INTENSIVECARE

MEDICINE

EImEANNUALUPDATE

JEAN-LOUIS VINCENT

INTENSIVECARE

MEDICINE

ANNUALUPDATE

2008

Editor

Jean-Louis VincentMD, PhD, FCCM, FCCP

Head, Department of Intensive CareErasme Hospital, Universite libre de Bruxelles

Brussels, Belgium

With 238 Figures and 90 Tables

~ Springer

JEAN-LoUIS VINCENT, MD, PHD, FCCM, FCCPHead, Department of Intensive CareErasme HospitalUniversite libre de BruxellesRoute de Lennik 8081070 BrusselsBelgium

ISBN978-0-387-77382-7

© 2008 Springer Science + Business Media Inc.

Printed on acid-free paper.

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Table of Contents

I Genetic Factors

Are Pharmacogenetics and Pharmacogenomics Important for CriticallyIII Patients?

C. KIRWAN, I. MACPHEE, and B. PHILIPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Genetic Susceptibility in ALI/ARDS: What have we Learned?R. CARTIN-CEBA, M.N. GONG, and O. GAJIC 13

Racial Disparities in Infection and Sepsis: Does Biology Matter?EB. MAYR, S. YENDE, and D.C. ANGUS 24

II Cardiac Issues

B-type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical CareP.E. OISHI, J.-H. Hsu, and J.R. FINEMAN 33

Cardiac Dysfunction in Septic ShockI. CINEL, R. NANDA, and R.P. DELLINGER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

The Consequences of Cardiac Autonomic Dysfunction in Multiple OrganDysfunction Syndrome

H. SCHMIDT, U. MULLER-WERDAN, and K. WERDAN 55

Quantification of Improved Left Ventricular Performance during CardiacResynchronization Therapy

B. LAMIA and M.R. PINSKY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Diastolic Dysfunction and Cardiac Failure in the Intensive Care UnitJ. POELAERT, E. OSIPOWSKA, and C. VERBORGH 76

Pharmacological Support of the Failing Right VentricleP.E WOUTERS, S. REX, and C. MISSANT 88

Perioperative CardioprotectionH.-J. PRIEBE 101

III Cardiopulmonary Resuscitation

Improving the Quality of Cardiac Arrest Resuscitation CareC]. DINE and B.S. ABELLA 113

Pediatric Cardiopulmonary Arrest and ResuscitationA. TOPJIAN, R.A. BERG, and V.M. NADKARNI 121

v

VI Table of Contents

Early Cooling in Cardiac Arrest: What is the Evidence?1. HAMMER, C. ADRIE, and J.-E TIMSIT 137

IV Emergencies

Management of Severe Accidental HypothermiaG.J. PEEK, P.R. DAVIS, and J.A. ELLERTON 147

Initial ICU Management of Skin Sloughing Diseases: Toxic Epidermal Necrolysisand Stevens-Johnson Syndrome

T.L. PALMIERI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 160

V Poisonings

Pathophysiology of Caustic IngestionM. OSMAN and D.N. GRANGER 171

Extracorporeal Life-Support for Acute Drug-induced Cardiac ToxicityB. MEGARBANE, N. DEYE, and EJ. BAUD 179

VI Acute Respiratory Failure

Epidemiology of Acute Respiratory Failure and Mechanical VentilationH.S. SURI, G. LI, and O. GAJIC 193

Esophagectomy and Acute Lung InjuryD.P. PARK, D. GOUREVITCH, and G.D. PERKINS 203

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe?P. PELOSI and P.R.M. Rocco 214

Regional Lung Function in Critically III Neonates: A New Perspective forElectrical Impedance Tomography

I. FRERICHS, J. SCHOLZ, and N. WEILER 224

Extracorporeal Lung Assist for Acute Respiratory Distress Syndrome:Past, Present and Future

R. Konr, U. STEINSEIFER, and R. ROSSAINT 235

VII Ventilatory Support

Protective Mechanical Ventilation: Lessons Learned from Alveolar MechanicsS. ALBERT, B. KUBIAK, and G. NIEMAN 245

Mechanical Ventilation for Acute Asthma ExacerbationsD. DE MENDOZA, M. LUJAN, and J. RELLO 256

Hypercapnia: Permissive, Therapeutic or Not at All?P. HASSETT, M. CONTRERAS, and J.G. LAFFEY 269

The Cardiopulmonary Effects of HypercapniaT. MANCA, L.c. WELCH, and J.1. SZNAJDER 282

High Frequency Oscillation for Acute Respiratory Failure in AdultsS.D. MENTZELOPOULOS, C. Roussos, and S.G. ZAKYNTHINOS 290

310

434

Table of Contents VII

Airway Pressure Release Ventilation : Promises and Potentials for ConcernJ. GUTIERREZ MEJIA, E. FAN, and N.D. FERGUSON 301

Post-operative Non-invasive VentilationS. JABER, G. CHANQUES, and B. JUNG

VIII Tracheostomy

Choice of Tracheostomy Tube: Does One Size Fit All?J. ORAM and A. BODENHAM 323

What's New in Percutaneous Dilational Tracheostomy?T.A. TRESCHAN, B. PANNEN, and M. BEIDERLINDEN 331

IX Infections

Novel Therapies in the Prevention of Ventilator-associated PneumoniaP.J. YOUNG and M.C. BLUNT 343

Management of Ventilator-associated PneumoniaM. FERRER, M. VALENCIA, and A. TORRES 353

Flucytosine Combined with Amphotericin B for Fungal InfectionsP.H.J. VAN DER VOORT 365

X Cellular Mechanisms in Sepsis

Apoptosis in Critical Illness: A Primer for the IntensivistZ. MALAM, J.C. MARSHALL 375

Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis:A Putative Role for Hypoxia Inducible Factor

T. REGUEIRA, S.M. JAKOB, and S. DJAFARZADEH 385

Gram-positive and Gram-negative Sepsis: Two Disease Entities?S. LEAVER, A. BURKE GAFFNEY, and T.W. EVANS 395

Methicillin-resistant Staphylococcus aureus-induced Sepsis: Role of Nitric OxideP. ENKHBAATAR, 1. TRABER, and D. TRABER 404

XI Sepsis Therapies

The Cardiovascular Management of SepsisB.C. CREAGH-BROWN, J. BALL, and M. HAMILTON 413

Terlipressin in Septic Shock: When and How Much?C. ERTMER, A. MORELLI, and M. WESTPHAL 423

Blood Purification Techniques in Sepsis and SIRSP.M. HONORE, O. JOANNES-BoYAU, and B. GRESSENS

Glutathione in Sepsis and Multiple Organ FailureU. FLARING and J. WERNERMAN 444

Selenocompounds and Selenium: A Biochemical Approach to SepsisX. FORCEVILLE and P. VAN ANTWERPEN 454

536

VIII Table of Contents

XII Metabolic Alterations

The Role of Hypoxia and Inflammation in the Expression and Regulationof Proteins Regulating Iron Metabolism

S. BRANDT, J. TAKALA, and P.M. LEPPER 473

Hyperammonemia in the Adult Critical Care SettingK. DAMS, W. MEERSSEMAN, and A. WILMER 481

Magnesium in the ICU: Sine qua nonF. ESEN and L. TELCI 491

Strict Glycemic Control: Not If and When, but Who and How?M.J. DE GRAAFF, P.E. SPRONK, and M.J. SCHULTZ 502

Cortisol Metabolism in Inflammation and SepsisB. VENKATESH and J. COHEN 514

XIII Fluid Management

Assessment of Perioperative Fluid BalanceM.T. GANTER and C.K. HOFER 523

Fluid Resuscitation and Intra-abdominal HypertensionI.E. DE LAET, J.J. DE WAELE, and M.L.N.G. MALBRAIN

XIV Acute Kidney Injury

Six Truths about Acute Kidney Injury that the Intensivist should be Aware ofE.A.J. HOSTE 551

Role of Poly(ADP-Ribose) Polymerase in Acute Kidney InjuryR. VASCHETTO, F.B. PLOTZ, and A.B.J. GROENEVELD 559

From Hemodynamics to Proteomics : Unraveling the Complexity of Acute KidneyInjury in Sepsis

M. MATEJOVIC, P. RADERMACHER, and V. THONGBOONKERD 568

XV Hemodynamic Assessment and Management

Towards Optimal Central Venous Catheter Tip PositionW. SCHUMMER, Y. SAKR, and C. SCHUMMER 581

From Arterial Pressure to Cardiac OutputM. CECCONI, A. RHODES, and G. DELLA Roccx 591

Hemodynamic Monitoring: Requirements of Less Invasive Intensive Care -Quality And Safety

A. VIEILLARD-BARON 602

Minimally Invasive Cardiac Output Monitoring: Toy or Tool?G. MARX and T. SCHUERHOLZ 607

Bioreactance: A New Method for Non-invasive Cardiac Output Monitor ingP. SQUARA 619

Goal-directed Hemodynamic Therapy for Surgical PatientsP. MORGAN and A. RHODES 631

785

Table of Contents IX

XVI Tissue Oxygenation

Use of Mixed Venous Oxygen Saturation in ICU PatientsM. LEONE, V. BLASCO, and C. MARTIN 641

Early Optimization of Oxygen Delivery in High-risk Surgery PatientsS.M. LOBO, E. REZENDE, and F. SUPARREGUI DIAS , 654

The Influence of Packed Red Blood Cell Transfusion on Tissue OxygenationS. SUTTNER and J. BOLDT 665

Recent Advancements in Microcirculatory Image Acquisition and AnalysisR. BEZEMER, M. KHALILZADA, and C. INCE 677

The Beneficial Effects of Increasing Blood ViscosityB.Y. SALAZAR VAZQUEZ, P. CABRALES, and M. INTAGLIETTA 691

XVII Anticoagulants in Organ Failure

Protein C and Antithrombin Levels in Surgical and Septic PatientsY. SAKR, N.C.M. YOUSSEF, and K. REINHART 703

Thrombophilia as a Risk Factor for Outcome in SepsisJ.-J. HOFSTRA, M. SCHOUTEN, and M. LEVI 713

The Effects of Activated Protein C on the Septic EndotheliumS.E. ORFANOS, N.A. MANIATIS, and A. KOTANIDOU 721

Improvement in Hemodynamics by Activated Protein C in Septic ShockX. MONNET, H. KSOURI, and J.-L. TEBOUL 730

XVIII Acute Bleeding

Gastrointestinal Hemorrhage on the Intensive Care UnitS.J. THOMSON, M.L. COWAN, and T.M. RAHMAN 739

Recombinant Activated Factor VII: The Delicate Balance between Efficacyand Safety

S. BELISLE, J.-F. HARDY, and P. VAN DER LINDEN 751

XIX Hepatic Disease

ICU Management of the Liver Transplant PatientG. DELLA ROCCA, M.G. COSTA, and P. CHIARANDINI 763

Liver Support with Fractionated Plasma Separation and Adsorption andPrometheusw

K. RIFAI, C. TETTA, and C. RONCO 777

Artificial Liver Support: Current StatusF. SALIBA, P. ICHAI, and D. SAMUEL

XX Neurological Crises

Encephalopathy in SepsisA. POLITO, S. SIAMI, and T. SHARSHAR 801

X Table of Contents

Multimodality Monitoring in Patients with Elevated Intracranial PressureD.B. SEDER, J.M. SCHMIDT, and S. MAYER 811

Managing Critically III Patients with Status EpilepticusS. LEG RIEL, J.P. BEDos, and E. AZOULAY 822

XXI Analgesia and Sedation

Sedation with Inhaled Anesthetics in Intensive CareEJ. BELDA, M. SORO, and A. MEISER " 839

Sedation or Analgo-sedation in the ICU: A Multimodality ApproachE MEURANT, A. BODART, and J.P. KOCH 850

XXII Outcomes

Time to Use Computerized Physician Order Entry in all ICUsJ. ALI and A. VUYLSTEKE 865

Quality of Life in Locked-in Syndrome SurvivorsM.-A. BRUNO, E PELLAS, and S. LAUREYS 881

Post-traumatic Stress Disorder in Intensive Care Unit SurvivorsJ. GRIFFITHS, A.M. HULL, and B.H. CUTHBERTSON 891

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907

List of Contributors

ABELLA BSDepartment of Emergency MedicineUniversity of Pennsylvania3400 Spruce Street, Ground RavdinPhiladelphia, PA 19104USA

ADRIE CDepartment of Intensive CareDelafontaine HospitalRue Dr P Delafontaine 293205 Saint DenisFrance

ALBERT SDepartment of SurgerySuny Upstate Medical University750 East Adams StreetSyracuse, NY 13210USA

ALI JDepartment of Anesthesiaand Critical CarePapworth HospitalCambridge, CB23 3REUnited Kingdom

AL-SUBAIE NGeneral Intensive Care UnitSt. James' WingSt. George 's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

ANGUS DCCRISMADepartment of Critical Care MedicineUniversity of Pittsburgh School ofMedicine605 Scaife Hall3550 Terrace StreetPittsburgh, PA 15261USA

AZOULAY EDepartment of Intensive CareHopital Saint-Louis 1Avenue Claude Vellefaux75010 ParisFrance

BALL JGeneral Intensive Care UnitSt George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

BAUD FJMedical Intensive Care and ToxicologyHopital Lariboisiere2, Rue Ambroise Pare75010 ParisFrance

BEDOSJPDepartment of Intensive Care MedicineH6pital Andre Mignot177 rue de Versailles78150 Le ChesnayFran ce

XI

XII List of Contributors

BEIDERLINDEN M

Department of AnesthesiologyUniversity HospitalMoorenstr. 540225 DusseldorfGermany

BELDA FJDepartment of Anesthesiaand Critical CareHospital Clinico UniversitarioBlasco Ibanez 1746010 ValenciaSpain

BELISLE SDepartment of AnesthesiologyInstitut de Cardiologie5000 Rue Belanger EstMontreal, QB HIT lC8Canada

BERG RA

Department of PediatricsUniversity of Arizona Schoolof Medicine1501 N Campbell Avenue,Tucson, AZ 85724USA

BEZEMER R

Department of PhysiologyAcademic Medical CenterUniversity of AmsterdamMeibergdreef 91105 AZ AmsterdamNetherlands

BLASCO VDepartment of Anesthesiaand Intensive CareHopital NordChemin des Bourrely13915 MarseilleFrance

BLUNT MC

Department of Critical CareQueen Elizabeth HospitalGayton RoadKing's Lynn,Norfolk, PE30 4ETUnited Kingdom

BODART A

Intensive Care UnitKirchberg HospitalRue E.Steighen, 92540 LuxemburgLuxembourg

BODENHAM A

Department of Anesthesia andIntensive CareLeeds General InfirmaryGt. George StLeeds, LSI 3EXUnited Kingdom

BOLDT JDepartment of Anesthesiologyand Intensive Care MedicineKlinikum der Stadt LudwigshafenBremserstr. 7967063 LudwigshafenGermany

BRANDT SDepartment of AnesthesiologyUniversity HospitalInselspital3010 BernSwitzerland

BRUNO MA

Coma Science GroupCyclotron Research Centre andNeurology DepartmentUniversity of Liege - Sart Tilman (B30)4000 LiegeBelgium

BURKE GAFFNEY A

Department of Critical CareRoyal Brompton HospitalSydney StreetLondon, SW3 6NPUnited Kingdom

CABRALES PLa Jolla Bioengineering Institute505 Coast Boulevard South Suite # 405La Jolla, CA 92037USA

CARTIN-CEBA RDepartment of Internal MedicineDivision of Pulmonary and CriticalCare MedicineMayo Clinic200 First Street SWRochester, MN 55905USA

CECCONI MDepartment of Anesthesia andIntensive Care MedicineUniversity HospitalPIe S.M. Misericordia 1533100 UdineItaly

CHANQUES GDepartment of Anesthesia and CriticalCareSaint Eloi University Hospital80 avenue Augustin Fliche34295 MontpellierFrance

CHiARANDlNI PDepartment of Anesthesia andIntensive Care MedicineAzienda Ospedaliero Universitaria S.M.della MisericordiaPIe S.M. Misericordia 1531100 UdineItaly

CINEL IDivision of Critical CareCooper University HospitalOne Cooper PlazaDorrance Building, Suite 393Camden, NJ 08103USA

COHEN JDepartment of Intensive CareRoyal Brisbane & Ipswich HospitalsUniversity of QueenslandQueensland 4029Australia

list of Contributors XIII

CONTRERAS MDepartment of AnesthesiaClinical Sciences InstituteNational University of IrelandGalwayIreland

COSTA MGDepartment of Anesthesia andIntensive Care MedicineAzienda Ospedaliero Universitaria S.M.della MisericordiaP.le S.M. Misericordia 1531100 UdineItaly

COWAN MLDepartment of GastroenterologySt George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

CREAGH-BROWN BC

General Intensive Care UnitSt George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

CUTHBERTSON BHHealth Services Research UnitHealth Sciences BuildingUniversity of AberdeenAberdeenUnited Kingdom

DAMS KMedical Intensive Care UnitUniversity HospitalHerestraat 493000 LeuvenBelgium

DAVIS PRDepartment of Emergency MedicineDefense Medical ServicesSouthern General HospitalGlasgow, G51 4TFUnited Kingdom

XIV List of Contributors

DE GRAAFF MJDepartment of Intensive CareAcademic Medical CenterMeibergdreef 91105 AZ AmsterdamNetherlands

DE LAET IEDepartment of Intensive CareZNA StuivenbergLange Beeldekensstraat 2672060 AntwerpBelgium

DELLA ROCCA G

Department of Anesthesia andIntensive Care MedicineAzienda Ospedaliero Universitaria S.M.della MisericordiaPIe S.M. Misericordia 1531100 UdineItaly

DELLINGER RP

Division of Critical CareCooper University HospitalOne Cooper PlazaDorrance Building, Suite 393Camden, NJ 08103USA

DE MENDOZA D

Critical Care DepartmentJoan XXIII University HospitalCarrer Mallafre Guasch 443007 TarragonaSpain

DE WAELE JJDepartment of Intensive CareUniversity HospitalDe Pintelaan 1859000 GhentBelgium

DEYE NMedical Intensive Care and ToxicologyHopital Lariboisiere2, Rue Ambroise Pare75010 ParisFrance

DINE CJDivision of Pulmonary, Allergy andCritical CareUniversity of Pennsylvania3400 Spruce Street, Ground RavdinPhiladelphia, PA 19104USA

DJAFARZADEH SDepartment of Intensive CareUniversity HospitalInselspital3010 BernSwitzerland

ELLERTON JABirbeck Medical GroupBridge LanePenrithCumbria CAll 8HWUnited Kingdom

ENKHBAATAR P

Department of AnesthesiologyUniversity of Texas Medical Branch610 Texas AveGalveston, TX 77555USA

ERTMER CDepartment of Anesthesiology andIntensive CareUniversity HospitalAlbert-Schweitzer-Str, 3348149 MuensterGermany

ESEN FDepartment of Anesthesiology andIntensive CareMedical Faculty of IstanbulUniversity of IstanbulCapa Klinikleri34093 IstanbulTurkey

EVANS TW

Department of Critical CareRoyal Brompton HospitalSydney StreetLondon, SW3 6NPUnited Kingdom

FAN EDepartment of Pulmonaryand Critical Care MedicineJohns Hopkins University1830 East Monument StreetBaltimore, MD 21205USA

FERGUSON ND

Department of Critical CareToronto Western Hospital399 Bathurst Street, F2-150Toronto, ON, M5T 2S8Canada

FERRERM

Pulmonology ServiceInstitut Clinic del ToraxHospital ClinicVillarroel 17008036 BarcelonaSpain

FINEMAN JRCardiovascular Research InstituteUniversity of California San Francisco513 Parnassus AvenueSan Francisco, CA 94143USA

FLARING UDepartment of Anesthesia andIntensi ve CareAstrid Lindgren's Children HospitalKarolinska University HospitalHuddinge14186 StockholmSweden

FORCEVILLE XDepartment of Intensive CareCentre Hospitalier de MeauxHopital Saint Faron6-8 Rue Saint Fiacre77104 MeauxFrance

List of Contributors XV

FRERICHS IDepartment of Anesthesiology andIntensive Care MedicineUniversity Medical Centerof Schleswig-HolsteinSchwanenweg 2124105 KielGermany

GAJIC aDepartment of Internal MedicineDivision of Pulmonary and CriticalCare MedicineMayo Clinic200 First Street SWRochester, MN 55905USA

GANTER MT

Institute of AnesthesiologyUniversity HospitalRaemistr. 1008091 ZurichSwitzerland

GONG MN

Department of Pulmonary, CriticalCare, and Sleep MedicineDepartment of MedicineMount Sinai Hospital1190 Fifth AvenueNew York, NY 10029USA

GOUREVITCH D

Department of SurgeryUniversity HospitalBirmingham NHS Foundation TrustBirmingham, B15 2TTUnited Kingdom

GRANGER DN

Department of Molecular and CellularPhysiologyLouisiana State University HealthSciences Center1501 Kings HighwayShreveport, LA 71103-3932USA

XVI List of Contributors

GRESSENS BDepartment of Intensive CareSt-Pierre Para-Universitary HospitalAvenue Reine Fabiola 91340 Ottignies-Louvain-La-NeuveBelgium

GRIFFITHS JNuffield Department of AnestheticsJohn Radcliffe HospitalHeadley WayOxford OX3 9DUUnited Kingdom

GROENEVELD ABJDepartment of Intensive CareVrije Universiteit Medical CentreDe Boelelaan 11171081 HV AmsterdamNetherlands

GUTIERREZ MEJIA JDepartment of Critical CareToronto Western Hospital399 Bathurst Street, F2-150Toronto, ON, M5T 258Canada

HAMILTON MGeneral Intensive Care UnitSt George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

HAMMER LDepartment of Intensive CareGrenoble University HospitalBP 21738043 GrenobleFrance

HARDY JFDepartment of AnesthesiologyInstitut de Cardiologie5000 Rue Belanger EstMontreal, QB HIT lC8Canada

HASSETT PDepartment of AnesthesiaClinical Sciences InstituteNational University of IrelandGalwayIreland

HOFER CKInstitute of Anesthesiology andIntensive Care MedicineTriemli City HospitalBirmensdorferstr. 4978063 ZurichSwitzerland

HOFSTRA IIDepartment of MedicineAcademic Medical CenterMeibergdreef 91105 AZ AmsterdamNetherlands

HONORE PMDepartment of Intensive CareSt-Pierre Para-Universitary HospitalAvenue Reine Fabiola 91340 Ottignies-Louvain-La-NeuveBelgium

HOSTE EAJSurgical Intensive Care Unit , 2k12-CGhent University HospitalDe Pintelaan 1859000 GentBelgium

Hsu JHDepartment of PediatricsKaohsiung Medical University HospitalNo. 100, Tzyou 1st Road Kaohsiung 807Taiwan

HULL AMConsultant PsychiatristMurray Royal HospitalPerth, PH2 7BHUnited Kingdom

ICHAi' PDepartment of Hepatobiliary SurgeryHopital Paul Brousse12, Av. P.V. Couturier94800 VillejuifFrance

INCE CDepartment of PhysiologyAcademic Medical CenterUniversity of AmsterdamMeibergdreef 91105 AZ AmsterdamNetherlands

INTAGLIETTA MUCSD-Bioengineering9500 Gilman Dr.La Jolla, CA 92093-0412USA

JABER SAnesthesia and Critical CareDepartmentSaint Eloi University Hospital80 avenue Augustin Fliche34295 MontpellierFrance

JAKOB SMDepartment of Intensive CareUniversity HospitalInselspital3010 BernSwitzerland

JOANNES-BoYAU 0Department of Intensive CareHaut Leveque University HospitalUniversity of Bordeaux IIAvenue de Magellan33604 PessacFrance

JUNG B

Department of Anesthesiaand Critical CareSaint Eloi University Hospital80 avenue Augustin Fliche34295 MontpellierFrance

KHALILZADA MDepartment of PhysiologyAcademic Medical CenterUniversity of AmsterdamMeibergdreef 91105 AZ AmsterdamNetherlands

List of Contributors XVII

KIRWAN CDepartment of Intensive CareSt George 's University of LondonRm 30, Jenner WingCranmer TerraceLondon, SW17 OREUnited Kingdom

KOCH JP

Intensive Care UnitKirchberg HospitalRue E. Steighen, 92540 LuxemburgLuxemburg

Kozr RSurgical Intensive Care MedicineUniversity HospitalPauwelsstr. 3052074 AachenGermany

KOTANIDOU A1st Department of Critical CareUniversity of Athens Medical SchoolEvangelismos General Hospital45-47 Ipsilandou St10675 AthensGreece

KSOURI HDepartment of Intensive CareCentre Hospitalier Universitaire deBicetre78, rue du General Leclerc94270 Le Krernlin-BicetreFrance

KUBIAK B

Department of SurgerySuny Upstate Medical University750 East Adams StreetSyracuse, NY 13210USA

LAFFEY JG

Department of AnesthesiaClinical Sciences InstituteNational University of IrelandGalwayIreland

XVIII List of Contributors

LAMIA BDepartment of Critical Care MedicineUniversity of Pittsburgh Medical Center606 Scaife Hall3550 Terrace StreetPittsburgh, PA 15261USA

LAUREYS SComa Science GroupCyclotron Research Centre andNeurology DepartmentUniversity of Liege .:-Sart Tilman (B30)4000 LiegeBelgium

LEAVER SDepartment of Critical CareRoyal Brompton HospitalSydney StreetLondon, SW3 6NPUnited Kingdom

LEG RIEL SDepartment of Intensive CareHopital Saint-Louis 1Avenue Claude Vellefaux75010 ParisFrance

LEONE MDepartment of Anesthesiology andIntensive Care MedicineHopital NordChemin des Bourrely13915 MarseilleFrance

LEPPER PMDepartment of Intensive CareUniversity HospitalInselspital3010 BernSwitzerland

LEVI MDepartment of MedicineAcademic Medical CenterMeibergdreef 91105 AZ AmsterdamNetherlands

LI GPulmonary DepartmentGuang An Mem HospitalBeijingChina

LOBO SMDivision of Critical Care MedicineDepartment of Internal MedicineMedical School-FUNFARME andHospital de BaseRua Antonio de Godoy 3548Centro Sao Jose do Rio Preto - SP -15015-100Brazil

LUJAN MDepartment of PneumologyCorporacio Sanitaria Pare TauliPare Pauli sin08208 SabadellSpain

MACPHEE IDepartment of Intensive CareSt George's University of LondonRm 30, Jenner WingCranmer TerraceLondon, SW17 OREUnited Kingdom

MALAM ZDivision of Critical CareRoom 4-007, Bond WingSt. Michael's Hospital30 Bond StreetToronto, ON M5W 1B8Canada

MALBRAIN MLNGDepartment of Intensive CareZNA StuivenbergLange Beeldekensstraat 2672060 AntwerpBelgium

MANCA TPulmonary and Critical Care MedicineFeinberg School of Medicine,Northwesten University240 E. Huron, McGaw Pavilion M-300Chicago, IL 60611USA

MANIATIS NAM. Simou LaboratoryUniversity of Athens Medical SchoolEvangelismos General Hospital3 Ploutarchou St10675 AthensGreece

MARSHALL JCDivision of Critical CareRoom 4-007, Bond WingSt. Michael's Hospital30 Bond StreetToronto, ON M5W IB8Canada

MARTIN CDepartment of Anesthesiologyand Intensive CareHopital NordChemin des Bourrely13915 MarseilleFrance

MARX

XX List of Contributors

MONNET XDepartment of Intensive CareCentre Hospitalier Universitaire deBicetre78, rue du General Leclerc94270 Le Krernlin-BicetreFrance

MORELLI ADepartment of Anesthesiologyand Intensive CareUniversity of Rome "La Sapienza"Via Barnaba Oriani 200197 RomeItaly

MORGAN P

General Intensive Care UnitSt. James' WingSt. George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

MULLER-WERDAN UDepartment of Medicine IIIMartin-Luther-UniversityHalle- WittenbergKlinikum KrollwitzErnst-Grube-Str. 40060097 Halle/SaaleGermany

NADKARNI VM

Department of Anesthesia and CriticalCare MedicineThe Children's Hospital of Philadelphia34th Street and Civic Center BoulevardPhiladelphia, PA 19104USA

NANDA RDivision of Critical CareCooper University HospitalOne Cooper PlazaDorrance Building, Suite 393Camden, NJ 08103USA

NIEMAN GDepartment of SurgerySuny Upstate Medical University750 East Adams StreetSyracuse, NY 13210USA

OISHI PE

Pediatric Critical CareUniversity of California513 Parnassus Avenue, Box 0106San Francisco, CA 94143USA

ORAM JDepartment of Anesthesia andIntensive CareLeeds General InfirmaryGt. George StLeeds, LSI 3EXUnited Kingdom

ORFANOS SE

2nd Department of Critical CareMedicineAttikon HospitalI, Rimini St.12462 HaidariGreece

OSIPOWSKA E

Department of AnesthesiologyUniversity Hospital of BrusselsLaarbeeklaan 1011090 BrusselsBelgium

OSMAN M

Department of Pediatric SurgeryAin Shams University Schoolof MedicineAbbasya SquareCairoEgypt

PALMIERI TLDept of SurgeryUC Davis Regional Burn Centerand Shriners Hospital for Children2425 Stockton Blvd., Suite 718Sacramento, CA 95817USA

PANNEN BDepartment of AnesthesiologyUniversity HospitalMoorenstr. 540225 DusseldorfGermany

PARK DPBirmingham Heartlands HospitalBordesley Green EastBirmingham, B9 5SSUnited Kingdom

PEEK GJCardiothoracic SurgeryGlenfield HospitalGroby RoadLeicester LE3 9QPUnited Kingdom

PELLAS FNeurorehabilitation Medicin eHopital CaremeauCHU30029 NimesFrance

PELOSI PDepartment of AnesthesiologyOspedlae di Circolo e FondazioneMacchiViale Borri 5721100 VareseItaly

PERKINS GDWarwick Medical SchoolUniversity of WarwickCoventry, CV4 7ALUnited Kingdom

PHILIPS BDepartment of Intensive CareSt George's University of LondonRm 30, Jenner WingCranmer TerraceLondon, SW17 OREUnited Kingdom

List of Contributors XXI

PINSKY MRDepartment of Critical Care MedicineUniversity of Pittsburgh Medical Center606 Scaife Hall3550 Terrace StreetPittsburgh, PA 15261USA

PLOTZ FBDepartment of Pediatric Intensive CareVrije Universiteit Medical CentreDe Boelelaan 11171081 HV AmsterdamNetherlands

POELAERT JDepartment of AnesthesiologyUniversity Hospital of BrusselsLaarbeeklaan 1011090 BrusselsBelgium

POLITO ARespiratory Muscle LaboratoryHopital Raymond PoincareBoulevard Raymont Poincare 10492380 GarchesFrance

PRIEBE HJDepartment of AnesthesiologyUniversity HospitalHugstetter Str. 5579106 FreiburgGermany

RADERMACHER PDept of AnesthesiaUniversity HospitalParkstrasse89073 UlmGermany

RAHMAN TMDepartment of GastroenterologySt George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

XXII List of Contributors

REGUEIRA TDepartment of Intensive Care MedicineUniversity HospitalInselspital3010 BernSwitzerland

REINHART KDept of Anesthesiology and IntensiveCareFriedrich-Schiller UniversityErlanger Allee 10307743 lenaGermany

RELLO JCritical Care DepartmentJoan XXIII University HospitalCarrer Mallafre Guasch 443007 TarragonaSpain

REX SDepartment of AnesthesiologyUniversity Hospital of the RWTHPauwelsstrasse 3052074 AachenGermany

REZENDE EIntensive Care DepartmentHospital do Servidor Publico EstadualRua Pedro de Toledo 1800Sao Paulo 040039901Brazil

RHODES AGeneral Intensive Care UnitSt. James' WingSt. George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

RIFAI KDepartment of Gastroenterology,Hepatology, and EndocrinologyMedical SchoolCarl Neuberg Strasse 130625 HannoverGermany

Rocco PRMLaboratory of Pulmonary InvestigationCarlos Chagas Filho BiophysicsInstituteFederal UniversityRio de JaneiroBrazil

RONCO CDepartment of Nephrology, Dialysisand Renal TransplantationSan Bortolo HospitalViale Rodolfi 3736100 VicenzaItaly

ROSSAINT R

Surgical Intensive Care MedicineUniversity HospitalPauwelsstr. 3052074 AachenGermany

Roussos CIntensive Care MedicineEvangelismos Hospital45-47 Ipsilandou Street10675 AthensGreece

SAKR YDept of Anesthesiology and Intens iveCareFriedrich-Schiller UniversityErlanger Allee 10307743 lenaGermany

SALAZAR VA.ZQUEZ BYUCSD-Bioengineering9500 Gilman Dr.La Jolla, CA 92093-0412USA

SALIBA FDepartment of Hepatobiliary SurgeryHopital Paul Brousse12, Av. P.v. Couturier94800 VillejuifFrance

SAMUEL DDepartment of Hepatobiliary SurgeryHopital Paul Brousse12, Av. P.V. Couturier94800 VillejuifFrance

SCHMIDT HDepartment of Medicine IIIMartin-Luther-UniversityHalle-WittenbergKlinikum KrollwitzErnst-Grube-Str. 40060097 Halle/SaaleGermany

SCHMIDT JMNeurological Intensive Care UnitNeurological InstituteColumbia University Medical Center710 West 168th StreetBox 39New York, NY 10032USA

SCHOLZ JDepartment of Anesthesiologyand Intensive Care MedicineUniversit y Medical Centerof Schleswig-HolsteinSchwanenweg 2124105 KielGermany

SCHOUTEN MDepartment of MedicineAcademic Medical CenterMeibergdreef 91105 AZ AmsterdamNetherlands

SCHUERHO LZ TDepartment of Anesthesiaand Intensive Care MedicineFriedrich Schiller UniversityErlanger Allee 10107747 lenaGermany

List of Contributors XXIII

SCHU LTZ MJDepartment of Intensive CareAcademic Medical CenterMeibergdreef 91105 AZ AmsterdamNetherlands

SCHUMMER CDept of Anesthesiologyand Intensive CareFriedrich-Schiller UniversityErlanger Allee 10107747 lenaGermany

SCHUMMER WDept of Anesthesiologyand Intensive CareFriedrich-Schiller UniversityErlanger Allee 10107747 lenaGermany

SEDER DBNeurological Intensive Care UnitDepartments of NeurologyNeurological InstituteColumbia University Medical Center710 West 168th Street, Box 39New York, NY 10032USA

SHARSHAR TRespiratory Muscle LaboratoryHopital Raymond PoincareBoulevard Raymont Poincare 10492380 GarchesFrance

SIAM I S

Respiratory Muscle LaboratoryHopital Raymond PoincareBoulevard Raymont Poincare 10492380 GarchesFrance

SORO MDepartment of Anesthesiaand Critical CareHospital Clinico UniversitarioBlasco Ibanez 1746010 ValenciaSpain

XXIV List of Contributors

SPRONK PEDepartment of Intensive CareAcademic Medical CenterMeibergdreef 9Il05 AZ AmsterdamNetherlands

SQUARA PICU CERICClinique Ambroise Pare27, Bd Victor Hugo92200 Neuilly-sur-SeineFrance

STEINSEIFER UChair of Applied Medical EngineeringUniversity HospitalPauwelsstr. 3052074 AachenGermany

SUPARREGUI DIAS F

Intensive Care UnitHospital Sao Lucas da PUCRSAv. Ipiranga 6690Porto Alegre 90610-000Brazil

SURI HS

Department of Internal MedicineDivision of Pulmonary and CriticalCare MedicineMayo Clinic200 First Street SWRochester, MN 55905USA

SUTTNER S

Department of Anesthesiology andIntensive Care MedicineKlinikum der Stadt LudwigshafenBremserstr. 7967063 LudwigshafenGermany

SZNAJDER JI

Pulmonary and Critical Care MedicineFeinberg School of Medicine,Northwesten University240 E. Huron, McGaw Pavilion M-300Chicago, IL 606IlUSA

TAKALA J

Department of Intensive CareUniversity HospitalInselspital3010 BernSwitzerland

TEBOUL JL

Department of Intensive CareCentre Hospitalier Universitaire deBicetre78, rue du General Leclerc94270 Le Kremlin-BicetreFrance

TELCI L

Department of Anesthesiology andIntensive CareMedical Faculty of IstanbulUniversity of IstanbulCapa Klinikleri34093 IstanbulTurkey

TETTA CInternational Research andDevelopmentFresenius Medical Care DeutschlandGmbH61346 Bad HomburgGermany

THOMSON SJ

Department of Intensive CareSt George's HospitalBlackshaw RoadLondon, SW17 OQTUnited Kingdom

THONGBOONKERD VMedical Molecular Biology UnitOffice for Research and DevelopmentFaculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand

TIMSIT JF

Department of Intensive CareGrenoble University HospitalBP 21738043 GrenobleFrance

TOPJIAN A

Department of Anesthesia and CriticalCare MedicineThe Children's Hospital of Philadelphia34th Street and Civic Center BoulevardPhiladelphia, PA 19104USA

TORRES A

Department of PneumonologyInstitut Clinic del ToraxHospital ClinicVillarroel 17008036 BarcelonaSpain

TRABER DDepartment of AnesthesiologyUniversity of Texas Medical Branch610 Texas AveGalveston, TX 77555USA

TRABER LDepartment of AnesthesiologyUniversity of Texas Medical Branch610 Texas AveGalveston, TX 77555USA

TRESCHAN TA

Department of AnesthesiologyUniversity HospitalMoorenstr. 540225 DusseldorfGermany

VALENCIA MDepartment of PneumonologyInstitut Clinic del ToraxHospital ClinicVillarroel 17008036 BarcelonaSpain

VAN ANTWERPEN PPharmacy InstituteService de Chimie PharmaceutiqueOrganiqueBId du Triomphe Campus PlaineCP205/051050 BrusselsBelgium

List ofContributors XXV

VAN DER LINDEN PDepartment of AnesthesiologyCHU Brugmann4 Place Arthur Van Gehuchten1020 BrusselsBelgium

VAN DER VOORT PHJDepartment of Intensive CareOnze Lieve Vrouw GasthuisP.O. Box 955001090 HM AmsterdamNetherlands

VASCHETTO RFaculty of MedicineUniversity of Eastern PiedmontNovaraItaly

VENKATESH B

Department of Intensive CarePrincess Alexandra & Wesley HospitalsUniversity of Queensland4066 QueenslandAustralia

VERBORGH CDepartment of AnesthesiologyUniversity Hospital of BrusselsLaarbeeklaan 1011090 BrusselsBelgium

VIEILLARD-BARON A

Department of Intensive CareHopital Ambroise Pare9 avenue Charles-de-Gaulle92104 BoulogneFrance

VUYLSTEKE A

Department of Anesthesiaand Critical CarePapworth HospitalCambridge, CB23 3REUnited Kingdom

XXVI List of Contributors

WEILER NDepartment of Anesthesiologyand Intensive Care MedicineUniversity Medical Centerof Schleswig-HolsteinSchwanenweg 2124105 KielGermany

WELCH LCPulmonary and Critical Care MedicineFeinberg School of Medicine,Northwesten University240 E. Huron, McGaw Pavilion M-300Chicago, IL 60611USA

WERDAN KDepartment of Medicine IIIMartin-Luther-UniversityHalle-WittenbergKlinikum KrollwitzErnst-Grube-Str. 40060097 Halle/SaaleGermany

WERNERMAN JDepartment of Anesthesiaand Intensive CareKarolinska University HospitalHuddinge14186 StockholmSweden

WESTPHAL MDepartment of Anesthesiologyand Intensive CareUniversity HospitalAlbert-Schweitzer-Str, 3348149 MuensterGermany

WILMER AMedical Intensive Care UnitUniversity HospitalHerestraat 493000 LeuvenBelgium

WOUTERS PFDepartment of AnesthesiologyGhent University HospitalDe Pintelaan 1859000 GhentBelgium

YENDE SCRISMADepartment of Critical Care MedicineUniversity of Pittsburgh Schoolof Medicine605 Scaife Hall3550 Terrace StreetPittsburgh, PA 15261USA

YOUNG PJDepartment of Critical Care MedicineQueen Elizabeth HospitalGayton RoadKing's Lynn, PE30 4ETUnited Kingdom

YOUSSEF NCMDept of Anesthesiologyand Intensive CareFriedrich-Schiller UniversityErlanger Allee 10307743 lenaGermany

ZAKYNTHINOS SGDepartment of Intensive CareEvangelismos Hospital45-47 Ipsilandou Street10675 AthensGreece

Common Abbreviations

XXVII

ALIARDSBALCBPCNSCOPDCTCVPDICDOzEEGEKGHIVICUILLPSMAPMOFMRINF-KBNONOSPACPAFPAlPAOPPARPPEEPRBCROSScvOzSIRSSOFASvOzTLRTNFVILIVOz

Acute lung injuryAcute respiratory distress syndromeBronchoalveolar lavageCardiopulmonary bypassCentral nervous systemChronic obstructive pulmonary diseaseComputed tomographyCentral venous pressureDisseminated intravascular coagulationOxygen deliveryElectroencephalogramElectrocardiogramHuman immunodeficiency virusIntensive care unitInterleukinLipopolysaccharideMean arterial pressureMultiple organ failureMagnetic resonance imagingNuclear factor-kappa BNitric oxideNitric oxide synthasePulmonary artery catheterPlatelet activating factorPlasminogen activator inhibitorPulmonary artery occlusion pressurePoly(ADP-ribose) polymerasePositive end-expiratory pressureRed blood cellReactive oxygen speciesCentral venous oxygen saturationSystemic inflammatory response syndromeSequential organ failure assessmentMixed venous oxygen saturationToll-like receptorTumor necrosis factorVentilator-induced lung injuryOxygen uptake

Section I

I Genetic Factors

1

Are Pharmacogenetics and PharmacogenomicsImportant for Critically III Patients?

C. KIRWAN, 1. MACPHEE, and B. PHILIPS

Introduction

Drugs are administered to patients using dosing regimens established from animaldata, clinical trials, and population studies . However, there may be enormous varia-tion in dose requirement, efficacy, and adverse effects between individuals within agiven population. Although this may partly be attributed to factors such as age, con-comitant drug interactions, co-morbidities, and the underlying disease itself, geneticfactors are estimated to account for 15- 30 % of between individual differences andfor some drugs the impact of genetics may be much higher [1,2]. Genetic variationmay influence all aspects of pharmacokinetics and pharmacodynamics and althoughthe clinical relevance of pharmacogenetics remains uncertain, the idea is developingthat some drug therapies may be individualized in the future.

Historically genetic variations have needed to be dramatic to be noticed. Forexample, the inherited deficiency of gluose-6-phosphate dehydrogenase results insevere hemolysis if such patients are exposed to primaquine. This was clearly inher-ited as large population variation was observed between African (deficiency is com-mon) and Caucasian (deficiency rare) patients . With the development of the HumanGenome Project it has become possible to look for less dramatic genetic variationswhich if understood may have significant impact on the use and administration ofdrugs to individuals.

This chapter will define pharmacogenetics and pharmacogenomics, describe howthe science has evolved over the last few years, and attempt to highlight the possibleimpact the developments will have in the management of critically ill patients .

Pharmacogenetics or Pharmacogenomics?

Historically, pharmacogenetics is the older term and emerged as individual varia-tion in the pharmacokinetic and pharmacodynamic response to drugs becameapparent [3- 5]. In general, pharmacogenetics identifies gene polymorphisms, whichgenerate phenotypes of clinical importance. To be clinically relevant, these polymor-phisms need to be either sufficiently common in the population or, if rare, of suffi-cient medical impact (e.g., the deletion of expression for pseudo-cholinesterase andthe metabolism of succinylcholine) to alter clinical management.

The development of the Human Genome Project [6] has coined the new term,pharmacogenomics. This term incorporates pharmacogenetics but has a rather bro-ader meaning, describing the wider influence of DNA sequence variation on pheno-type and the effect on drug handling and efficacy. Pharmacogenomics also includes

3

4 C. Kirwan, I. MacPhee, and B. Philips

Table 1. Areas of pharmacology in which genetic polymorphism may alter a patient's risk of toxicity ortherapeutic benefit

Process Target Drug Example

Absorption ATP-binding cassette B1 (ABCB1) Phenytoin

Metabolism [Phase 1] CYP2D6 CodeineCYP2C9 Wafarin

Metabolism [Phase 2] Uridine diphosphate-glucuronosyltransferase (UGT1 A1) IrinotecanThiopurine S- methyltransferase (TPMT) Azathioprine

Excretion Sodium lithium countertransport (SLC) transporters Lithium

DNA repair XRCC1 Oxaliplatin

Cellular target ~rad renoreceptor Asthma therapy

the application of genomic technologies to new drug discovery and further charac-terization of older drugs. Unlike other factors influencing drug response, inheriteddeterminants generally remain stable throughout a person's lifetime ( Table 1).

Pharmacogenetics, Pharmacogenomics, and Drug Metabolism

Phase I reactions (oxidation, reduction, and hydrolysis) and phase II conjugationreactions (acetylation, glucuronidation, sulfation, and methylation) are influencedby a number of genetic polymorphisms. Early discoveries include the metabolism ofdrugs such as succinylcholine and isoniazid or hydralazine. Four allelic genes codingfor plasma cholinesterase cause wide variation in activity and therefore rate ofhydrolysis of succinylcholine [7] and a common genetic variation in the phase II,N-acetylation, pathway causes large differences in the half-life and plasma concen-trations of drugs metabolized by N-acetyltransferase including isoniazid, hydral-azine, and procainamide.

Currently, more than 30 families of enzyme complexes responsible for drugmetabolism have been described in humans and numerous variations exist in thegenes encoding the many enzymes and proteins. Several reviews illustrate the waysthese variants may be clinically important [2, 8-10] but the real clinical significancefor most remains unstudied and uncertain. A clinical effect is most likely to be nota-ble for drugs metabolized under predominately monogenic control and for thosewhich possess narrow toxic or therapeutic ratios [2, 11-13], although significanthaplotypes and frequent linkage disequilibria are also recognized.

Although a number of different types of polymorphisms have been shown toinfluence drug response, single nucleotide polymorphisms (SNPs) are likely to bethe most profitable in terms of pharmacogenomics analysis. SNPs are the most com-mon variant class in the human genome with one occurring at approximately every1000 base pairs. It is because these genetic variations are so common and technol-ogy exists for their rapid genotyping that SNPs are capable of revealing genomic var-iation on a scale which is not yet possible with other types of DNA polymorphism.One important clinical example found by this technique concerns the thiopurinemethyltransferase (TPMT) gene. Approximately 100 SNPs have been identified onthe TPMT gene but four in particular markedly increase the risk of bone marrow

Are Pharmacogenetics and Pharmacogenomics Important for Critically III Patients? 5

failure after administration of 6-mercaptopurine or azathioprine [14]. Other exam-ples where data from SNP studies has suggested a clinical effect are found in thefields of gastroesophageal reflux, epilepsy, and human immunodeficiency virus(HIV) [15-17].

Clinically Relevant Genetic Polymorphisms in Critical Care

Pharmacogenetics is a new science to critical care. The heterogeneity of patients andcomplexity of drug regimens makes investigation fraught with difficulty. The follow-ing is a selection of some of the more important systems that may have clinical sig-nificance.

The Cytochrome P4S0 Isoenzymes

Approximately 12 cytochrome P450 (CYP) isoenzymes of families CYP1, CYP2,CYP3 are collectively respons ible for most phase I reactions in the human liver. Col-lectively they account for over 60 % of all drug elimination [18]. Alleles of the CYPenzymes are allocated a number. The wild type is allocated the number *1 and theterminology for an individual homozygous for the wild type allele (e.g., CYP3A4)would be CYP3A4 *1/*1.

CYP3AMidazolam, a benzodiazepine commonly used in anesthesia and intensive care med-icine, is exclusively metabolized by CYP3A. Enzymes in the CYP3A sub-family(CYP3A4 and CYP3A5) are the most abundant CYPs in the human liver. CYP3A4 isthe most predominant form expressed in liver cells but CYP3A5 may contribute tomore than 50 % of the hepatic CYP3A activity in the one third of the population thatexpress both enzymes [19]. There is a large genetic variability in both of theseenzymes and many different alleles have been described. A number are rare andmany alleles of CYP3A4 have little or no significance on endogenous substratemetabolism [20, 21]. CYP3A5 is, however, more significant. Polymorphic CYP3A5expression is strongly correlated with a single nucleotide change, designatedCYP3AS *3 [22]. Volunteers who are homozygous (CYP3AS *3/*3) for the CYP3Aallele showed marked loss of enzyme activity and thus midazolam clearance, whengiven midazolam in the presence of itraconazole (CYP3A4 and CYP3A5 inhibitor)[19, 23] and can be considered funct ional non-expressers. For patients undergoingsolid-organ transplant, the CYP3AS *3/*3 genotype confers a lower dose require-ment of tacrolimus for both loading and maintenance. Patients with CYP3AS *1/*1or *1/*3have a delay in achieving target blood tacrolimus concentrations and geno-typing may help in the initial dosing of tacrolimus after transplantation [24].

CYP2B6CYP2B6 is one of the most polymorphic CYP genes in the liver with over 100 SNPsdescribed, numerous complex haplotypes, and distinct ethnic frequencies. Itsexpression in the liver is highly variable with some individuals expressing more than100 fold more enzyme than others [18]. CYP2B6 has not been extensively investi-gated but clinical substrates include cyclophosphamide, anti retrov irals, syntheticopioids (e.g., methadone) , and propofol [25].