2008 yearbook of intensive care and emergency medicine 2008

Cartin-Ceba RDepartment of Internal Medicine Division of Pulmonary and Critical Department of Anesthesia and Intensive Care Medicine Saint Eloi University Hospital 80 avenue Augustin Fli

Yearbook of Intensive Care

Edited by J.-L Vincent

of Intensive Care and Emergency

Edited by J.-L Vincent

With 238 Figures and 90 Tables

Head, Department of Intensive Care

Erasme Hospital, Universit´e libre de Bruxelles

Route de Lennik 808, B-1070 Brussels, Belgium

ISBN 978-3-540-77289-7 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

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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

B-type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical Care

P.E Oishi, J.-H Hsu, and J.R Fineman 33Cardiac Dysfunction in Septic Shock

I Cinel, R Nanda, and R.P Dellinger 43The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ

III Cardiopulmonary Resuscitation

Improving the Quality of Cardiac Arrest Resuscitation Care

C.J Dineand B.S Abella 113Pediatric Cardiopulmonary Arrest and Resuscitation

, and V.M Nadkarni 121

V

Early Cooling in Cardiac Arrest: What is the Evidence?

L Hammer, C Adrie, and J.-F Timsit 137

IV Emergencies

Management of Severe Accidental Hypothermia

G.J Peek, P.R Davis, and J.A Ellerton 147Initial ICU Management of Skin Sloughing Diseases: Toxic Epidermal Necrolysisand Stevens-Johnson Syndrome

T.L Palmieri 160

V Poisonings

Pathophysiology of Caustic Ingestion

M Osmanand D.N Granger 171Extracorporeal Life-Support for Acute Drug-induced Cardiac Toxicity

B M ´egarbane, N Deye, and F.J Baud 179

VI Acute Respiratory Failure

Epidemiology of Acute Respiratory Failure and Mechanical Ventilation

H.S Suri, G Li, and O Gajic 193Esophagectomy and Acute Lung Injury

D.P Park, D Gourevitch, and G.D Perkins 203Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe?

P Pelosi and P.R.M Rocco 214Regional Lung Function in Critically Ill Neonates: A New Perspective for

Electrical Impedance Tomography

I Frerichs, J Scholz, and N Weiler 224Extracorporeal Lung Assist for Acute Respiratory Distress Syndrome:

Past, Present and Future

R Kopp, U Steinseifer, and R Rossaint 235

VII Ventilatory Support

Protective Mechanical Ventilation: Lessons Learned from Alveolar Mechanics

S Albert, B Kubiak, and G Nieman 245Mechanical Ventilation for Acute Asthma Exacerbations

D De Mendoza, M Lujan, and J Rello 256Hypercapnia: Permissive, Therapeutic or Not at All?

P Hassett, M Contreras, and J.G Laffey 269The Cardiopulmonary Effects of Hypercapnia

T Manca, L.C Welch, and J.I Sznajder 282High Frequency Oscillation for Acute Respiratory Failure in Adults

S.D Mentzelopoulos, C Roussos, and S.G Zakynthinos 290

Airway Pressure Release Ventilation: Promises and Potentials for Concern

J Guti ´errez Mej´ia, E Fan, and N.D Ferguson 301Post-operative Non-invasive Ventilation

S Jaber, G Chanques, and B Jung 310

VIII Tracheostomy

Choice of Tracheostomy Tube: Does One Size Fit All?

J Oramand A Bodenham 323What’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 Pneumonia

P.J Youngand M.C Blunt 343Management of Ventilator-associated Pneumonia

M Ferrer, M Valencia, and A Torres 353Flucytosine Combined with Amphotericin B for Fungal Infections

P.H.J van der Voort 365

X Cellular Mechanisms in Sepsis

Apoptosis in Critical Illness: A Primer for the Intensivist

Z Malam, J.C Marshall 375Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis:

A Putative Role for Hypoxia Inducible Factor

T Regueira, S.M Jakob, and S Djafarzadeh 385Gram-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 Oxide

P Enkhbaatar, L Traber, and D Traber 404

XI Sepsis Therapies

The Cardiovascular Management of Sepsis

B.C Creagh-Brown, J Ball, and M Hamilton 413Terlipressin in Septic Shock: When and How Much?

C Ertmer, A Morelli, and M Westphal 423Blood Purification Techniques in Sepsis and SIRS

P.M Honor ´e, O Joannes-Boyau, and B Gressens 434Glutathione in Sepsis and Multiple Organ Failure

U Fläringand J Wernerman 444Selenocompounds and Selenium: A Biochemical Approach to Sepsis

X Forcevilleand P Van Antwerpen 454

Table of Contents VII

XII Metabolic Alterations

The Role of Hypoxia and Inflammation in the Expression and Regulation

of Proteins Regulating Iron Metabolism

S Brandt, J Takala, and P.M Lepper 473Hyperammonemia in the Adult Critical Care Setting

K Dams, W Meersseman, and A Wilmer 481

Magnesium in the ICU: Sine qua non

F Esenand L Telci 491Strict Glycemic Control: Not If and When, but Who and How?

M.J De Graaff, P.E Spronk, and M.J Schultz 502Cortisol Metabolism in Inflammation and Sepsis

B Venkateshand J Cohen 514

XIII Fluid Management

Assessment of Perioperative Fluid Balance

M.T Ganterand C.K Hofer 523Fluid Resuscitation and Intra-abdominal Hypertension

I.E de Laet, J.J De Waele, and M.L.N.G Malbrain 536

XIV Acute Kidney Injury

Six Truths about Acute Kidney Injury that the Intensivist should be Aware ofE.A.J Hoste 551Role of Poly(ADP-Ribose) Polymerase in Acute Kidney Injury

R Vaschetto, F.B Plötz, and A.B.J Groeneveld 559From 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 Position

W Schummer, Y Sakr, and C Schummer 581From Arterial Pressure to Cardiac Output

M Cecconi, A Rhodes, and G Della Rocca 591Hemodynamic Monitoring: Requirements of Less Invasive Intensive Care –

Quality And Safety

A Vieillard-Baron 602Minimally Invasive Cardiac Output Monitoring: Toy or Tool?

G Marxand T Schuerholz 607Bioreactance: A New Method for Non-invasive Cardiac Output Monitoring

P Squara 619Goal-directed Hemodynamic Therapy for Surgical Patients

and A Rhodes 631

XVI Tissue Oxygenation

Use of Mixed Venous Oxygen Saturation in ICU Patients

M Leone, V Blasco, and C Martin 641Early Optimization of Oxygen Delivery in High-risk Surgery Patients

S.M Lobo, E Rezende, and F Suparregui Dias 654The Influence of Packed Red Blood Cell Transfusion on Tissue Oxygenation

S Suttnerand J Boldt 665Recent Advancements in Microcirculatory Image Acquisition and Analysis

R Bezemer, M Khalilzada, and C Ince 677The Beneficial Effects of Increasing Blood Viscosity

B.Y Salazar V ´azquez, P Cabrales, and M Intaglietta 691

XVII Anticoagulants in Organ Failure

Protein C and Antithrombin Levels in Surgical and Septic Patients

Y Sakr, N.C.M Youssef, and K Reinhart 703Thrombophilia as a Risk Factor for Outcome in Sepsis

J.-J Hofstra, M Schouten, and M Levi 713The Effects of Activated Protein C on the Septic Endothelium

S.E Orfanos, N.A Maniatis, and A Kotanidou 721Improvement in Hemodynamics by Activated Protein C in Septic Shock

X Monnet, H Ksouri, and J.-L Teboul 730

XVIII Acute Bleeding

Gastrointestinal Hemorrhage on the Intensive Care Unit

S.J Thomson, M.L Cowan, and T.M Rahman 739Recombinant Activated Factor VII: The Delicate Balance between Efficacy

and Safety

S B ´elisle, J.-F Hardy, and P Van der Linden 751

XIX Hepatic Disease

ICU Management of the Liver Transplant Patient

G Della Rocca, M.G Costa, and P Chiarandini 763Liver Support with Fractionated Plasma Separation and Adsorption and

Multimodality Monitoring in Patients with Elevated Intracranial Pressure

D.B Seder, J.M Schmidt, and S Mayer 811Managing Critically Ill Patients with Status Epilepticus

S Legriel, J.P Bedos, and E Azoulay 822

XXI Analgesia and Sedation

Sedation with Inhaled Anesthetics in Intensive Care

F.J Belda, M Soro, and A Meiser 839Sedation or Analgo-sedation in the ICU: A Multimodality Approach

F Meurant, A Bodart, and J.P Koch 850

XXII Outcomes

Time to Use Computerized Physician Order Entry in all ICUs

J Aliand A Vuylsteke 865Quality of Life in Locked-in Syndrome Survivors

M.-A Bruno, F Pellas, and S Laureys 881Post-traumatic Stress Disorder in Intensive Care Unit Survivors

J Griffiths, A.M Hull, and B.H Cuthbertson 891

Subject Index 907

Suny Upstate Medical University

750 East Adams Street

605 Scaife Hall

3550 Terrace StreetPittsburgh, PA 15261USA

Azoulay EDepartment of Intensive CareHˆopital Saint-Louis 1

Avenue Claude Vellefaux

75010 ParisFranceBall JGeneral Intensive Care Unit

St George’s HospitalBlackshaw RoadLondon, SW17 0QTUnited KingdomBaud FJ

Medical Intensive Care and ToxicologyHˆopital Lariboisi`ere

2, Rue Ambroise Par´e

75010 ParisFranceBedos JPDepartment of Intensive Care MedicineHˆopital Andr´e Mignot

177 rue de Versailles

78150 Le ChesnayFrance

XI

and Critical Care

Hospital Clinico Universitario

Department of Critical Care

Queen Elizabeth Hospital

2540 LuxemburgLuxembourgBodenham ADepartment of Anesthesia andIntensive Care

Leeds General Infirmary

Gt George StLeeds, LS1 3EXUnited KingdomBoldt J

Department of Anesthesiologyand Intensive Care MedicineKlinikum der Stadt LudwigshafenBremserstr 79

67063 LudwigshafenGermany

Brandt SDepartment of AnesthesiologyUniversity Hospital

Inselspital

3010 BernSwitzerlandBruno MAComa Science GroupCyclotron Research Centre andNeurology DepartmentUniversity of Li`ege – Sart Tilman (B30)

4000 Li`egeBelgiumBurke Gaffney ADepartment of Critical CareRoyal Brompton HospitalSydney Street

London, SW3 6NPUnited KingdomCabrales P

La Jolla Bioengineering Institute

505 Coast Boulevard South Suite # 405

La Jolla, CA 92037USA

Cartin-Ceba R

Department of Internal Medicine

Division of Pulmonary and Critical

Department of Anesthesia and

Intensive Care Medicine

Saint Eloi University Hospital

80 avenue Augustin Fliche

34295 Montpellier

France

Chiarandini P

Department of Anesthesia and

Intensive Care Medicine

Azienda Ospedaliero Universitaria S.M

Division of Critical Care

Cooper University Hospital

One Cooper Plaza

Dorrance Building, Suite 393

Camden, NJ 08103

USA

Cohen J

Department of Intensive Care

Royal Brisbane & Ipswich Hospitals

University of Queensland

Queensland 4029

Australia

Contreras MDepartment of AnesthesiaClinical Sciences InstituteNational University of IrelandGalway

IrelandCosta MGDepartment of Anesthesia andIntensive Care MedicineAzienda Ospedaliero Universitaria S.M.della Misericordia

P.le S.M Misericordia 15

31100 UdineItalyCowan MLDepartment of Gastroenterology

St George’s HospitalBlackshaw RoadLondon, SW17 0QTUnited KingdomCreagh-Brown BCGeneral Intensive Care Unit

St George’s HospitalBlackshaw RoadLondon, SW17 0QTUnited KingdomCuthbertson BHHealth Services Research UnitHealth Sciences BuildingUniversity of AberdeenAberdeen

United KingdomDams K

Medical Intensive Care UnitUniversity Hospital

Herestraat 49

3000 LeuvenBelgiumDavis PRDepartment of Emergency MedicineDefense Medical Services

Southern General HospitalGlasgow, G51 4TF

United Kingdom

List of Contributors XIII

de Graaff MJ

Department of Intensive Care

Academic Medical Center

Department of Anesthesia and

Intensive Care Medicine

Azienda Ospedaliero Universitaria S.M

Division of Critical Care

Cooper University Hospital

One Cooper Plaza

Dorrance Building, Suite 393

Camden, NJ 08103

USA

de Mendoza D

Critical Care Department

Joan XXIII University Hospital

Carrer Mallafre Guasch 4

University of Pennsylvania

3400 Spruce Street, Ground RavdinPhiladelphia, PA 19104

USADjafarzadeh SDepartment of Intensive CareUniversity Hospital

Inselspital

3010 BernSwitzerlandEllerton JABirbeck Medical GroupBridge Lane

PenrithCumbria CA11 8HWUnited KingdomEnkhbaatar PDepartment of AnesthesiologyUniversity of Texas Medical Branch

610 Texas AveGalveston, TX 77555USA

Ertmer CDepartment of Anesthesiology andIntensive Care

University HospitalAlbert-Schweitzer-Str 33

48149 MuensterGermanyEsen FDepartment of Anesthesiology andIntensive Care

Medical Faculty of IstanbulUniversity of IstanbulCapa Klinikleri

34093 IstanbulTurkeyEvans TWDepartment of Critical CareRoyal Brompton HospitalSydney Street

London, SW3 6NPUnited Kingdom

Fan E

Department of Pulmonary

and Critical Care Medicine

Johns Hopkins University

1830 East Monument Street

Baltimore, MD 21205

USA

Ferguson ND

Department of Critical Care

Toronto Western Hospital

Cardiovascular Research Institute

University of California San Francisco

Astrid Lindgren’s Children Hospital

Karolinska University Hospital

Huddinge

14186 Stockholm

Sweden

Forceville X

Department of Intensive Care

Centre Hospitalier de Meaux

Hˆopital Saint Faron

6–8 Rue Saint Fiacre

77104 Meaux

France

Frerichs IDepartment of Anesthesiology andIntensive Care Medicine

University Medical Center

of Schleswig-HolsteinSchwanenweg 21

24105 KielGermanyGajic ODepartment of Internal MedicineDivision of Pulmonary and CriticalCare Medicine

Mayo Clinic

200 First Street SWRochester, MN 55905USA

Ganter MTInstitute of AnesthesiologyUniversity HospitalRaemistr 100

8091 ZurichSwitzerlandGong MNDepartment of Pulmonary, CriticalCare, and Sleep Medicine

Department of MedicineMount Sinai Hospital

1190 Fifth AvenueNew York, NY 10029USA

Gourevitch DDepartment of SurgeryUniversity HospitalBirmingham NHS Foundation TrustBirmingham, B15 2TT

United KingdomGranger DNDepartment of Molecular and CellularPhysiology

Louisiana State University HealthSciences Center

1501 Kings HighwayShreveport, LA 71103–3932USA

List of Contributors XV

Gressens B

Department of Intensive Care

St-Pierre Para-Universitary Hospital

Avenue Reine Fabiola 9

1340 Ottignies-Louvain-La-Neuve

Belgium

Griffiths J

Nuffield Department of Anesthetics

John Radcliffe Hospital

Headley Way

Oxford OX3 9DU

United Kingdom

Groeneveld ABJ

Department of Intensive Care

Vrije Universiteit Medical Centre

De Boelelaan 1117

1081 HV Amsterdam

Netherlands

Guti ´errez Mej´ıa J

Department of Critical Care

Toronto Western Hospital

Department of Intensive Care

Grenoble University Hospital

IrelandHofer CKInstitute of Anesthesiology andIntensive Care MedicineTriemli City HospitalBirmensdorferstr 497

8063 ZurichSwitzerlandHofstra JJDepartment of MedicineAcademic Medical CenterMeibergdreef 9

1105 AZ AmsterdamNetherlands

Honor ´e PMDepartment of Intensive CareSt-Pierre Para-Universitary HospitalAvenue Reine Fabiola 9

1340 Ottignies-Louvain-La-NeuveBelgium

Hoste EAJSurgical Intensive Care Unit, 2k12-CGhent University Hospital

De Pintelaan 185

9000 GentBelgiumHsu JHDepartment of PediatricsKaohsiung Medical University Hospital

No 100, Tzyou 1st Road Kaohsiung 807Taiwan

Hull AMConsultant PsychiatristMurray Royal HospitalPerth, PH2 7BHUnited KingdomIcha¨ı P

Department of Hepatobiliary SurgeryHˆopital Paul Brousse

12, Av P.V Couturier

94800 VillejuifFrance

Saint Eloi University Hospital

80 avenue Augustin Fliche

Department of Intensive Care

Haut Leveque University Hospital

and Critical Care

Saint Eloi University Hospital

80 avenue Augustin Fliche

St George’s University of London

Rm 30, Jenner WingCranmer TerraceLondon, SW17 0REUnited KingdomKoch JPIntensive Care UnitKirchberg HospitalRue E Steighen, 9

2540 LuxemburgLuxemburgKopp RSurgical Intensive Care MedicineUniversity Hospital

Pauwelsstr 30

52074 AachenGermanyKotanidou A

1stDepartment of Critical CareUniversity of Athens Medical SchoolEvangelismos General Hospital45–47 Ipsilandou St

10675 AthensGreeceKsouri HDepartment of Intensive CareCentre Hospitalier Universitaire deBicˆetre

78, rue du G´en´eral Leclerc

94270 Le Kremlin-BicˆetreFrance

Kubiak BDepartment of SurgerySuny Upstate Medical University

750 East Adams StreetSyracuse, NY 13210USA

Laffey JGDepartment of AnesthesiaClinical Sciences InstituteNational University of IrelandGalway

Ireland

List of Contributors XVII

Lamia B

Department of Critical Care Medicine

University of Pittsburgh Medical Center

Coma Science Group

Cyclotron Research Centre and

Department of Critical Care

Royal Brompton Hospital

Department of Anesthesiology and

Intensive Care Medicine

ChinaLobo SMDivision of Critical Care MedicineDepartment of Internal MedicineMedical School-FUNFARME andHospital de Base

Rua Antˆonio de Godoy 3548Centro Sao Jos´e do Rio Preto – SP –15015–100

BrazilLujan MDepartment of PneumologyCorporacio Sanitaria Parc TauliParc Pauli s/n

08208 SabadellSpain

MacPhee IDepartment of Intensive Care

St George’s University of London

Rm 30, Jenner WingCranmer TerraceLondon, SW17 0REUnited KingdomMalam ZDivision of Critical CareRoom 4–007, Bond Wing

St Michael’s Hospital

30 Bond StreetToronto, ON M5W 1B8Canada

Malbrain MLNGDepartment of Intensive CareZNA Stuivenberg

Lange Beeldekensstraat 267

2060 AntwerpBelgiumManca TPulmonary and Critical Care MedicineFeinberg School of Medicine,

Northwesten University

240 E Huron, McGaw Pavilion M-300Chicago, IL 60611

USA

Maniatis NA

M Simou Laboratory

University of Athens Medical School

Evangelismos General Hospital

3 Ploutarchou St

10675 Athens

Greece

Marshall JC

Division of Critical Care

Room 4–007, Bond Wing

Department of Anesthesia and

Intensive Care Medicine

Friedrich Schiller University

Erlanger Allee 101

07747 Jena

Germany

Matejovic M

1stMedical Department, ICU

Chalres University Medical School

and Teaching Hospital

Alej svobody 80

304 60 Plzen

Czech Republic

Mayer SA

Neurological Intensive Care Unit

Departments of Neurology and

of Medicine

605 Scaife Hall

3550 Terrace StreetPittsburgh, PA 15261USA

Meersseman WMedical Intensive Care UnitUniversity Hospital

Herestraat 49

3000 LeuvenBelgium

M ´egarbane BMedical Intensive Care and ToxicologyHˆopital Lariboisi`ere

2, Rue Ambroise Par´e

75010 ParisFranceMeiser AAnesthesiology Department

St Josef-HospitalGudrunstr 56

44791 BochumGermanyMentzelopoulos SDIntensive Care MedicineEvangelismos Hospital45–47 Ipsilandou Street

10675 AthensGreeceMeurant FIntensive Care UnitKirchberg HospitalRue E Steighen, 9

2540 LuxemburgLuxembourgMissant CDepartment of Acute Medical SciencesKatholieke Universiteit LeuvenMinderbroederstraat 19 – bus 7003

3000 LeuvenBelgium

List of Contributors XIX

Monnet X

Department of Intensive Care

Centre Hospitalier Universitaire de

and Intensive Care

University of Rome “La Sapienza”

Via Barnaba Oriani 2

The Children’s Hospital of Philadelphia

34th Street and Civic Center Boulevard

Philadelphia, PA 19104

USA

Nanda R

Division of Critical Care

Cooper University Hospital

One Cooper Plaza

Dorrance Building, Suite 393

Camden, NJ 08103

USA

Nieman GDepartment of SurgerySuny Upstate Medical University

750 East Adams StreetSyracuse, NY 13210USA

Oishi PEPediatric Critical CareUniversity of California

513 Parnassus Avenue, Box 0106San Francisco, CA 94143USA

Oram JDepartment of Anesthesia andIntensive Care

Leeds General Infirmary

Gt George StLeeds, LS1 3EXUnited KingdomOrfanos SE

2ndDepartment of Critical CareMedicine

Attikon Hospital

1, Rimini St

12462 HaidariGreeceOsipowska EDepartment of AnesthesiologyUniversity Hospital of BrusselsLaarbeeklaan 101

1090 BrusselsBelgiumOsman MDepartment of Pediatric SurgeryAin Shams University School

of MedicineAbbasya SquareCairo

EgyptPalmieri TLDept of Surgery

UC Davis Regional Burn Centerand Shriners Hospital for Children

2425 Stockton Blvd., Suite 718Sacramento, CA 95817USA

Birmingham Heartlands Hospital

Bordesley Green East

Department of Intensive Care

St George’s University of London

606 Scaife Hall

3550 Terrace StreetPittsburgh, PA 15261USA

Plötz FBDepartment of Pediatric Intensive CareVrije Universiteit Medical Centre

De Boelelaan 1117

1081 HV AmsterdamNetherlands

Poelaert JDepartment of AnesthesiologyUniversity Hospital of BrusselsLaarbeeklaan 101

1090 BrusselsBelgiumPolito ARespiratory Muscle LaboratoryHˆopital Raymond Poincar´eBoulevard Raymont Poincar´e 104

92380 GarchesFrancePriebe HJDepartment of AnesthesiologyUniversity Hospital

Hugstetter Str 55

79106 FreiburgGermanyRadermacher PDept of AnesthesiaUniversity HospitalParkstrasse

89073 UlmGermanyRahman TMDepartment of Gastroenterology

St George’s HospitalBlackshaw RoadLondon, SW17 0QTUnited Kingdom

List of Contributors XXI

Critical Care Department

Joan XXIII University Hospital

Carrer Mallafre Guasch 4

Intensive Care Department

Hospital do Servidor Publico Estadual

Rua Pedro de Toledo 1800

Federal UniversityRio de JaneiroBrazil

Ronco CDepartment of Nephrology, Dialysisand Renal Transplantation

San Bortolo HospitalViale Rodolfi 37

36100 VicenzaItaly

Rossaint RSurgical Intensive Care MedicineUniversity Hospital

Pauwelsstr 30

52074 AachenGermanyRoussos CIntensive Care MedicineEvangelismos Hospital45–47 Ipsilandou Street

10675 AthensGreeceSakr YDept of Anesthesiology and IntensiveCare

Friedrich-Schiller UniversityErlanger Allee 103

07743 JenaGermany

UCSD-Bioengineering

9500 Gilman Dr

La Jolla, CA 92093–0412USA

Saliba FDepartment of Hepatobiliary SurgeryHˆopital Paul Brousse

12, Av P.V Couturier

94800 VillejuifFrance

Samuel D

Department of Hepatobiliary Surgery

Hˆopital Paul Brousse

and Intensive Care Medicine

University Medical Center

and Intensive Care Medicine

Friedrich Schiller University

Erlanger Allee 101

07747 Jena

Germany

Schultz MJDepartment of Intensive CareAcademic Medical CenterMeibergdreef 9

1105 AZ AmsterdamNetherlands

Schummer CDept of Anesthesiologyand Intensive CareFriedrich-Schiller UniversityErlanger Allee 101

07747 JenaGermanySchummer WDept of Anesthesiologyand Intensive CareFriedrich-Schiller UniversityErlanger Allee 101

07747 JenaGermanySeder DBNeurological Intensive Care UnitDepartments of NeurologyNeurological InstituteColumbia University Medical Center

710 West 168thStreet, Box 39New York, NY 10032USA

Sharshar TRespiratory Muscle LaboratoryHˆopital Raymond Poincar´eBoulevard Raymont Poincar´e 104

92380 GarchesFranceSiami SRespiratory Muscle LaboratoryHˆopital Raymond Poincar´eBoulevard Raymont Poincar´e 104

92380 GarchesFranceSoro MDepartment of Anesthesiaand Critical Care

Hospital Clinico UniversitarioBlasco Ibanez 17

46010 ValenciaSpain

List of Contributors XXIII

Spronk PE

Department of Intensive Care

Academic Medical Center

Intensive Care Unit

Hospital Sao Lucas da PUCRS

Av Ipiranga 6690

Porto Alegre 90610–000

Brazil

Suri HS

Department of Internal Medicine

Division of Pulmonary and Critical

Department of Anesthesiology and

Intensive Care Medicine

Klinikum der Stadt Ludwigshafen

Bremserstr 79

67063 Ludwigshafen

Germany

Sznajder JI

Pulmonary and Critical Care Medicine

Feinberg School of Medicine,

Inselspital

3010 BernSwitzerlandTeboul JLDepartment of Intensive CareCentre Hospitalier Universitaire deBicˆetre

78, rue du G´en´eral Leclerc

94270 Le Kremlin-BicˆetreFrance

Telci LDepartment of Anesthesiology andIntensive Care

Medical Faculty of IstanbulUniversity of IstanbulCapa Klinikleri

34093 IstanbulTurkeyTetta CInternational Research andDevelopment

Fresenius Medical Care DeutschlandGmbH

61346 Bad HomburgGermany

Thomson SJDepartment of Intensive Care

St George’s HospitalBlackshaw RoadLondon, SW17 0QTUnited KingdomThongboonkerd VMedical Molecular Biology UnitOffice for Research and DevelopmentFaculty of Medicine Siriraj HospitalMahidol University

BangkokThailandTimsit JFDepartment of Intensive CareGrenoble University Hospital

BP 217

38043 GrenobleFrance

Topjian A

Department of Anesthesia and Critical

Care Medicine

The Children’s Hospital of Philadelphia

34th Street and Civic Center Boulevard

4 Place Arthur Van Gehuchten

1020 BrusselsBelgiumvan der Voort PHJDepartment of Intensive CareOnze Lieve Vrouw GasthuisP.O Box 95500

1090 HM AmsterdamNetherlands

Vaschetto RFaculty of MedicineUniversity of Eastern PiedmontNovara

ItalyVenkatesh BDepartment of Intensive CarePrincess Alexandra & Wesley HospitalsUniversity of Queensland

4066 QueenslandAustraliaVerborgh CDepartment of AnesthesiologyUniversity Hospital of BrusselsLaarbeeklaan 101

1090 BrusselsBelgiumVieillard-Baron ADepartment of Intensive CareHˆopital Ambroise Par´e

9 avenue Charles-de-Gaulle

92104 BoulogneFrance

Vuylsteke ADepartment of Anesthesiaand Critical Care

Papworth HospitalCambridge, CB23 3REUnited Kingdom

List of Contributors XXV

Weiler N

Department of Anesthesiology

and Intensive Care Medicine

University Medical Center

Pulmonary and Critical Care Medicine

Feinberg School of Medicine,

and Intensive Care

Karolinska University Hospital

De Pintelaan 185

9000 GhentBelgiumYende SCRISMADepartment of Critical Care MedicineUniversity of Pittsburgh School

of Medicine

605 Scaife Hall

3550 Terrace StreetPittsburgh, PA 15261USA

Young PJDepartment of Critical Care MedicineQueen Elizabeth Hospital

Gayton RoadKing’s Lynn, PE30 4ETUnited KingdomYoussef NCMDept of Anesthesiologyand Intensive CareFriedrich-Schiller UniversityErlanger Allee 103

07743 JenaGermanyZakynthinos SGDepartment of Intensive CareEvangelismos Hospital45–47 Ipsilandou Street

10675 AthensGreece

Common Abbreviations

XXVII

I Genetic Factors I

Are Pharmacogenetics and Pharmacogenomics

Important for Critically Ill Patients?

C Kirwan, I 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 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

varia-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

I

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

Absorption ATP-binding cassette B1 (ABCB1) PhenytoinMetabolism [Phase 1] CYP2D6

CYP2C9

CodeineWafarinMetabolism [Phase 2] Uridine diphosphate-glucuronosyltransferase (UGT1A1)

Thiopurine S – methyltransferase (TPMT)

IrinotecanAzathioprineExcretion Sodium lithium countertransport (SLC) transporters Lithium

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

charac-Pharmacogenetics, Pharmacogenomics, and Drug Metabolism

Phase I reactions (oxidation, reduction, and hydrolysis) and phase II conjugationreactions (acetylation, glucuronidation, sulfation, and methylation) are influenced

by 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 every

1000 base pairs It is because these genetic variations are so common and 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

technol-One important clinical example found by this technique concerns the thiopurine

methyltransferase (TPMT) gene Approximately 100 SNPs have been identified on

the TPMT gene but four in particular markedly increase the risk of bone marrow

I

failure after administration of 6-mercaptopurine or azathioprine [14] Other 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].

exam-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 P450 Isoenzymes

Approximately 12 cytochrome P450 (CYP) isoenzymes of families CYP1, CYP2,CYP3 are collectively responsible 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 CYP 3A4 *1/*1.

CYP3A

Midazolam, a benzodiazepine commonly used in anesthesia and intensive care 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, designated

med-CYP3A5 *3 [22] Volunteers who are homozygous (med-CYP3A5 *3/*3) for the CYP3A

allele 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 functional non-expressers For patients undergoing

solid-organ transplant, the CYP 3A5 *3/*3 genotype confers a lower dose

require-ment of tacrolimus for both loading and maintenance Patients with CYP 3A5 *1/*1

or * 1/*3 have a delay in achieving target blood tacrolimus concentrations and

geno-typing may help in the initial dosing of tacrolimus after transplantation [24]

CYP 2B6

CYP2B6 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 than

100 fold more enzyme than others [18] CYP2B6 has not been extensively gated but clinical substrates include cyclophosphamide, anti retrovirals, syntheticopioids (e.g., methadone), and propofol [25]

investi-Are Pharmacogenetics and Pharmacogenomics Important for Critically Ill Patients? 5

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CYP 2C9

Warfarin therapy is complicated by significant interpatient variability in sensitivityleading to significant risk of both under and overdosing and potential harm to eachpatient Consequently, warfarin regimens require regular prothrombin time (PTT)testing, especially on the initiation of therapy This difficulty in predicting individualrequirements may be, in part, attributable to inherited differences in metabolism[26, 27] Warfarin is hydroxylated to an inactive metabolite by CYP2C9 [27] Carriers

of CYP2C9 variants have significantly lower dose requirements for warfarin relative

to individuals with wild-type genotypes The presence of these variants in tion with clinical factors has been found to account for 26 % of the interpatient vari-ation in warfarin dosing requirements [28, 29]

conjunc-CYP2C19

CYP2C19 was originally identified as the enzyme responsible for the metabolism ofphenytoin and has since had the metabolism of the proton pump inhibitors attrib-uted to it Alleles conferring reduced enzyme activity are observed with high fre-quency in a number of races including up to 23 % of Asians and 8 % of Caucasiansand black Africans Seven variants associated with reduced activity have been iden-

tified with CYP 2C19*2 and *3 being the most common Patients homozygous for the

wild type gene have a poorer response to standard proton pump dosing thanpatients with the variant genes This difference is measurable in terms of gastric pHwith higher pH values being observed in patients with reduced CYP2C19 activity

CYP 2D6

CYP2D6 is the most widely studied enzyme of all the CYP450 isoenzymes and manydrugs are substrates, including dihydrocodeine, tramadol, tricyclic antidepressants,

readily achievable, phenotypic description based on the metabolism of sparteinedivided people into extensive metabolizers, poor metabolizers, and ultrarapid meta-bolizers Approximately 7 to 10 % of European Caucasians are poor metabolizers

compared with 1 % of Chinese and Japanese Alleles CYP 2D6*3, *4 and *5 produce

inactive enzyme [18] However, CYP2D6 activity is generally lower in Chinese than

Europeans because of the CYP 2D6*10 allele, expressed in 50 % of the Chinese

popu-lation Conversely in black Ethiopians, gene duplication gives rise to the ultrarapidmetabolizer phenotype in 29 % of the population Not all of these variations willconfer significant clinical effect but there are some important examples Tramadolhas an active metabolite and possibly greater opioid effect (including adverseeffects) in patients with the poor metabolizer phenotype, but may be less efficacious

or even ineffective in patients with the ultralipid metabolizer phenotype Similarly,metoprolol efficacy may be enhanced with the poor metabolizer phenotype as maythe effect of antipsychotics when given in standard doses [18]

Adrenoreceptors

shown to affect cardiac function and response to drugs [30, 31] A polymorphism inthe 1receptor gene with the substitution of glycine (Gly389) for arginine (Arg389),

if found in association with a genetic variant of the 2-adrenoceptor (deletion of 4consecutive amino acids [ 2CDel322 – 325]), is strongly linked to the development ofcongestive heart failure both in transgenic mouse models and humans [30, 31] The

I

1Arg389 genotype has an enhanced response to -adrenoceptor agonists conferring

a 200 % increase in agonist stimulated activity [30, 31] The 2CDel322 – 325 has asubstantially decreased agonist function, with the normal negative feedback mecha-nisms to the release of norepinephrine inhibited This combined effect may accountfor the associated increased risk of heart failure secondary to sustained adrenergicactivation The implication to critical illness and the use of adrenergic agonists orantagonists is yet to be studied

A variety of polymorphisms of the 2-adrenoceptor with potential clinical tance have been observed The normal desensitization and hypo-responsiveness ofthe 2-adrenoceptor with continuous exposure of vascular endothelium to agonists

impor-is exaggerated in patients with a substitution of Gly for Arg at position 16 [32] Thimpor-ispolymorphism has strong linkage disequilibrium with position 27, where a substitu-tion of glutamic acid (Glu) for glutamine (Gln) confers enhanced vasodilatation inresponse to agonists Individuals homozygous for Arg16 show rapid desensitization

to agonist mediated vasodilatation and those homozygous for Glu27 show enhancedagonist-mediated vasodilatation [32] These are not uncommon alleles Of 400 vol-unteers (ethnicity unclear) in America, 25 % were homozygous for Arg16 and Gln27,

12 % for Gly16 and Glu27, and 8 % for Gly16 and Gln27 [32] Again, the impact ofthe alleles on patient outcome in critical care remains uncertain

A perhaps rarer (0.5 – 2.3 % population) but better understood polymorphism ofthe 2-adrenoceptor is the substitution of isoleucine (Ile) for threonine (Thr) atposition 164 This allele has been known for some time to be associated withdecreased survival from heart failure More recently it has been shown that Ile164

confers a markedly decreased response in vivo to 2agonists, blunting vasodilatationand indirectly enhancing 1-adrenoceptor sensitivity [33]

Other Polymorphisms with Potential Clinical Importance in Critical Care

One of the most serious adverse reactions to heparin is heparin-induced topenia (HIT) with the potential to cause severe thromboembolic complications anddeath Heparin induced antibodies recognize and bind to heparin-platelet factor 4complexes and subsequently activate platelets via the platelet Fc -receptor to medi-ate HIT A single-nucleotide polymorphism commonly occurs in the platelet Fc -receptor gene affecting platelet aggregation [34] and an association between theplatelet-Fc -receptor gene and the risk for HIT has been reported by some investi-gators [34, 35], although not all [36] The largest of these studies included 389patients with a history of HIT, 351 patients with a history of thrombocytopenia orthrombosis due to other causes, and 256 healthy blood donors [35] The results sug-gested that the codon 131 genotype of the platelet Fc -receptor increases the risk ofHIT and worsens its clinical outcome In the future, it may be possible to genotypecandidates for heparin therapy to identify those at risk for drug-induced thrombo-embolic complications, in whom more intensive patient surveillance or alternativeanticoagulant therapy may be used

thrombocy-Digoxin is a substrate for P-glycoprotein (P-gp), an adenosine dependent drug efflux pump Recently, P-gp has been implicated in a number ofpharmacokinetic interactions [37] For example, an increase in serum digoxin con-centration after the initiation of amiodarone and quinidine therapy occurs second-ary to inhibition of P-gp in both the intestines and renal tubules, increasing digoxinabsorption and decreasing total-body digoxin clearance respectively P-gp is

triphosphate-encoded by the multidrug resistance gene (ABCB 1 or MDR-1), located on the long

Are Pharmacogenetics and Pharmacogenomics Important for Critically Ill Patients? 7

I

arm of chromosome 7 Sixteen SNPs have so far been identified in the ABCB 1 gene

[38] Most of the polymorphisms do not change the encoded amino acid or occur in

with the expression of P-gp in the intestines [39] A study of healthy volunteersshowed those with the T/T genotype had a twofold lower expression of P-gp thanthose with the C/C genotype [40] This should result in higher blood or tissue con-centrations of digoxin (and other drugs that are P-gp substrates) in individuals withthe T/T genotype This was confirmed in a study where subjects with the T/T geno-type had plasma digoxin levels 38 % greater than the maximum concentration insubjects with the C/C genotype; this difference was significant [40] Thus, patientswith the T/T genotype may require lower dosages of drugs that are P-gp substrates

to maintain therapeutic concentrations Alternatively the C/C homozygote, throughincreased expression of P-gp, may have sub-therapeutic concentrations of P-gp sub-strates and consequently experience underdosing However, there is some contro-versy as to the reproducibility of this genotype-phenotype association The main

phenotypic characteristic of ABCB 1 knockout mice is the loss of the blood-brain

barrier to drugs [41] Genetically determined low levels of P-gp expression may dispose to neurotoxicity

pre-Morphine is conjugated with glucuronic acid by the enzyme transferase 2B7 (UGT2B7), to form the active and potent metabolite, morphine-6-glucuronide (M6G) and the inactive metabolite morphine-3-glucuronide (M3G)[42] Following glucuronidation, metabolites are eliminated by glomerular filtration

UDP-glucuronosyl-Allelic variants in the genes encoding for UGT2B7 [43], opioid receptors (OPRM 1

gene) [44], or the transporter proteins for transport across the blood brain barrier

thus, the clinical efficacy of morphine Furthermore, genetic variability in the opioid system, such as the catecholamine metabolizing enzyme, catechol-O-methyl-transferase (COMT), although not directly involved in morphine metabolism, canalso modify the efficacy of morphine [46]

non-Response to steroids may similarly be affected by polymorphisms Mutations of

the glucocorticoid receptor gene (GR-gene) have been associated with corticosteroid

resistance possibly having wide ranging effects on metabolism, immune function,and response to stress [47]

Population Variations in Pharmacogenetics (Table 2)

Some genotype frequencies appear to be highly dependent on the ethnicity of thepopulation studied This broad picture of expression can allow some pharmacogene-tic therapeutic assumptions to be made without individual knowledge of phenotypebut, perhaps more importantly, it gives the clinician an indication to look moreclosely within certain populations for specific pharmacogenetic polymorphismswhen certain drugs are being considered This is demonstrated very clearly as part

of the investigation into polymorphisms of P-gp Ameyaw and colleagues [48] ined 1280 subjects from 10 ethnic groups The frequency of the 3435T allele in the

exam-ABCB 1 gene (associated with lower expression of P-gp) was significantly influenced

by ethnicity The T allele frequency was 0.16 in the African-Americans, 0.52 in theCaucasians, and 0.47 in the Chinese In support of this, a study of another P-gp sub-strate, tacrolimus, revealed that African-Americans had lower plasma concentrations

of tacrolimus than white subjects given equal dosages [49]

I

Table 2.Examples of population variation in clinically important pharmacogenetic polymorphisms

Drug Metabolizing Enzyme Example of Drug

(UGT1A1)

Irinotecan 10.9 % Whites

4 % Chinese

1 % JapaneseThiopurine S-methyltransferase (TPMT) Azathioprine 1 : 300 Whites

1 : 2500 AsiansCatechol-O-methyltransferase (COMT) Levodopa 25 % Whites

Challenges to Implementing Pharmacogenetics in Critically Ill Patients

The concept that all drug dosing regimens would benefit from routine genotyping islikely to remain unfounded The number of variables affecting pharmacokineticsand pharmacodynamics means that for most drugs the value of genotyping will below The most obvious question perhaps is why bother with genotyping when thera-peutic monitoring is possible Pharmacogenetics is most likely to have a role whenconsidering drugs for which speed of reaching therapeutic concentrations is impor-tant (e.g., tacrolimus, phenytoin) or for drugs with narrow therapeutic ranges andhigh toxicity There may be legal and ethical considerations to genomic-based thera-peutics and pharmacogenetics but specific directed genotyping, perhaps based onethnicity may be warranted For clinical trials pharmacogenetics may prove a funda-mental tool

The main difficulty remains in quantifying the contribution of genetic variation

to inter-individual differences in drug metabolism in critically ill patients All ies will be confounded by other factors that influence drug absorption, eliminationand action, including pre-existing disease and interaction with co-administeredmedications Undoubtedly the stress response to critical illness contributes toaltered drug effect, for example, through altered protein binding

stud-The liver and especially the kidneys are often affected by critical illness and both

of these have fundamental roles in the metabolism and excretion of drugs Datafrom patients with chronic renal failure suggest the presence of a circulating cyto-kine that inhibits the metabolic action of the CYP3A enzymes [50] with the possibil-ity that patients with certain phenotypes will be more affected than others [19] Thiseffect could be further complicated by some of the treatments we instigate Thecytokine is suggested to be somewhere between 10 and 15 kDa in size and notaltered or removed by hemodialysis [50] but so far, no study has been done to see

if it passes through the membrane of hemofiltration or hemodiafiltration

As a consequence of these difficulties, the majority of studies examining the ence of genetic variation on drug effect have focused on patients outside the inten-sive care unit (ICU) and typically in non-hospitalized individuals However, if vali-dated, the effective use of some drugs whose efficacy and safety appear to beaffected by polymorphisms may be improved by pharmacogenetic studies

influ-Are Pharmacogenetics and Pharmacogenomics Important for Critically Ill Patients? 9

I

The practical value of pharmacogenetics to clinical medicine is still debatable formost drugs However, as the human genome project develops, more polymorphisms

of potential importance will be revealed, particularly for drugs where precise dosing

is important for efficacy and to avoid toxicity or where rapidity in achieving targettherapeutic concentrations is required Nevertheless, the long-term prospects for crit-ical care pharmacogenetics are still unclear The application of pharmacogenetics tothe understanding of differences in drug actions in non-acutely ill populations couldprovide insight into how to investigate these effects in patients requiring critical care

It would seem logical to investigate drugs with narrow toxic and therapeutic ranges,and in which genetic variation correlates highly with either drug tolerance or risk oftoxicity It may also be worth concentrating on disease processes and treatments,common to critical care, which may exaggerate the effect of some polymorphisms(e.g., acute renal failure and renal support) For drugs that are well tolerated and effi-cacious over a broad range of serum concentrations, in depth studies of pharmacoge-netics are unlikely to yield benefit but for others there may be benefit and it may not

be long before bedside genotyping is available to aid in clinical prescribing

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pharmacogeno-2 Weinshilboum R (2003) Inheritance and drug response N Engl J Med 348:529 – 537

3 Evans WE, Johnson JA (2001) Pharmacogenomics: the inherited basis for interindividual ferences in drug response Annu Rev Genomics Hum Genet 2:9 – 39

dif-4 Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics Science 286:487 – 491

5 McLeod HL, Evans WE (2001) Pharmacogenomics: unlocking the human genome for better drug therapy Annu Rev Pharmacol Toxicol 41:101 – 121

6 Lander ES, Linton LM, Birren B, et al (2001) Initial sequencing and analysis of the human genome Nature 409:860 – 921

7 Kalow W (1956) Familial incidence of low pseudocholinesterase level Lancet 2:576

8 Evans WE, McLeod HL (2003) Pharmacogenomics – drug disposition, drug targets, and side effects N Engl J Med 348:538 – 549

9 Roses AD (2000) Pharmacogenetics and the practice of medicine Nature 405:857 – 865

10 Wilkins MR, Roses AD, Clifford CP (2000) Pharmacogenetics and the treatment of cular disease Heart 84:353 – 354

cardiovas-11 Higashi MK, Veenstra DL, Kondo LM, et al (2002) Association between CYP2C9 genetic ants and anticoagulation-related outcomes during warfarin therapy JAMA 287:1690 – 1698

vari-12 Kalow W (1997) Pharmacogenetics in biological perspective Pharmacol Rev 49:369 – 379

13 Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990) Genetic variation in response

to 6-mercaptopurine for childhood acute lymphoblastic leukaemia Lancet 336:225 – 229

14 Evans WE (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine apy Ther Drug Monit 26:186 – 191

ther-15 Lanfear DE, Marsh S, Cresci S, Spertus JA, McLeod HL (2004) Frequency of compound types associated with beta-blocker efficacy in congestive heart failure Pharmacogenomics 5:553 – 558

geno-16 Quirk E, McLeod H, Powderly W (2004) The pharmacogenetics of antiretroviral therapy: a review of studies to date Clin Infect Dis 39:98 – 106

17 Siddiqui A, Kerb R, Weale ME, et al (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1 N Engl J Med 348:1442 – 1448

18 Gardiner SJ, Begg EJ (2006) Pharmacogenetics, drug-metabolizing enzymes, and clinical practice Pharmacol Rev 58:521 – 590

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19 Kuehl P, Zhang J, Lin Y, et al (2001) Sequence diversity in CYP3A promoters and ization of the genetic basis of polymorphic CYP3A5 expression Nat Genet 27:383 – 391

character-20 He P, Court MH, Greenblatt DJ, Von Moltke LL (2005) Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo Clin Phar- macol Ther 77:373 – 387

21 Ng FL, Holt DW, MacPhee IA (2007) Pharmacogenetics as a tool for optimising drug therapy

in solid-organ transplantation Expert Opin Pharmacother 8:2045 – 2058

22 Hustert E, Haberl M, Burk O, et al (2001) The genetic determinants of the CYP3A5 phism Pharmacogenetics 11:773 – 779

polymor-23 Yu KS, Cho JY, Jang IJ, et al (2004) Effect of the CYP3A5 genotype on the pharmacokinetics

of intravenous midazolam during inhibited and induced metabolic states Clin Pharmacol Ther 76:104 – 112

24 Relling MV, Hoffman JM (2007) Should pharmacogenomic studies be required for new drug approval? Clin Pharmacol Ther 81:425 – 428

25 Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M (2007) Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance Pharmacogenomics 8:

743 – 759

26 Furuya H, Fernandez-Salguero P, Gregory W, et al (1995) Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagula- tion therapy Pharmacogenetics 5:389 – 392

27 Takahashi H, Kashima T, Nomizo Y, et al (1998) Metabolism of warfarin enantiomers in nese patients with heart disease having different CYP2C9 and CYP2C19 genotypes Clin Pharmacol Ther 63:519 – 528

Japa-28 Freeman BD, McLeod HL (2004) Challenges of implementing pharmacogenetics in the cal care environment Nat Rev Drug Discov 3:88 – 93

criti-29 Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD (2002) The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin J Am Coll Surg 194:267 – 273

30 Mialet Perez J, Rathz DA, Petrashevskaya NN, et al (2003) Beta 1-adrenergic receptor morphisms confer differential function and predisposition to heart failure Nat Med 9:

poly-1300 – 1305

31 Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002) Synergistic polymorphisms

of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure N Engl J Med 347:1135 – 1142

32 Dishy V, Sofowora GG, Xie HG, et al (2001) The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization N Engl J Med 345:

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33 Dishy V, Landau R, Sofowora GG, et al (2004) Beta2-adrenoceptor Thr164Ile polymorphism

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34 Burgess JK, Lindeman R, Chesterman CN, Chong BH (1995) Single amino acid mutation of

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thrombocytope-35 Carlsson LE, Santoso S, Baurichter G, et al (1998) Heparin-induced thrombocytopenia: new insights into the impact of the FcgammaRIIa-R-H131 polymorphism Blood 92:1526 – 1531

36 Arepally G, McKenzie SE, Jiang XM, Poncz M, Cines DB (1997) Fc gamma RIIA H/R 131 morphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis Blood 89:370 – 375

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P-glycopro-38 Cascorbi I, Gerloff T, Johne A, et al (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects Clin Pharmacol Ther 69:169 – 174

39 Min DI, Lee M, Ku YM, Flanigan M (2000) Gender-dependent racial difference in disposition

of cyclosporine among healthy African American and white volunteers Clin Pharmacol Ther 68:478 – 486

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40 Hoffmeyer S, Burk O, von Richter O, et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P- glycoprotein expression and activity in vivo Proc Natl Acad Sci USA 97:3473 – 3478

41 Schinkel AH, Smit JJ, van Tellingen O, et al (1994) Disruption of the mouse mdr1a protein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs Cell 77:491 – 502

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44 Klepstad P, Rakvag TT, Kaasa S, et al (2004) The 118 A G polymorphism in the human opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease Acta Anaesthesiol Scand 48:1232 – 1239

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Genetic Susceptibility in ALI/ARDS:

What have we Learned?

R Cartin-Ceba, M.N Gong, and O Gajic

Introduction

Since its initial description in 1967 [1], and subsequent definition in 1992 by theAmerican-European Consensus Conference [2], acute lung injury/acute respiratorydistress syndrome (ALI/ARDS) and all the different facets of this devastating illness– etiology, pathophysiology, epidemiology, management, and genetics – havebecome better understood Recent reports from the United States document that thissyndrome affects 190,000 patients annually with a mortality exceeding 35 % [3] Theincidence in European countries and Australia varies significantly, but is generallylower, ranging from 16 to 34 cases per 100,000 person-years at risk [4 – 6]

While several environmental risk factors clearly predispose to the development ofALI/ARDS [7], the expression of the syndrome and its attributable morbidity andmortality are highly variable A growing interest in genetic epidemiology and geno-mics in critical illness is illustrated in a prophetic statement by Villar et al back in2001: “Critical care medicine in the 21stCentury: from CPR (cardiopulmonary resus-citation) to PCR (polymerase chain reaction)”[8] The exponential growth of geno-mic studies has had a positive impact on the understanding of genetic determinants

in the development and outcome of critical care syndromes as well as on the standing of underlying pathophysiologic mechanisms Most studies have focused onthe genetic background of sepsis-septic shock and ALI/ARDS

under-In ALI/ARDS, multiple biologically plausible candidate genes have been fied However, ALI/ARDS is a complex syndrome where alterations in single genesare unlikely to explain the abnormal processes involved in alveolar permeabilityedema and inflammation that characterize this syndrome Unfortunately, most ofthe studies have been limited by design/analysis, definition of an appropriate pheno-type and controls, and ethnic/racial disparities

identi-For the intensivist taking care of patients with ALI/ARDS, the main questionsregarding genomics in this disease are: 1) Can a genetic marker identify patientswho are more susceptible to develop ALI/ARDS? 2) Can a genetic marker identifypatients who are more or less likely to respond to a specific therapy? 3) Can agenetic marker identify patients who are more likely to do poorly so that a progno-sis can be discussed with the patient and family?

Researchers interested in ALI/ARDS look for potential new insights into thepathogenesis of this syndrome, so that more effective treatment approaches may

be developed The aim of this chapter is to review the advances in knowledgeabout candidate genes implicated in the development and prognosis of ALI/ARDS

We will also describe the challenges and limitations of genetic epidemiology studydesigns and outline important steps that future studies ought to consider in order

13

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to provide the answers to the clinical and research questions related to critical ness.

ill-Basic Principles of Genomic Association Studies Related

to Critical Care Syndromes

Rather than a disease of a single etiology, ALI/ARDS is a heterogeneous syndromeand, as such, presents important challenges for genomic association studies Most ofthe initial molecular studies in ALI/ARDS were focused on protein biomarkers, ofwhich several have been associated with the development and prognosis of ALI/ARDS, including surfactant protein B [9], tumor necrosis factor (TNF)- [10], inter-leukin (IL)-6 and IL-1 [11], von Willebrand’s factor antigen [12], and plasminogenactivator inhibitor (PAI)-1 [13] The main objectives of trying to identify geneticmarkers in ALI/ARDS are: Assessment of susceptibility (which patients exposed tocommon triggers of ALI/ARDS will develop the syndrome); prognostication of out-comes (which patients will have worse outcomes); and what intervention can bemade based on the genetic abnormalities (what abnormal pathway can be inter-vened on in a successful manner to improve outcomes of this critical disease) Manyquestions related to the objectives outlined above are still unanswered: Why dosome patients with sepsis develop ALI/ARDS while others do not? Why do somepatients with ALI/ARDS develop multiple organ failure (MOF) and others do not?Can we predict patients at high risk of developing ALI/ARDS and/or poor outcomebased on the genetic background? What is the interaction between the environmentand the genome for the developing of ALI/ARDS? Why are some patients more sus-ceptible to adverse reactions of treatments, such as ventilator-associated lung injury(VALI)?

Given the problems and questions outlined above, a genomic approach was dered by the Human Genome Project that was finished in 2001 [14] The number ofgenes existing in the human DNA code was found to be around 25,000 [14] Thisproject helped to identify around 10 million common single nucleotide polymor-phisms (SNPs) SNP is a DNA variant that represents a variation in a single base and

hin-is used to describe the genetic variation between individuals In 2003, the Hap Mapproject [15] was started in order to determine the SNPs that contain the most pat-terns of human genetic variation, which is estimated to decrease the number of sig-nificant SNPs to about 300,000 to 600,000

Gene expression and function has been studied by approaching one gene andanalyzing its phenotype (either diseased or not) in diseases with classic Mendelianinheritance This process is not adequate for analysis of complex and heterogeneoussyndromes such as ALI/ARDS, where multiple interactions exist between differentgenes and environmental exposures Furthermore, as a syndrome that has emergedonly recently with the advance of life support interventions, ALI/ARDS is not known

to be a disease that presents as a familial cluster or familial aggregation; therefore,linkage mapping studies have not yet been possible or have very limited value in thesearch of candidate genes in ALI/ARDS Lastly, the advanced age of most patientswith ALI/ARDS limits the availability of parents and even siblings for family basedassociation studies Given these limitations, candidate gene-based unrelated case-control studies are the most common approach utilized in the search of genetic sus-ceptibility to ALI/ARDS In such studies, a genetic variant is genotyped in a popula-tion for which phenotypic information is available (ALI/ARDS) If a correlation is

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