2009 yearbook of intensive care and emergency medicine annual volumes 2009 www dof3tna net

Royal Victoria InfirmaryQueen Victoria Road Newcastle upon Tyne, NE2 4HH United Kingdom Beale R Department of Adult Critical Care Guy’s and St Thomas’ NHS Foundation Trust St Thomas’ Hos

Yearbook of Intensive Care

Edited by J.-L Vincent

of Intensive Care and Emergency

Edited by J.-L Vincent

With 172 Figures and 96 Tables

Head, Department of Intensive Care

Erasme Hospital, Universit´e libre de Bruxelles

Route de Lennik 808, B-1070 Brussels, Belgium

ISBN 978-3-540-92275-9 Springer-Verlag Berlin Heidelberg New YorkISSN 0942-5381

This work is subject to copyright All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustra- tions, recitation, broadcasting, reproduction on microfilm or in any other way, and storage

in data banks Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag Violations are lia- ble for prosecution under the German Copyright Law.

Springer is a part of Springer Science+Business Media

publica-Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and medications contained in this book In every individual case the user must check such information by consulting the relevant literature Typesetting: FotoSatz Pfeifer GmbH, D-82166 Gräfelfing

Printing: Stürtz GmbH, D-97080 Würzburg

21/3150 – 5 4 3 2 1 0 – Printed on acid-free paper

Table of Contents

I Genomics and Proteomics

Rethinking Sepsis: New Insights from Gene Expression Profiling Studies

B.M Tang, S.J Huang, and A.S McLean 3Mitochondrial Genetics and Sepsis

A Pyle, P Chinnery, and S Baudouin 14Lung Proteomics in Intensive Care

E Kipnisand K Hansen 23

II Inflammatory Response

The Host Response to Sepsis

T.J Hommes, W.J Wiersinga, and T van der Poll 39Endotoxin Tolerance: Mechanisms and Clinical Applicability

A Draisma, J.G van der Hoeven, and P Pickkers 51Oxidative Stress and Endothelial Dysfunction during Sepsis

O Huet, A Harrois, and J Duranteau 59Measurement of Carbon Monoxide: From Bench to Bedside

F Corr ˆea, F.E Nacul, and Y Sakr 65Monitoring Immune Dysfunction in Septic Patients: Toward Tailored Immunotherapy

F Venet, A Lepape, and G Monneret 81

III Current and Future Management of Sepsis

Source Control in the ICU

J.J De Waele, M.M.L.G Malbrain, and I.E De laet 93IgM-enriched Immunoglobulins in Sepsis

F Esenand S Tugrul 102Clarithromycin: A Promising Immunomodulator in Sepsis

E.J Giamarellos-Bourboulis 111High-flow Hemofiltration as an Adjunctive Therapy in Sepsis

P.M Honor ´e, O Joannes-Boyau, and W Boer 119Economic and Social Burden of Severe Sepsis

E Silvaand D.V Araujo 129

IV Proposed Targets for New Therapies

Lymphocyte Apoptosis in Sepsis and Potential Anti-apoptotic Strategies

S Weber, B Baessler, and S Schroeder 141The Pivotal Role of Beta-adrenoreceptors in Critical Illness PathophysiologyG.L Acklandand A.J Patterson 151Non-septic Acute Lung Injury and Inflammation: Role of TLR4

E Lorne, H Dupont, and E Abraham 162Hydrogen Sulfide: A Metabolic Modulator and a Protective Agent in AnimalModels of Reperfusion Injury

C Szab ´o, P Asfar, and P Radermacher 171

V Septic Shock

‘Myocardial Depression’ or ‘Septic Cardiomyopathy’

K Werdan, A Oelke, and U Müller-Werdan 183Determinants of Tissue PCO2in Shock and Sepsis: Relationship to the

C Hartog, F.M Brunkhorst, and K Reinhart 233Impact of Hydroxethyl Starch on Renal Function

G Marx, L Hüter, and T Schuerholz 243Rational Approach to Fluid Therapy in Acute Diabetic Ketoacidosis

J Ocholaand B Venkatesh 254

VII Hemodynamic Support

Cardiac Filling Volumes and Pressures in Assessing Preload Responsivenessduring Fluid Challenges

R.-M.B.G.E Breukers, R.J Trof, and A.B.J Groeneveld 265Update on Preload Indexes: More Volume than Pressure

G Della Rocca, M.G Costa, and L Spagnesi 275Monitoring Arterial Blood Pressure and Cardiac Output using Central or

Peripheral Arterial Pressure Waveforms

J Smith, L Camporota, and R Beale 285Intrathoracic Pressure Regulation for the Treatment of Hypotension

I Cinel, A Metzger, and R.P Dellinger 297Functional Hemodynamic Monitoring: A Personal Perspective

M.R Pinsky 306

VIII Airway Management

Endotracheal Intubation in the ICU

S Jaber, B Jung, and G Chanques 313Pediatric Advanced Airway Management Training for Non-anesthesia Residents

A Nishisaki, V.M Nadkarni, and R.A Berg 322Automatic Tube Compensation in the Weaning Process

J Cohen, M Shapiro, and P Singer 332

IX Mechanical Ventilation

Extracorporeal Membrane Oxygenation for Cardiac and Pulmonary Indications:

Improving Patient Safety

R Kopp, S Leonhardt, and S Kowalewski 341Patient-ventilator Interaction during Non-invasive Ventilation

P Jolliet, D Tassaux, and L Vignaux 350Variable Mechanical Ventilation: Breaking the Monotony

M Gama de Abreu, P.M Spieth, and P Pelosi 359Life-threatening Asthma: Focus on Lung Protection

H Quiroz Mart´ınezand N.D Ferguson 372

X Respiratory Monitoring

Bedside Monitoring of Diaphragm Electrical Activity during Mechanical Ventilation

C Sinderby, L Brander, and J Beck 385Electrical Impedance Tomography

E.L.V Costa, R Gonzalez Lima, and M.B.P Amato 394Regional Ventilation Delay Index: Detection of Tidal Recruitment using

Electrical Impedance Tomography

T Muders, H Leupschen, and C Putensen 405Different Approaches to the Analysis of Volumetric Capnography

F Suarez Sipmann, S.H Böhm, and G Tusman 413Variation in Extravascular Lung Water in ALI/ARDS Patients using Open

Post-pneumonectomy Pulmonary Edema

D Cook, E Powell, and F Gao-Smith 473The Role of Phenylephrine in Perioperative Medicine

C Ertmer, A Morelli, and M Westphal 483Role of the Calcium Sensitizer, Levosimendan, in Perioperative Intensive

Care Medicine

S Rehberg, P Enkhbaatar, and D.L Traber 498Inhaled Nitric Oxide Therapy in Adult Cardiac Surgery

B.C Creagh-Brownand T.W Evans 511

XII Cardiac Function

Use of Natriuretic Peptides in the Emergency Department and the ICU

T Reichlin, M Noveanu, and C Mueller 523Abnormalities of the ST Segment

D Gallo, J.M Pines, and W Brady 531Functional Mitral Regurgitation in the Critically Ill

J Poelaert 543

XIII Cardiopulmonary Resuscitation

Feedback to Improve the Quality of CPR

J Yeung, J Soar, and G.D Perkins 555The Post-cardiac Arrest Syndrome

J.P Nolanand R.W Neumar 565Use of a Standardized Treatment Protocol for Post-cardiac Resuscitation CareM.A Kuiper, P.E Spronk, and M.J Schultz 575Therapeutic Hypothermia after Cardiac Arrest

G Ristagnoand W Tang 589

XIV Renal Function

Biomarkers of Acute Kidney Injury in Critical Illness

F Adamsand B Venkatesh 603The Role of Biomarkers in Cardiac Surgery-associated Acute Kidney Injury

A Shaw, M Stafford-Smith, and M Swaminathan 612Neutrophil Gelatinase-associated Lipocalin: An Emerging Biomarker for

E Levesqueand F Saliba 646

Acute-on-chronic Liver Failure in Cirrhosis: Defining and Managing Organ

Dysfunction

D Shawcrossand J Wendon 658

XVI Nutrition

The Curse of Overfeeding and the Blight of Underfeeding

N.-H.W Lohand R.D Griffiths 675Enteral Feeding during Circulatory Failure: Myths and Reality

M.M Bergerand R.L Chiolero 683Enteral Nutrition with Anti-inflammatory Lipids in ALI/ARDS

A Pontes-Arrudaand S.J DeMichele 695Glutamine Supplementation in ICU Patients

A Berg, O Rooyackers, and J Wernerman 705

XVII Glucose Control

Burn Causes Prolonged Insulin Resistance and Hyperglycemia

G.G Gauglitzand M.G Jeschke 719Glucose Variability in Critically Ill Patients

N.A Ali, J.S Krinsley, and J.-C Preiser 728

XVIII Adrenal Function

Corticosteroid Biology in Critical Illness: Modulatory Mechanisms and Clinical

M Levi 769

XX Neurological Aspects

The Role of Imaging in Acute Brain Injury

R.D Stevens, A Pustavoitau, and P van Zijl 783Monitoring and Managing Raised Intracranial Pressure after Traumatic

Brain Injury

M Smith 801Sepsis-associated Encephalopathy

S Siami, A Polito, and T Sharshar 809

XXI Malignancies

Acute Tumor Lysis Syndrome: Diagnosis and Management

M Darmon, M Roumier, and E Azoulay 819Life-threatening Neurological Complications in Patients with Malignancies

S Legrieland E Azoulay 828Should We Admit Critically Ill Cancer Patients to the ICU?

D.D Benoit, P.O Depuydt, and J.M Decruyenaere 845

XXII Drug Dosing

Optimizing Drug Dosing in the ICU

X Liu, P Kruger, and M.S Roberts 859Relevant CYP450-mediated Drug Interactions in the ICU

I Sprietand W Meersseman 870

XXIII Sedation and Analgesia

Sedation and Pain Management in the ICU

M.A Mirskiand J.J Lewin III 881The Role of Dexmedetomidine in Intensive Care

R Rahman West, A Rhodes, and R.M Grounds 906Monitoring Delirium in the ICU

M Seeling, A Heymann, and C Spies 915

XXIV ICU Management

Intensive Care for the Elderly: Current and Future Concerns

H Wunsch, A.T Jones, and D.C Scales 935ICU Performance: Managing with Balanced Scorecards

K Shukriand F.S.M Ali 944

XXV End-of-Life Issues

Towards a Neuro-scientific Explanation of Near-death Experiences?

A Vanhaudenhuyse, M Thonnard, and S Laureys 961Managing Conflict at the End-of-Life

K Hillmanand J Chen 969Strengths and Weaknesses of Substitute Decision Making in the ICU

A Lautrette, E Azoulay, and B Souweine 979

Subject Index 989

List of Contributors

Abdel-Razeq SS

Section of Trauma, Surgical Critical

Care, and Surgical Emergencies

Yale University School of Medicine

Department of Intensive Care

Princess Alexandra Hospital

and Critical Care

Hospital Clinico Universitario de

PO Box 15215Dammam 31444Saudi ArabiaAli NADivision of Pulmonary, Allergy,Critical Care, and Sleep MedicineDepartment of Internal Medicine201G DHLRI

Columbus, OH 43210USA

Amato MBPRespiratory Intensive Care UnitUniversity of Sao Paulo School ofMedicine

Av Dr Arnaldo 45501246–903 Sao Paulo, SPBrazil

Araujo DVDepartment of Internal MedicineMedical Sciences School

Universidade do Estado do Rio deJaneiro

Rio de JaneiroBrazil

Asfar PDepartment of Intensive Careand Hyperbaric MedicineCentre Hospitalo-UniversitaireRue Dominique Larrrey

49933 AngersFrance

Royal Victoria Infirmary

Queen Victoria Road

Newcastle upon Tyne, NE2 4HH

United Kingdom

Beale R

Department of Adult Critical Care

Guy’s and St Thomas’ NHS Foundation

Trust

St Thomas’ Hospital, 1stFloor East Wing

Westminster Bridge Road

London, SE1 7EH

and Critical Care

Hospital Clinico Universitario de

Department of Intensive Care

Ghent University Hospital

De Pintelaan 185

9000 Ghent

Belgium

Berg ADepartment of Anesthesia andIntensive Care

Karolinska InstituteHuddinge University

14186 StockholmSweden

Berg RADepartment of Anesthesiologyand Critical Care

The Children’s Hospital of Philadelphia

34thStreet and Civic Center BoulevardPhiladelphia, PA 19104

USABerger MMDepartment of Adult Intensive Careand Burns

Centre Hospitalier UniversitaireVaudois

Rue du Bugnon 47

1011 LausanneSwitzerlandBoer WDepartment of NephrologyAtrium Medical Center

6410 CX HeerlenNetherlandsBöhm SHCSEM Nanomedicine DivisionResearch Centre for NanomedicineSchulstrasse 1

7302 LandquartSwitzerlandBrady WDepartment of Emergency MedicineUniversity of Virginia Health System

1215 Lee StreetCharlottesville, VA 22908–0699USA

Brander LDepartment of Intensive CareUniversity Hospital Inselspital

30110 BernSwitzerland

Breukers RMBGE

Department of Intensive Care

VU University Medical Center

Department of Adult Critical Care

Guy’s and St Thomas’ NHS Foundation

Trust

St Thomas’ Hospital, 1stFloor East Wing

Westminster Bridge Road

London, SE1 7EH

United Kingdom

Chanques G

Intensive Care Unit, Department of

Anesthesiology (DAR B)

CHU, Hˆopital Saint Eloi

80 avenue Augustin Fiche

Mitochondrial Research Group

Institute of Ageing and Health

Newcastle University

Newcastle upon Tyne, NE2 4HH

United Kingdom

Chiolero RLDepartment of Adult Intensive Careand Burns

Centre Hospitalier UniversitaireVaudois

Rue du Bugnon 47

1011 LausanneSwitzerlandCinel IDepartment of Critical CareCooper University HospitalOne Cooper Plaza

Dorrance Building, Suite 393Camden, NJ 08103

USACohen JGeneral Intensive Care UnitRabin Medical CenterCampus BeilinsonPetah Tikva 49100Israel

Cook DDepartment of Anesthesia, CriticalCare and Pain

Birmingham Heartlands HospitalBordesley Green East

Birmingham, B9 5SSUnited KingdomCorr ˆea FDepartment of Anesthesiologyand Intensive Care

Friedrich-Schiller UniversityErlanger Allee 103

07743 JenaGermanyCosta ELVRespiratory Intensive Care UnitUniversity of Sao Paulo School

of Medicine

Av Dr Arnaldo 45501246–903 Sao Paulo, SPBrazil

Department of Critical Care

Royal Brompton Hospital

Department of Intensive Care

Ghent University Hospital

One Cooper PlazaDorrance Building, Suite 393Camden, NJ 08103

USADeMichele SJStrategic and International R & DAbbott Nutrition

3300 Stelzer RoadColumbus, OH 43219USA

Depuydt PODepartment of Intensive CareGhent University Hospital

De Pintelaan 185

9000 GhentBelgiumDevarajan PDepartment of Nephrology andHypertension

Cincinnati Children’s Hospital MedicalCenter

University of Cincinnati

3333 Burnet AvenueCincinnati, OH 45229–3039USA

De Waele JJSurgical Intensive Care UnitGhent University Hospital

De Pintelaan 185

9000 GhentBelgiumDraisma ADepartment of Intensive CareRadboud University Nijmegen MedicalCenter

PO Box 9101

6500 HB NijmegenNetherlandsDubin AUnit of Applied PharmacologyFaculty of Medical Science

La Plata National University

1900 La Plata, Buenos AiresArgentina

Dupont H

Department of Anesthesiology

and Intensive Care

Centre Hospitalier Universitaire

78 rue du G´en´eral Leclerc

94275 Le Kremlin Bicˆetre Cedex

France

Edul VSK

Unit of Applied Pharmacology

Faculty of Medical Science

La Plata National University

1900 La Plata, Buenos Aires

and Intensive Care

University Hosptial of Münster

and Intensive Care

Medical Faculty of Istanbul

London, SW3 6NPUnited KingdomFerguson NDToronto Western Hospital

399 Bathurst Street, 2MCL-411MToronto, ON M5T 2S8

CanadaFerrando CDepartment of Anesthesiologyand Critical Care

Hospital Clinico Universitario deValencia

Avenida Blasco Ibanez 17

46010 ValenciaSpain

Gabriella CDepartment of Anesthesia andIntensive Care

Azienda Ospedaliero-Universitaria S.M.della Misericordia

P.le S M Misericordia 15

33100 UdineItalyGallo DDepartment of Emergency MedicineUniversity of Virginia Health System

1215 Lee StreetCharlottesville, VA 22908–0699USA

Gama de Abreu MDepartment of Anesthesiologyand Intensive Care

University Hospital Carl Gustav CarusFetscherstr 74

01307 DresdenGermanyGao-Smith FDepartment of Anesthesia, CriticalCare and Pain

Birmingham Heartlands HospitalBordesley Green East

Birmingham, B9 5SSUnited Kingdom

4thDepartment of Internal Medicine

Attikon University Hospital

University of Sao Paulo

Av Prof Melo Moraes 2231

and Critical Care

Hadassah Hebrew University Medical

Department of Intensive Care

VU University Medical Center

De Boelelaan 1117

1081 HV Amsterdam

Netherlands

Grounds RMDepartment of Anesthesiologyand Intensive Care

Friedrich-Schiller-UniversityErlanger Allee 101

07743 JenaGermanyHansen KCancer Center Proteomics CoreUniversity of Colorado DenverUCD Anschutz Medical Campus, RC-1South, L18–1303

PO Box 6511, Campus Box 8119Aurora, CO 80045

USAHarrois ADepartment of Anesthesia and SurgicalIntensive Care

CHU de Bicˆetre

78 rue du G´en´eral Leclerc

94275 Le Kremlin Bicˆetre CedexFrance

Hartog CDepartment of Anesthesiologyand Intensive Care

Friedrich-Schiller UniversityErlanger Allee 101

07743 JenaGermanyHeymann ADepartment of Anesthesiology andIntensive Care

Campus Charit´e Mitte und CampusVirchow-Klinikum

Charit´e-Universitätsmedizin BerlinAugustenburger Platz 1

13353 BerlinGermanyHillman KThe Simpson Center for Health SystemsResearch

Liverpool HospitalLocked Bag 7103Liverpool BC, NSW 1871Australia

Department of Intensive Care

St-Pierre Para-Universitary Hospital

Avenue Reine Fabiola 9

1340 Louvain-la-Neuve

Belgium

Huang SJ

Department of Intensive Care

Nepean Clinical School

78 rue du G´en´eral Leclerc

94275 Le Kremlin Bicˆetre Cedex

Department of Translational Physiology

Academic Medical Center

CHU, Hˆopital Saint Eloi

80 avenue Augustin Fiche

34295 Montpellier Cedex 5

France

Jeschke MGGalveston Burns UnitShriners Hospitals for Children

815 Market StreetGalveston, TX 77550USA

Joannes-Boyau ODepartment of Anesthesia andIntensive Care II

University of Bordeaux II

33600 PessacFranceJolliet PDepartment of Intensive CareUniversity Hospital

1211 Geneva 14SwitzerlandJones ATDepartment of Intensive Care Medicine

St Thomas HospitalWestminster Bridge RoadLondon, SE17 EHUnited KingdomJung B

Intensive Care Unit, Department

of AnesthesiologyCHU, Hˆopital Saint Eloi

80 avenue Augustin Fiche

34295 Montpellier Cedex 5France

Kaplan LJSection of Trauma, Surgical CriticalCare, and Surgical EmergenciesYale University School of Medicine

330 Cedar Street, BB-310New Haven, CT 06520USA

Kipnis EDepartment of Surgical Intensive CareHˆopital Huriez

Centre Hospitalier R´egionalUniversitaire de Lille

1 rue Michel Polonovski

59037 LilleFrance

Columbia University College

of Physicians and Surgeons

190 W Broad St

Stamford, CT 06902

USA

Kruger P

Intensive Care Unit

Princess Alexandra Hospital

Ipswich Road

Woolloongabba, Brisbane

Australia

Kuiper MA

Department of Intensive Care

Medical Center Leeuwarden

PO Box 888

8901 BR Leeuwarden

Netherlands

Laureys S

Coma Science Group

Cyclotron Research Centre

and Intensive Care

CHU Gabriel Montpied

58 rue Montalembert

63000 Clermont-Ferrand

France

Legriel SDepartment of Intensive CareHˆopital Andr´e Mignot

177 rue de Versaille

78150 Le ChesnayFrance

Leonhardt SPhilips Chair of Medical InformationTechnology

RWTH Aachen University

52074 AachenGermanyLepape AIntensive Care UnitCentre Hospitalier Lyon-SudChemin du Grand Revoyet

69495 Pierre-BeniteFrance

Levesque EDepartment of Intensive CareHˆopital Paul Brousse

12, Av Paul Vaillant Couturier

94800 VillejuifFranceLevi MDepartment of Medicine (F-4)Academic Medical CenterUniversity of AmsterdamMeibergdreef 9

1105 AZ AmsterdamNetherlands

Lewin III JJThe Johns Hopkins Medical Institutions

600 N Wolfe StreetCarnegie 180Baltimore, MD 21287–6180USA

Liu XTherapeutics Research UnitPrincess Alexandra HospitalIpswich Road

Woolloongabba, Brisbane, QLD 4102Australia

Universit´e Jules Verne de Picardie

Centre Hospitalier Universitaire

Department of Intensive Care

Nepean Clinical School

Dorrance Building, Suite 393Camden, NJ 08103

USAMirski MADepartment of Anesthesiologyand Critical Care

69437 Lyon cedex 03France

Monnet XDepartment of Medical Intensive CareHˆopital de Bicˆetre

78 rue du G´en´eral Leclerc

94270 Le Kremlin-BicˆetreFrance

Morelli ADepartment of Anesthesiology andIntensive Care

University of Rome „La Sapienza”

Viale del Policlinico 155

00161 RomeItaly

The Children’s Hospital of Philadelphia

34thStreet and Civic Center Boulevard

Philadelphia, PA 19104

USA

Neumar RW

Department of Emergency Medicine

University of Pennsylvania School

The Children’s Hospital of Philadelphia

34thStreet and Civic Center boulevardPhiladelphia, PA 19104

USANolan JPDepartment of Anesthesiology andIntensive Care

Royal United HospitalCombe Park

Bath, BA1 3NGUnited KingdomNoveanu MDepartment of MedicineUniversity HospitalPetersgraben 4

4031 BaselSwitzerlandOchola JDepartment of Intensive CarePrincess Alexandra Hospital

199 Ipswich RoadBrisbane, QLD 4102Australia

Oelke ADepartment of Medicine IIIUniversitätsklinikum HalleMartin-Luther-UniversityHalle-WittenbergErnst-Grube-Str 40

06097 Halle/SaaleGermany

Patterson AJDepartment of AnesthesiaStanford University Medical Center

300 Pasteur DriveStanford, CA 94305USA

Department of Intensive Care

Radboud University Nijmegen Medical

General Intensive Care Unit

Raymond Poincar´e Teaching Hospital

Rua Ildefonso Albano 777/403Fortaleza, Ceara 60115–000Brazil

Powell EDepartment of Anesthesia, CriticalCare and Pain

Birmingham Heartlands HospitalBordesley Green East

Birmingham, B9 5SSUnited KingdomPreiser JCDepartment of Intensive CareCentre Hospitalier Universitaire deLi`ege

Domaine Universitaire Sart Tilman B35

4000 Li`ege 1BelgiumPustavoitau ADepartments of Anesthesiologyand Critical Care

Johns Hopkins HospitalMeyer 8–140, 600 N Wolfe StBaltimore, MD 21287

USAPutensen CDepartment of Anesthesiologyand Intensive Care

University of BonnSigmund Freud Strasse 25

53105 BonnGermanyPyle AMitochondrial Research GroupInstitute of Ageing and HealthNewcastle University

Newcastle upon Tyne, NE2 4HHUnited Kingdom

Quiroz Martinez HInterdepartmental Division

of Critical CareToronto Western Hospital

399 Bathurst Street, 2MCL-411MToronto, ON M5T 2S8

Canada

Weil Institute of Critical Care Medicine

35100 Bob Hope Drive

Rancho Mirage, CA 92270

USA

Roberts MSIntensive Care UnitPrincess Alexandra HospitalIpswich Road

Woolloongabba, Brisbane, QLD 4102Australia

Robin EDepartment of Surgical intensive CareHˆopital Huriez

Centre Hospitalier R´egionalUniversitaire de Lille

1 rue Michel Polonovski

59037 LilleFranceRooyackers ODepartment of Anesthesia andIntensive Care

Karolinska InstituteHuddinge University

14186 StockholmSweden

Roumier MDepartment of Medical Intensive CareHˆopital Saint-Louis

1 Avenue Claude Vellefaux

75010 ParisFranceSakr YDepartment of Anesthesiologyand Intensive Care

Friedrich-Schiller UniversityErlanger Allee 103

07743 JenaGermanySaliba FHepatobiliary CenterHˆopital Paul Brousse

12, Av Paul Vaillant Couturier

94800 VillejuifFranceSamama CMDepartment of Anesthesiologyand Intensive Care

Hotel-Dieu University Hospital

1 Place du Parvis de Notre-Dame

75181 Paris Cedex 04France

Scales DC

Department of Critical Care

Sunnybrook Health Sciences Centre

2075 Bayview Avenue, Room D108

Department of Intensive Care and

Laboratory of Experimental Intensive

Care and Anesthesiology

Academic Medical Center at the

and Intensive Care

Campus Charit´e Mitte und Campus

General Intensive Care Unit

Rabin Medical Center

Campus Beilinson

Petah Tikva 49100

Israel

Sharshar TGeneral Intensive Care UnitRaymond Poincar´e Teaching Hospital(AP-HP)

104 boulevard Raymond Poincar´e

92380 GarchesFranceShaw ADepartment of AnesthesiologyDuke University Medical CenterDurham, NC 27710

USAShawcross DDepartment of HepatologyKing’s College HospitalDenmark Hill

London, SE5 9RSUnited KingdomShukri KDepartment of Critical CareKing Fahad Specialist Hospital

PO Box 15215Dammam 31444Saudi ArabiaSiami SGeneral Intensive Care UnitRaymond Poincar´e Teaching Hospital(AP-HP)

104 Boulevard Raymond Poincar´e

92380 GarchesFranceSilva EIntensive Care UnitHospital Albert EinsteinSao Paulo, SP 05651–901Brazil

Sinderby CDepartment of Critical Care

St Michael’s Hospital

30 Bond StreetRoom 4–072, Queen WingToronto, ON M5B 1W8Canada

Singer P

General Intensive Care Unit

Rabin Medical Center

Campus Beilinson

Petah Tikva 49100

Israel

Smith J

Department of Adult Critical Care

Guy’s and St Thomas’ NHS Foundation

Trust

St Thomas’ Hospital, 1stFloor East

Wing

Westminster Bridge Road

London, SE1 7EH

United Kingdom

Smith M

Department of Neuroanesthesia and

Neuroscience Critical Care

The National Hospital for Neurology

and Medical Intensive Care

CHU Gabriel Montpied

Campus Charit´e Mitte und CampusVirchow-Klinikum

Charit´e-Universitätsmedizin BerlinAugustenburger Platz 1

13353 BerlinGermanySpieth PMDepartment of Anesthesiology andIntensive Care

University Hospital Carl Gustav CarusFetscherstrasse 74

01307 DresdenGermanySpriet IPharmacy DepartmentUniversity HospitalHerestraat 49

3000 LeuvenBelgiumSpronk PEDepartment of Intensive CareGelre Hospitals (Lukas site),

PO Box 9014

7300 DS ApeldoornNetherlandsSprung CLGeneral Intensive Care UnitDepartment of Anesthesiology andCritical Care

Hadassah Hebrew University MedicalCenter

PO Box 12000Jerusalem, 91120Israel

Stafford-Smith MDepartment of AnesthesiologyDuke University Medical CenterErwin Road

Durham, NC 27710USA

Department of Critical Care

Fundacion Jimenez Diaz-UTE

Avda de los Reyes Catolicos 2

Department of Intensive Care

Nepean Clinical School

University of Sydney

Sydney NSW 2750

Australia

Tang W

Weil Institute of Critical Care

35100 Bob Hope Drive

78 rue du G´en´eral Leclerc

94270 Le Kremlin-BicˆetreFrance

Thonnard MComa Science GroupCyclotron Research CentreUniversity of Li`egeSart-Tilman-B30

4000 Li`egeBelgiumTraber DLInvestigational Intensive Care UnitDepartment of AnesthesiologyThe University of Texas Medical Branch

301 University BlvdGalveston, TX 77555–0833USA

Trof RJDepartment of Intensive Care

VU University Medical Center

De Boelelaan 1117

1081 HV AmsterdamNetherlands

Tugrul SDepartment of Anesthesiology andIntensive Care

Medical Faculty of IstanbulUniversity of IstanbulCapa Klinikleri

34093 IstanbulTurkeyTusman GDepartment of AnesthesiologyHospital Privado de ComunidadCordoba 4545

7600 Mar del PlataArgentina

Vallet BDepartment of Surgical Intensive CareHˆopital Huriez

Centre Hospitalier R´egionalUniversitaire de Lille

1 rue Michel Polonovski

59037 LilleFrance

van der Hoeven JG

Department of Intensive Care Medicine

Radboud University Nijmegen

Medical Center

PO Box 9101

6500 HB Nijmegen

Netherlands

Van der Poll T

Academic Medical Center

Coma Science Group

Cyclotron Research Centre

Department of Intensive Care

Princess Alexandra & Wesley Hospitals

University of BonnSigmund-Freud-Strasse 25

53105 BonnGermanyWeiss YGGeneral Intensive Care UnitDepartment of Anesthesiologyand Critical Care

Hadassah Hebrew UniversityMedical Center

PO Box 12000Jerusalem, 91120Israel

Wendon JLiver Intensive Care Unit and Institute

of Liver StudiesKing’s College HospitalDenmark Hill

London, SE5 9RSUnited KingdomWerdan KDepartment of Medicine IIIUniversitätsklinikum HalleMartin-Luther-UniversityHalle-WittenbergErnst-Grube-Str 40

06097 Halle/SaaleGermany

Wernerman JDepartment of Anesthesiaand Intensive Care K32Karolinska InstituteHuddinge University

14186 StockholmSweden

Westphal MDepartment of Anesthesiologyand Intensive Care

University Hosptial of MünsterAlbert-Schweitzer-Str 33

48149 MünsterGermany

622 W 168thSt, PH5–505New York, NY 10032USA

Yeung JAcademic Department of Anesthesia,Critical Care and Pain

Heart of England NHS FoundationTrust

Bordesley Green EastBirmingham, B9 5SSUnited Kingdom

Common Abbreviations

AKI Acute kidney injury

ALI Acute lung injury

APACHE Acute physiology and chronic health evaluationARDS Acute respiratory distress syndrome

CABG Coronary artery bypass graft

COPD Chronic obstructive pulmonary disease

CVP Central venous pressure

DIC Disseminated intravascular coagulopathyEEG Electroencephalogram

EKG Electrocardiogram

EVLW Extravascular lung water

FiO2 Inspired fraction of oxygen

FRC Functional residual capacity

HES Hydroxyethyl starch

HSP Heat shock protein

ICG Indocyanine green

ICP Intracranial pressure

ICU Intensive care unit

IL Interleukin

LPS Lipopolysaccharide

MAP Mean arterial pressure

MAPK Mitogen-activated protein kinase

MRI Magnetic resonance imaging

NF-κB Nuclear factor-kappa B

NO Nitric oxide

NOS Nitric oxide synthase

PAC Pulmonary artery catheter

PAOP Pulmonary artery occlusion pressure

PEEP Positive end-expiratory pressure

ROS Reactive oxygen species

ScvO2 Central venous oxygen saturation

SIRS Systemic inflammatory response syndromeSOFA Sequential organ failure assessment

SvO2 Mixed venous oxygen saturation

TLR Toll-like receptor

TNF Tumor necrosis factor

I Genomics and Proteomics I

Rethinking Sepsis: New Insights from

Gene Expression Profiling Studies

B.M Tang, S.J Huang, and A.S McLean

Introduction

Critically ill patients encompass an enormously heterogeneous population and, assuch, therapeutic interventions, including drug therapy, can produce multiple out-comes in different patient subgroups For example, researchers not only look for an

‘average effect’ of a drug on a typical patient, but also seek to understand individualvariability The presence of variability impacts significantly on the success of clinicaltrials and failure to identify this variability can result in the clinical trial beingunder-powdered to detect a treatment effect For clinicians, failure to recognize vari-ability can result in unintended toxicity or excessive harm in certain patients Hence,understanding variability is critically important in both research and clinical prac-tice

Nowhere is the relevance of patient variability more evident than in sepsis Overthe last two decades, numerous clinical trials have been conducted, all producingmixed results It has been commonly observed that various patient populationsresponded differently to the same drug, ranging from marginal beneficial effect insome subgroups, to nil effect or increased toxicity in others

Investigators have attempted to address the heterogeneity issue by stratifyingpatients into groups who have different baseline mortality risk Theoretically, identi-fying those patients who are most likely to respond to treatment will ensure maxi-mal benefits and minimal harms In the case of recombinant activated protein C(drotecogin alfa (activated)), such subgroups have been identified [1, 2] For manyother drugs, no particular subgroups were found, although investigators have longsuspected patient heterogeneity was the reason for failure in these trials [3]

There is now an increased recognition that our failure to give the right treatment

to the right patient reflects our current limitations in identifying and measuring erogeneity in critically ill patients [4, 5] In this chapter, we will redefine heterogene-ity in sepsis patients using a simple conceptual model We then review findings fromrecent studies that provide new insights into the sources of heterogeneity in thesepatients

het-How to Identify and Measure Heterogeneity

Current methods to define patient heterogeneity in sepsis are grossly inadequate.Traditional criteria such as age, clinical settings or disease severity are commonlyused to enlist patients into clinical trials However, these are crude measures of theinherent heterogeneity of a very complex syndrome in a diverse patient population

I

Trial design, clinical settings, treatment duration

Age, gender, disease severity

Heart, lung, kidney

Neutrophils, lymphocytes, endothelium

Receptors, cytokines, microbial products

Polymorphisms, gene-expression, proteomics

Although simple physiological parameters (e.g., systemic inflammatory responsesyndrome [SIRS] criteria), organ level indices (e.g., circulatory failure), or a combi-nation of both (e.g., APACHE score) have been proved to be helpful in epidemiologi-cal studies, they are too non-specific as criteria to stratify patients in clinical trials.With the exception of recombinant activated protein C and anti-tumor necrosis fac-tor (TNF) therapy, attempts to select patients based on disease severity or baselinemortality risk have consistently failed, as evidenced from analyses of clinical trials

on anti-coagulant therapy, anti-inflammatory drugs, or low-dose corticosteroids [11,12] Investigators can also measure a vast array of physiological parameters andserum cytokines in sepsis patients However, we do not know how these measure-ments relate to the observed heterogeneity, nor do we know how they can be used

to predict a patient’s possible response to a new drug Consequently, there is rently no agreed upon method to identify and measure heterogeneity in sepsispatients

cur-Sources of Heterogeneity in Sepsis Patients

The sources of heterogeneity are multiple and manifest at different levels Study andpatient level variables (e.g., trial design, disease severity) are easy to discern, as thisinformation is readily available from published reports of clinical trials Our currentunderstanding of heterogeneity derives mainly from these variables [8] While thedata from these variables is useful, they represent only the tip of an iceberg (Fig 1).The iceberg model provides a qualitative overview of the sources of heterogeneity.The complexity of the data increases progressively downwards in this model (Fig 1).Data on organ and cellular level variables demonstrate a diverse range of complexbehavior exhibited by different organs (e.g., liver vs kidney) [9] and different cells

Fig 1.The iceberg model to conceptualize the sources of heterogeneity in sepsis trials Variables on theupper levels of the model are easier to discern and study Complexity of the data increases towards thelower levels, with most variables yet to be discovered or understood at the genomic level

I

(e.g., leukocytes vs endothelium) [10] Data from molecular level studies are evenmore complex, with over 50 mediators found to be involved at multiple points dur-ing the host response to sepsis [11].

The highest level of complexity, however, lies at the genomic level Here, a vastmyriad of data is accessible to only a handful of researchers in a few highly special-ized research institutions Yet, these data are potentially the richest source of infor-mation and may help us identify and measure the observed clinical heterogeneity insepsis patients Here, we will highlight some important findings from this rapidlyexpanding area of research

New Insights from Gene-expression Studies

The field of genomic science includes the study of genetic polymorphism, mics, and gene-expression profiling (see Table 1 for more details) The emergingfields of proteomics and genetic polymorphism have been reviewed elsewhere [12,13] This chapter will focus on insights obtained from studies of gene-expressionprofiling, a field with the most promising potential to assist us understand thesources of heterogeneity in sepsis

proteo-Over the last 5 years, we have undertaken a large scale, systematic interrogation

of the host response in sepsis at a transcriptional level [14 – 16] The microarraytechnique is a powerful tool that allows us to sift through a massive amount of the

Table 1.Glossary

Proteomics: A new technology that involves large-scale study of protein composition and function.

Typically, it involves cataloguing all the expressed proteins in a particular cell or tissue type, using

techniques such as two-dimensional gel electrophoresis or mass spectrometry A single mass

spec-trometry experiment can identify over 2,000 proteins

Gene-expression profiling: A high-throughput technology that measures the activity of thousands of

genes at once, to create a global picture of cellular function Cells respond changes in their

environ-ment by making messenger RNA (i.e., gene-expression), which in turn encodes for various proteins

that carry out the appropriate cellular function A single experiment can measure an entire genome

simultaneously, in some cases over 25,000 genes This technology therefore provides a more global

picture than proteomics

Polymorphism: A common biological phenomenon in which phenotype variations arise due to

differ-ence in DNA sequdiffer-ence among individuals The most frequent type of polymorphism is the

single-nucleotide polymorphism (SNP), which can be a substitution, a deletion, or an insertion of a single

nucleotide It is thought to be one of the causes of the individual variability in the susceptibility to

infectious disease

Microarray: The commonest platform used in gene-expression profiling experiments It is a

two-dimensional grid of DNA genes or gene fragment spots, usually arranged on a glass slide or silicone

wafer A typical microarray contains 10,000 – 200,000 microscopic probes The probes on the microarray

are either a short oligonucleotide or a cDNA Probe-target hybridization is usually detected and

quan-tified by fluorescence-based detection This allows the determination of relative abundance of nucleic

acid sequences in the sample

Network Analysis: An analysis method that seeks to study the relationships and interactions between

various parts of a cell signaling system (metabolic pathways, organelles, cells, and organisms) and to

integrate this information to understand how biological systems function

I

genetic information contained within the human genome (see Table 1 for moredetails) We examined the gene-expression profiles of 164 critically ill patientsadmitted to the intensive care unit (ICU) of a university-affiliated teaching hospital.The patient cohort consists of a full range of sepsis syndromes (from sepsis to septicshock) in a wide variety of clinical settings (medical, surgical and obstetric) Ourfindings reveal some interesting insights with regard to transcriptional heterogene-ity.

Limitation of Current Risk Stratification Methods

Our data shows that there is no difference in the host response between sepsis,severe sepsis, and septic shock at a transcriptional level Classification of septicpatients into sepsis, severe sepsis, and septic shock is one of the commonest ways tostratify patient into different risk groups and is supported by a large amount of datafrom epidemiological studies [17] However, the use of these criteria has failed toidentify treatment-responsive groups in most clinical trials Fundamental questionshave therefore been raised on the effectiveness of such criteria to define the complexrange of heterogeneity found in septic patients [18] Our data provide the first geno-mic evidence that the grouping of patients based on such criteria is too limited torepresent the full spectrum of heterogeneity in sepsis patients A more precise defi-nition of the subgroups in sepsis is needed, perhaps by using not just simple clinicalvariables (e.g., heart rate or creatine values), but also more sophisticated methodssuch as genomic studies

Host Response in Sepsis is More Complex Than Previously Thought

Investigators have delivered a huge amount of molecular information on sepsis at anunprecedented level of complexity This is well demonstrated by a seminal study byCalvano et al., in which volunteers were given endotoxin and their gene-expressionprofiles measured [19] A total of 3,714 genes were found to have their expressionintensity altered by the endotoxin challenge This is an impressively large numberbecause it represents over 14 % of the protein-coding genes When these genes werefollowed at 2, 4, 6, 9 and 24 hours, more complex changes were exhibited In addi-tion, the authors performed network analysis (see Table 1 for more details) andreported a further discovery of a vast interconnecting network of cellular activities.For example, by honing in on just one gene alone (i.e., nuclear factor kappa B), theauthors unveiled a total of 619 interactions between 150 genes With over threethousand genes showing simultaneous changes, the number of potential interactions

is immeasurable The immense complexity of these data provides an exciting tunity to develop a potentially more powerful method to classify sepsis patients intoclinically relevant and molecularly precise subgroups

oppor-There Is Strong Evidence of Heterogeneity at the Genomic Level

Patient subgroups can be identified using gene-expression studies, but first there is

a need to explore all the genomic variability within any defined population of sepsispatients To this end, we recently undertook a review of all the gene-expression stud-ies that had identified genomic markers of sepsis [14 – 16, 20 – 22] We performed apair-wise comparison of all the signature genes between each study Our analysis ofthese studies reveals two important findings (Fig 2)

I

Ramilo Tang-2

McDunn

Tang-1

Prucha

5 1

1 3

2

4

3

Tang-2 138 Ramilo 137 McDunn 85 Tang-1 Prucha 50 50

Fig 2.List of putative genes in

sepsis Total number of genes in

each data set is shown in the insert

References for included studies:

Tang-2 [14], Ramilo [20], McDunn

The second finding is that there is minimal overlapping in the lists of signaturegenes among studies The genomic markers of sepsis seem to vary from one patientpopulation to another This finding persists even after the analysis is restricted tostudies that had comparable study design, disease spectrum, or clinical settings.This finding indicates that the spectrum of heterogeneity at a transcriptional level islarge It is likely that the current studies revealed only a very small portion of thisenormous variability

Genomic Heterogeneity

To explore genomic heterogeneity further in the context of biological pathways, werecently conducted network analysis (seeTable 1for more details) using our micro-array datasets We examined all the relevant biological pathways implicated in sep-sis, including those involved in immunity and inflammatory responses We thencompared our findings to other gene-expression studies that used similar analysistechniques [19, 23, 24] These analyses addressed two important questions: 1) whatgive rise to genomic heterogeneity; 2) where are the main sources of variability?

What Gives Rise To Genomic Heterogeneity?

Our analyses suggest that the vast connectivity of the molecular signaling systemgives rise to heterogeneity Traditionally, cellular function is conceptualized as indi-vidual components working in a linear fashion to produce a series of predictablebiological effect However, network analysis data suggest a far more complex picture

It shows that cellular functions are governed by vast gene regulatory networks.While there are main hubs in these networks, there are also extensive collateral sub-

I

networks that will provide alternative routes This is akin to the airline network,where travelers can arrive at the same destination via complex re-routing or the use

of alternative airlines Consequently, there is a large amount of redundancy in itssignaling system To complicate matters further, there are conflicting feedback loopsacting on each hub For any given biological signal, multiple outcomes are possibledepending on a variety of factors, such as the temporal pattern of each feedbackloop and summation of individual stimuli Cellular function is therefore a result of

an integrative process Such a system gives rise to a huge potential for variabilityand, hence, heterogeneity

Main Sources of Genomic Variability

Given the enormity and the complexity of the data, investigators need to hone intothe main sources of the variability Our data, along with those from other studies[19, 23, 24], allow us to narrow our focus down to four gene regulatory networks(Fig 3)

Fig 3.Four gene regulatory networks (JAK, STAT, NF-κß and p38 MAPK) BCL2: B-cell CLL/lymphoma 2;CREB: cAMP responsive element binding protein; DUSP: dual specificity phosphatase; FADD: Fas-associated

receptor; IRAK: interleukin-1 receptor-associated kinase; JAK: Janus kinase; LPS: lipopolysaccharide; MAPK:

nuclear factor kappa-B; SOCS: suppressor of cytokine signaling; STAT: transducer and activator of tion protein; TLR: Toll-like receptor; TNF: tumor necrosis factor; TNFRSF1B: TNF receptor superfamily, mem-ber 1B; TRADD: TNF receptor-associated death domain protein; TRAF2: TNF receptor-associated factor-2

transcrip-I

All four networks have been implicated in the immune response to sepsis Althoughother molecular networks have also been implicated, these four networks are themost consistent findings reported by the gene-expression studies we surveyed.While each network has been extensively studied in the past, the gene-expressionstudies provide a global overview of all these networks and their individual compo-nents They reflect a growing body of data that will help researchers explain hetero-geneity However, these data represent only a glimpse of the vast genomic landscape.

We still do not fully understand the complex inter-relationship between these works and the dynamic interaction between components of each pathway More in-depth studies focusing on gene regulatory networks are therefore needed in thefuture

net-Further Questions on an Existing Sepsis Model

Our analysis of the gene-expression studies also revealed two unexpected findingswith regard to the role of the immune response First, there is a noticeable absence

of the activation of pro-inflammatory genes According to the currently acceptedmodel of sepsis, the host response is a biphasic process in which an initial hyper-inflammatory phase is followed by a later, anti-inflammatory phase that manifests asfunctional immune suppression [25] This has not been supported by data from thegene-expression studies we surveyed, where investigators rarely reported the activa-tion of well-known inflammatory genes, such as TNF, interleukin (IL)-1, IL-2, IL-6,

or IL-10 Second, the gene-expression studies suggest that immune suppression ispresent in both the early and late phases of sepsis Again, this is in contrast to theestablished model of sepsis where immune suppression is thought to occur later Infact, it is now well established that the simplistic strategy of treating early sepsis as

a pro-inflammatory phenomenon has been proven ineffective

Put together, these data suggest that the established model of sepsis is too plistic to account for the wide range of immune abnormalities observed in sepsispatients The insight that both hyper-immune and hypo-immune status can occurearly in sepsis further reinforces our notion that the pathogenesis of sepsis is muchmore complex and heterogeneous than we previously thought

sim-There are important therapeutic implications of the above findings First, sepsishas long been defined as a pro-inflammatory or hypo-inflammatory syndrome Such

a dichotomization ignores the complexity of sepsis and leads to simplistic strategiessuch as neutralizing elevated cytokines or replacing a compound when its serumlevel is low Second, septic patients have been treated as an immunologically homo-geneous group However, there are likely to be many heterogeneous immune pheno-types Giving drugs without sufficient information about the patient’s underlyingimmunological status can result in benefit in some phenotypes but harm in others.With an increased recognition of immunological heterogeneity, some authors arenow advocating that the immune status needs to be accurately assessed beforepatients are recruited into clinical trials [26] However, currently available biomarkerassays capture only a fraction of all known immune abberations in sepsis For exam-ple, serum measurements of inflammatory cytokines (e.g IL-1, IL-6, or TNF-α) arewidely used But a far greater number of molecules have been observed to be abnor-mally elevated in septic patients Functional testing of immune cells (e.g., cell prolif-eration or human-leukocyte antigen [HLA]-DR expression) has also been used, but

it measures only a few pathways and hence provides only a partial view of the

over-I

all immunological status Here, we propose that a gene-expression profiling nique is better suited to assess global immune dysfunction in sepsis.

tech-Functional Mapping of Sepsis Genome to Monitor Immune Function

Gene-expression profiling can be used to characterize the immunological status ofseptic patients on a genome-wide scale This is because there are advantages of thistechnique over conventional biomarker assays First, gene-expression profiling canhandle much larger volumes of data, often measuring thousands of genes simulta-neously This capability is unmatched by conventional assays Second, many cellulardysfunctions are often unmeasurable by normal assays, because their expression isdownregulated or their expressed proteins are below the dynamic range of detec-tion These dysfunctions can be easily detected by gene-expression profiling

We undertook gene-expression analysis of thirty-five critically ill patients (sepsis

= 25, control = 10) Circulating mononuclear cells were used because these cells play

a major role in the immune response in sepsis We then compared the sion profile of the sepsis and control patients The analysis was performed on over

gene-expres-130 biological pathways, including those known to be involved in immunologicalfunctions Some of the important findings are presented inTable 2

Table 2.Biological pathways implicated in sepsis

calcium/calmodulin-dependent kinase (CaMK)

specificity phosphatases

I

Table 2.(cont.)

of genes

p-value

in the broken heart)

macrophage

gene expression

Th1 development

activation

As expected, well known pathways such as Toll-like receptor (TLR) or TNF signalingare confirmed to be involved in sepsis However, our analysis also discovered a largenumber of pathways, many of which have not been studied previously with regard totheir involvement in sepsis This analysis demonstrates that it is feasible to assayimmunological dysfunction on a global scale and to yield highly valuable biologicalinformation regarding the roles of both established and unknown pathways Based

on the data above, we hypothesize that a comprehensive architecture of the gene ulatory network of immune response in sepsis can be constructed using gene-expression data Such a database should include transcriptional information on: 1)all functional pathways; 2) all possible interactions between genes and molecules; 3)how the system functions as a whole in response to perturbations (e.g., to trauma,ischemia, or infectious stimuli); 4) mathematical modeling which will help investiga-tors predict the existence of hidden interactions or feedback loops

reg-I

Based on the review above, we would argue for a greater appreciation of the plexity of the immune status in sepsis Current models of sepsis are limited in theirability to account for the huge range of heterogeneity in sepsis patients New datashow that immunological dysfunction gives rise to much of the observed variability

com-We, therefore, propose that functional mapping of immunological aberrations bygene-expression studies holds the key to the understanding, measuring, and moni-toring of heterogeneity in sepsis patients Such a database will allow future research-ers to better understand the variability of drug response In the long term, it willhelp clinicians design drug treatment based on individual variability; this is the ulti-mate goal of individualized medicine

7 Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C (2004) Meta-analysis: The effect of steroids on survival and shock during sepsis depends on the dose Ann Intern Med 141: 47 – 56

8 Macias W, Vallet B, Bernard GR, et al (2004) Sources of variability on the estimate of ment effect in the PROWESS trial: implications for the design and conduct of future studies

treat-in severe sepsis Crit Care Med 32: 2385 – 2391

9 Dear J, Yasuda H, Hu X, et al (2006) Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis Kidney Int 69: 832 – 836

10 Annane D, Bellissant E, Cavaillon J (2005) Septic shock Lancet 365: 63 – 78

11 Marshall J (2003) Such stuff as dreams are made on: mediator-directed therapy in sepsis Nat Rev Drug Discov 2: 391 – 405

12 Holmes CL, Russell JA, Walley KR (2003) Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy Chest 124: 1103 – 1115

13 Nguyen A, Yaffe M (2003) Proteomics and systems biology approaches to signal transduction

in sepsis Crit Care Med 31: S1-S6

14 Tang B, McLean A, Dawes I, Huang S, Lin R (2008) Gene-expression profiling of peripheral blood mononuclear cells in sepsis Crit Care Med (in press)

15 Tang B, McLean A, Dawes I, Huang S, Lin R (2007) The use of gene-expression profiling to identify candidate genes in human sepsis Am J Respir Crit Care Med 176: 676 – 684

16 Tang B, McLean A, Dawes I, Huang S, Cowley M, Lin R (2008) Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients Crit Care Med 36:

I

19 Calvano SE, Xiao W, Richards DR, et al (2005) A network-based analysis of systemic mation in humans Nature 437: 1032 – 1037

inflam-20 Ramilo O, Allman W, Chung W, et al (2007) Gene expression patterns in blood leukocytes discriminate patients with acute infections Blood 109: 2066 – 2077

21 McDunn J, Husain K, Polpitiya A, et al (2008) Plasticity of the systemic inflammatory response to actue infection during critical illness: development of the riboleukogram Plo- sOne 3: e1564

22 Prucha M, Ruryk A, Boriss H, Moller E, Zazula R, Russwurm S (2004) Expression profiling: toward an application in sepsis diagnostics Shock 22: 29 – 33

23 Shanley TP, Cvijanovich N, Lin R, et al (2007) Genome-level longitudinal expression of naling pathways and gene networks in pediatric septic shock Mol Med 13: 495 – 508

sig-24 Johnson S, Lissauer M, Bochicchio G, Moore R, Cross A, Scalea T (2007) Gene expression profiles differentiate between sterile SIRS and early sepsis Ann Surg 245: 611 – 621

25 Hotchkiss R, Karl I (2003) The pathophysiology and treatment of sepsis N Engl J Med 348:

138 – 150

26 Monneret G, Venet F, Pachot A, Lepape A (2008) Monitoring immune dysfunction in the tic patient: a new skin for the old ceremony Mol Med 14: 64 – 78

sep-I