areas under the receiveroperating curves (AUC–ROC) describing the relationshipbetween urine NGAL level and the development of AKIwithin 24 and 48 hours were 0.71 and 0.64, respectively.However, urine NGAL only marginally improved the per-formance of a clinical prediction model alone. It should benoted that the clinical prediction model used was not a val-idated tool in clinical use. Nonetheless, these data under-score the necessity of quantifying the additionalcontribution of new diagnostic and prognostic AKIbiomarkers beyond what is predictable using currentlyavailable clinical data and diagnostic tools. In another recentstudy, for example, plasma and urine NGAL values at ICUadmission were significantly related to AKI severity, but theAUC-ROCs for plasma and urine NGAL were comparablewith those of admission eGFR.46 However, NGAL analysisadded significant accuracy to the prediction of AKI in com-bination with eGFR alone or to other clinical parameters.

Cruz et al. evaluated the diagnostic accuracy of plasmaNGAL for the early detection of AKI and need for RRT inanother relatively large, single-centre adult ICU study.45

Plasma NGAL was a good diagnostic marker for AKI devel-opment within the next 48 hours (AUC-ROC 0.78, 95% CI0.65–0.90) and predicted AKI development within 48 hoursindependent of three severity-of-illness scores. Peak plas-ma NGAL concentrations increased with worsening AKIseverity, defined by the maximum RIFLE stage reached inthe ICU. The authors suggested that plasma NGAL can diag-nose AKI up to 48 hours before a clinical diagnosis can beestablished based on the RIFLE system criteria.

Interestingly, Cruz et al. did not find differences in plas-ma NGAL between patients with sepsis and those without,47

which is in contrast to the findings of Bagshaw et al.48 theseauthors found that septic AKI was associated with signifi-




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cantly higher plasma and urine NGAL levels at enrolmentcompared with non-septic AKI (p<0.001). Plasma NGALshowed fair discrimination for AKI progression andalthough urine NGAL performed less well, peak urineNGAL predicted AKI progression better in non-septic AKI.In critically ill children, it has been demonstrated that plas-ma NGAL is increased in those with sepsis and septic shock,even in the absence of AKI.40 This is not unexpected becauseNGAL is released from activated neutrophils. Another trialin critically ill adults reported that urinary NGAL, thoughindependently associated with AKI, yielded only very mod-erate discrimination at 48 hours.44

As pointed out in an editorial,14 NGAL estimations maypredict AKI occurring within 24 hours (and maybe evenwithin 48 hours), but they are not truly specific becauseother comorbidities in critically ill patients can also induceelevated NGAL levels. This may also explain why the pre-dictive ability of NGAL for AKI appears to be far better inless ill children than in adults in the ICU, as was found in arecent systematic review and meta-analysis by Haase et al.49

In this review, age was identified as an effective modifier ofNGAL value with a better predictive ability in children thanadults. However, an accompanying editorial pointed to sev-eral important limitations to the existing knowledge onNGAL (and other biomarkers) that emerged from the meta-analysis.50 Most of the studies were single-centred, with lownumbers of patients and outcome endpoints, and relative-ly ‘homogenous populations of relatively non-complexforms’ of AKI were studied. The difficulties of defining AKIusing SCr, analytical problems in many studies using‘home-grown’ ELISA to measure NGAL with wide rangesof ‘normal’ values, and potential publication bias should allbe taken into account.

A recent observational study of patients undergoing elec-tive coronary angiography found a large range of prepro-cedural urinary NGAL levels, with half the cohortdemonstrating an increase and half a decrease in the abso-lute values of urinary NGAL after angiography, irrespectiveof the preprocedural levels. When designing studies withat-risk individuals where urinary NGAL may be used as amarker, this variability should be taken into account.51

Furthermore, Haase-Fielitz et al. observed that the predic-tive value of plasma NGAL in cardiac surgery varied accord-ing to the AKI definition used and was higher for moresevere AKI.52

In a recent editorial, my colleagues and I discussed theperformance of many of these biomarkers, including NGAL,by comparing the AUC-ROC curves with clinical and rou-tine biochemical outcome parameters.53 This comparisonrevealed that, until now, none of the biomarkers has demon-strated a clear additional value beyond the traditionalapproach in clinical decision-making in patients with AKI.

Temporal patterns of increases in urinary biomarker con-centrations can occur in patients who develop AKI after car-diopulmonary bypass. Biomarkers such as NGAL andL-FABP have higher accuracy early, with diminishing accu-racy 4–6 hours after surgery. By contrast, IL-18 and KIM-1 have lower accuracy at 2–4 hours after surgery, withincreasing accuracy at 12–24 hours after surgery. Manyauthors are already now pleading for the analysis of a ‘panel’of biomarkers.54

Finally, routine urine and serum NGAL measurementsmay not be cost-effective or practical to perform in the typ-ical ICU until effective interventions for early AKI are dis-

covered. Bedside measurements of serum NGAL takeapproximately 10 minutes and cost about $10. Even a singletest on admission in an average-sized ICU would cost manythousands of dollars in materials and staff time each year.

CONCLUSIONNovel biomarkers, including those discussed in more detailin this review, can be of use in unravelling the biochemicaland biological processes that occur during AKI and are theresult of top-quality biological research. However, opti-mism regarding their use in the approach to clinical AKIshould at present be tempered. We believe that, first of all,a careful clinical appraisal is still the mainstay of early diag-nosis and therapy. So far, none of the biomarkers hasdemonstrated a clear additional value in the clinical deci-sion-making process. Their unlimited use risks distractingfrom important clinical evaluation, resulting in worseinstead of better outcomes for patients and, in the best case,a waste of money. We hope that future studies will evalu-ate the performance of biomarkers on top of clinical andbasic biochemical parameters, and couple the results witha therapeutic intervention.

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CORRESPONDENCE TO:Norbert Lameire MD, PhDUniversity HospitalDe Pintelaan 1859000 GentBelgiumE-mail: [email protected]




PRODUCT NEWS A review of the latest developments


■■■ ADVANCING NASAL TUBEA self-advancing nasal jejunal feeding tube, theTiger 2, from Cook Medical allows peristalsis topull it directly and safely into the small bowel. Thisprovides quick enteral access for the delivery ofnutrition and/or medication. It reduces the risk ofperforation or misplacement that can occur withweighted-tipped feeding tubes and also avoidscostly endoscopy or fluoroscopy.

The early postpyloric placement allows nutritionalgoals to be met sooner which could lead to a shorterlength of ICU stay. It is intended to provide short-term enteral access for delivery of nutrition andmedication to the small bowel. Supplied sterile inpeel-open packages, it is intended for one-time use.

■ For more information about this product go to

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■■■ FIGHTS CYTOKINE STORMCytoSorb™, from CytoSorbents, is a new therapyapproved as an extracorporeal cytokine filter. It isbased on a highly biocompatible, porous polymerbead that can capture and absorb cytokines in the~10–50 kDa sweet spot where cytokines reside.

The therapy is flexible as it is compatible withstandard haemodialysis machines. It also aims toreduce cytokines and mitigate cytokine storm that isassociated with multiple organ failure and death incritical care illness. In a randomised, controlled clini-cal trial, treatment led to a statistically significant30–50% reduction in key cytokines and an improve-ment in 28-day mortality in a subgroup of patientswith very high cytokine levels. ■ For more information about this product go to

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■■■ OPTIMISED MONITORINGA flexible platform PulsioFlex® optimised for peri-oper-ative monitoring has been launched by PulsionMedical Systems. It can be adapted to individualneeds to allow detection of peri-operative deteriorationof haemodynamics; pre-and inter-operative volumeoptimisation; patients with increased post-operativerisk profile; post-operative management of haemody-namic complications. It also covers special risk andfunction monitoring in liver surgery. There is a brilliant8” LED colour screen with high resolution.

With the PulsioFlex platform the StepWISE mon-itoring concept will be implemented consistently inthe peri-operative field. The system can be adapt-ed to meet individual patient’s needs at any time.


www.pulsion.com

■■■ RAPID BRAIN COOLRhinoChill® is a unique hypothermia device thatuses conductive cooling which allows the efficientdiffusion of thermal energy to cool the brain.Evaporative cooling allows the nebulised coolant toevaporate within the nasal cavity. Convective cool-ing means blood is cooled as it passes through ornear the nasopharynx. The brain and body aresubsequently cooled haematogenously.

Using RhinoChill it is possible to effectively pre-serve the brain during cerebral ischaemia events.Therapeutic hypothermia can be started in the fieldand continued until the cooled patient is connectedto a maintenance cooling device in the ICU. It iseasy to use, portable and compact.


www.benechill.com

■■■ ORAL CARE FOR VAPTo make oral care for ventilator dependent patientseasier, Kimberly-Clark has introduced flexible sys-tems which allow direct input from nurses. TheKIMVENT Oral Care Kits can be kept at the bedsideand easy access packaging in individual packs facili-tates making the right choice at the right time.

The packaging increases the visibility of the oralcare procedure, while the no leak packs are in dif-ferent colours. The kits include a flexible toothbrushwith soft gentle bristles that remove dental plaque,debris and secretions. A pliable suction catheterhelps to remove oral secretions from the oropha-ryngeal area. Prep Packs are available with self-cleaning covered Yankauer and suction handle.■ For more information about this product go to

www.vap.kchealthcare.com

■■■ COOLING THAT WORKSThe innovative KOOL-KIT® Therapeutic TemperatureManagement System has been introduced byCincinatti Sub-Zero is a really effective cooling sys-tem. It is unique as it provides full body coverage andcombines a head wrap, patient vest and lower bodyblanket with the advanced Blanketrol® 111 hyper-hypothermia system. This provides an integratedmodular approach while finely administered thera-peutic cooling and rewarming is achieved.

An analysis of blood flows confirms the benefits.Around 7% flows through the area treated by thehead wrap every minute, 33% flows through vascu-lar treated by the Kool-Kit vest, 26% flows throughthe groin treated by the lower body blanket.


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INTL Journal of Intensive Care Winter 2011

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