Ε. Faist J. L . Meakins F. W. Schildberg (Eds.)

Host Defense Dysfunction in Trauma, Shock and Sepsis Mechanisms and Therapeutic Approaches

With 416 Figures and 153 Tables

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

Table of Contents

Section I

General Aspects/Perspectives

Progress in Trauma Care T h r o u g h Understanding the Cell Biology of in jury ( A . E . B a u e ) 3

Trauma, Sepsis and I m m u n e Defects (J. A. Mann ick ) 15

Cl inical Factors Influencing Host Defense Integri ty (J. L . Meakins) 23

The Intensive Care U n i t of T o m o r r o w ( H . J. Dieterich, Κ. Peter) 31

Section 2

Host Defense Integrity—Response and Stress

H o w the Immune System Discriminates Infectious Nonself from Noninfectious Self (C. A. Janeway Jr.) 39

Signal Transduct ion Mechanisms: Pathophysiologic Alterat ions ( Μ . M . Sayeed) 49

Neuroendocrine Regulat ion of Immune Func t ion (J. W. Holaday, J. R. Kenner , P. F. Smith, H . U . Bryant , E. W. Bernton) 59

V I I I Contents

Beneficial Effects of Stress Response Blockade on Patients Undergoing Surgery (H . Kehlet) 67

The Impact of Preexisting Disease Condi t ions for Host Defense In tegr i ty i n Traumatized and Cri t ica l ly 111 Patients (Ν. V . Chris tou, J. M . Tellado) 73

Section 3

From Injury to Multiple Organ Failure: Sequential Steps of Host Defense Impairment

3.1 Shock and Ischemia

Oxygen Radical-Mediated Endothel ial Cell In jury (G. O. T i l l , P. A. Ward) 85

Characteristics of Neu t roph i l Dysfunction (G. F. Babcock, C. L . Whi te -Owen, J. W. Alexander, G . D . W a r d e n ) . . . 95

Endothelial Dysfunction as an Early Cri t ica l Event in Ischemia and Shock (A. M . Lefer, X . M a ) 107

Role of Oxidants, Proinf lammatory Agents, and Granulocytes in the Post Ischemic Intestine (P. Kubes, D . N . Granger) 113

Hepatic Parenchymal and Nonparenchymal Cells in Hemorrhage and Ischemia ( M . G. Clemens) 127

Acute L u n g In ju ry F o l l o w i n g Shock and M a j o r T rauma (G. Schlag, Η . Redl) 139

Hemorrhage-Induced Alterat ions in Cel l -Mediated I m m u n e Funct ion ( I . H . Chaudry, A. Ayala, D . M e l d r u m , W . Ertel) 149

3.2 Intermediate Inflammatory Phase

Sepsis and M u l t i p l e Organ Failure: The Result of Whole Body Inf lammation (R. J. Goris) 161

Contents IX

M u l t i p l e Organ Fai lure ( M O F ) , and Whole Body Inf lammat ion After M u l t i p l e T r a u m a (G. Regel, Η . C. Pape, F. K o o p m a n n , J. A. Sturm) 171

Neutrophils , Cytokines, Oxygen Radicals, and L u n g In ju ry (P. A. Ward , M . S. M u l l i g a n , J. S. Warren) 177

The Role of ß 2 - Leukocyte Integrins I n V i v o (S. R. Sharar, Ν . B. Yedder, W . J. Mi lesk i , C. L . Rice, J. M . Har lan , R. K . Winn ) 181

The Angry Macrophage and Its Impact on Host Response Mechanisms (R. V. Maier ) 191

Eicosanoids, Cytokines and Altered Metabol ic C o n t r o l in the Evo lu t ion of the Posttraumatic Host Defense Failure Syndromes (Adul t Respiratory Distress Syndrome and M u l t i p l e Organ Failure Syndrome) (J. H . Siegel) 199

Diagnostic Role of N e w Media tors and Markers of In f lammat ion i n Mul t i p l e Injured Patients (D. Nas t -Ko lb , Ch . Waydhas, M . Jochum, M . Spannagl, W . Machleidt , Κ Η . Duswald , L . Schweiberer) 221

Jn.ravascular Ac t iva t ion of Polymorphonuclear Neut rophi l s i n Cr i t ica l ly 111 Anergic Patients (J. M . Tellado, Ν . V . Chris tou) 229

Mediators of Remote L u n g In jury ( Τ Lindsay, J. H i l l , C. R. Valerie, D . Shepro, Η . B. Hechtman) 235

3.3 Sepsis

Inmuno log ic Dyshomeostasis in M u l t i p l e Organ Failure: T i e Gut -L ive r Axis ((J C. Marshal l ) 243

T i m o r Necrosis Factor and Other Cytokines as Media tors of Clinical Sepsis (S F. L o w r y ) 253

T ie Protein C System in Septic Shock <F. B. Taylor ) 263

X Contents

Leukocyte-Endothel ia l Interact ions i n T rauma and Sepsis ( H . Redl, G . Schlag, Η . P. Dinges, R. Kneidinger, J. Davies) 277

Role of Oxygen Radicals in M u l t i p l e Organ Failure ( H . P. Fr iedl , O. Trentz , G . O . T i l l , P. A. Ward) 287

Arachidonic Ac id M e t a b o l i s m i n Endotoxemia and Sepsis: Therapeutic Approaches (J. A. Cook , E. L i , P. V . Halushka) 297

Section 4

Immune Mechanisms for the Control of Infection Under Physiologic and Stressful Conditions

Biology and Func t ion o f C y t o t o x i c T-Cells (R. C Bleackley) 311

Immune Response o f Heat Shock Proteins (S. Η. E. Kaufmann) 317

Prostaglandins Media te the Expression o f a 72-kDa Heat Shock Protein i n H u m a n Fibroblas ts (A. E. Heufelder, Β. Ε. Wenzel , R. S. Bahn) 323

Glucocor t i co id - Immune System Interact ions in Injury and Sepsis (S. E. Calvano) 331

Hemorrhagic Shock Inh ib i t s Myelopoies is Independent of Bacterial Trans loca t ion ( D . H . Liv ings ton , J. Hseih, T . M u r p h y , B. F. Rush Jr.) 339

Monocyte H L A - D R Ant igen Expression: Its Reproducibi l i ty in Asymptomat ic Volunteers and Cor re la t ion wi th Cl in ica l Infection (W. G. Cheadle, M . J. Hershman, S. R. Wellhausen, Η. C Polk Jr.). . . . 349

Phenotypic and Func t iona l Characteristics of Peripheral B lood Lymphocytes in a Defined G r o u p o f Poly t rauma Patients (G. C. Spagnoli, M . Heberer, P. Vogelbach, R. Rosso, J. J ö r g e n s e n , F. Harder) 355

Cell-Mediated I m m u n i t y D u r i n g and After Cardiopulmonary Bypass (A. Paccagnella, S. DeAnge l i , M . M o r d a c c h i n i , G. Caenaro, A . Nie r i , P. Rosi, P. M i c h i l o n , M . Calo , G . Zanardo , L . Salvador, C. Fur lan, G. Simini) 359

Contents X I

Altera t ions in Funct ion and Phenotype of Monocy tes f rom Patients w i t h Septic Disease: Predictive Value and N e w Therapeut ic Strategies ( H . D . V o l k , Μ . Thieme, U . Ruppe, S. H e y m , W - D . Docke , D . Manger, S. Zuckermann , A. Golosubow, B. Nieter , Η . K l u g , R. van Baehr) . . . . 365

Effects o f Exercise on the Immune System w i t h Special Reference to N a t u r a l K i l l e r Cells (Β . K . Pedersen) 373

In terac t ion of Immune, Interferon, and O p i o i d Systems in Professional Athletes (E. Gotovtseva, I . Surkina, P. Uchakin , J. Shchur in , S. Pschenichkin, N . Kos t , A. Zozulya, O. I lyinsky) 379

Section 5

Inflammatory Mechanisms in Traumatic and Septic Injury

Whi te Cells in Burn Patients (D . N . Herndon , T. C. Rutan, J. M l a k a r , D . F leming) 385

Fibronect in Degradation: A n In V i t r o M o d e l o f N e u t r o p h i l Mediated Endothel ia l Cell Damage ( K . D . Forsyth) 391

Adenosine Inhibi ts Postischemic Leukocyte Adherence to the Endothe l ium of Postcapillary Venules via A 2 -Recep to r ( D . Nol te , H . A. Lehr, Κ. Messmer) 399

Prostaglandin E , Inhibi ts the S t imula t ion of Neu t roph i l s I n V i t r o and I n V i v o and Improves Cardio-Respiratory Funct ions in M u l t i p l y Traumat ized Patients at Risk of A d u l t Respiratory Distress Syndrome (A. Dwenger, M . L . Ner i ich , E. Jonas, G . Schweitzer, J. A . Sturm, H . Tscherne) 403

Product ion and .Characterization of Peptide-Specific M o n o c l o n a l Antibodies that Recognize a Neoepitope on H o g C5a ( U . H ö p k e n , Α. S t rüber , Μ. Oppermann, Μ . M o h r , Κ . Η . M ü c k e , Η. Burchardi , Ο . Gö tze ) 411

The Oxidat ive Burst Reaction of Neu t roph i l s is Reduced by the Acute Phase Serum Amylo id -Α Protein (R. P. L inke , V. Bock, G. Valet, G. Rothe) 419

X I I Contents

Interact ion o f Pentoxifylline and Adenosine in the I n h i b i t i o n of Superoxide A n i o n Product ion of H u m a n Polymorphonuclear Leukocytes ( M . Thiel , Η. Bardenheur, C. Madler , K . Peter) 423

Adhesive Interactions of Neutrophi ls w i t h Endothel ia l Cells (C. W. Smith, O. Abbassi, S. B. Shappell, D . C. Anderson, L . V. M c l n t i r e , Τ. K . K i sh imo to ) 431

Endothelial Cel l S t imula t ion by A n t i - C D 9 Antibodies (K . D . Forsyth) 437

Decrease in Leukotr iene Synthesis from Leukocytes Isolated in Septic Patients ( H . Lessire, B. M i l e , M . Pfisterer, Τ. Ν . Nguyen, Ε. Torwesten, C. Puchstein, Β. M . Peskar) 443

Aggravat ion o f Ischemia-Reperfusion In jury in the Striated Muscle Microc i rcu la t ion by Acute Endotoxemia ( H . A. Lehr, Κ. Kawasaki , Τ. J. Galla , D . Nol te , K . Messmer) 449

Selective I n h i b i t i o n of Polymorphonuclear Leukocyte Oxidat ive Burst and C D 1 l b / C D 16 Expression by Prostaglandin E 2

(J. A. Lieberman, F. M . W a l d m a n , J. K . Horn ) 453

The Role of Lysosomal Cysteine Proteinases as Markers of Macrophage Ac t iva t ion and as Nonspecific Mediators of In f lammat ion (W. Machleidt , I . Assfalg-Machleidt, A. Bi l l ing , D . F r ö h l i c h , Μ . Jochum, Τ. Joka, D . Nas t -Ko lb ) 459

Endothel in Mediates a C a 2 + Ac t iva t ion Signal in H u m a n Monocytes ( M . Hur iba i , D . S. Margol i s , M . A. M c M i l l e n ) 465

N i t r i c Oxide Synthesis in Sponge M a t r i x Allografts Coincides wi th the In i t i a t ion o f the Allogeneic Response (J. M . Langrehr, J. Stadler, Τ . R. Bil l iar , W. H . Schraut, R. L . Simmons, R. A. Hoffman) 471

Neu t roph i l Elastase Induces L u n g In ju ry F o l l o w i n g Lower L i m b Ischemia (R. Welbourn , G . Go ldman , D . Shepro, Η . B. Hechtman) 477

P M N Elastase i n Local Infection (Κ. M . Peters, K . Koberg , H . Kehren, Κ . W . Zilkens) 481

Contents X I I I

Opioids f rom I m m u n e Cells Interact w i t h Receptors on Sensory Nerves to I n h i b i t Noc icep t ion i n In f l ammat ion (C. Stein, A. H . S. Hassan, R. Przewlocki , C. Epplen, C. Gramsch, K . Peter, A. Herz) 485

Section 6

Hepatocellular Injury in Ischemia, Trauma and Sepsis

A n I n V i t r o M o d e l of Hepatic Fai lure in Septic Shock (T. H ä r t u n g , Α. Wendel) 493

Ischemia-Reperfusion In ju ry of the Liver: Role of Neutrophi ls and Xanthine Oxidase ( M . D . Menger, M . J. Mül l e r , Η . P. Fr iedl , O. Trentz, K . Messmer). . . . 499

N i t r i c Oxide Regulates Prostaglandin E 2 Release by Rat Kupffer Cells (J. Stadler, Β. G . Harbrecht , Μ . D i Silvio, R. D . Curran , M . L . Jordan, R. L . Simmons, Τ. R. Bi l l iar ) 505

C3a and C5a in Liver Transplantat ions D u r i n g Bypass, Reperfusion and the Postoperative Phase ( M . Har tmann , L . Verner) 511

Effect of Superoxide Dismutase on Altered Hepatic Calc ium Regulation D u r i n g Gramnegative Sepsis (S. Rose, J. Dike , V. B ü h r e n , O. Trentz, Μ . M . Sayeed) 517

Role of Liver Macrophages (Kupffer Cells) i n Bacterial Cell Wal l - Induced Hepatic In f l ammat ion (T. Kossmann, C. Manthey , J. B. Al len , C. Morgan t i -Kossmann , K . Ohura , S. E. Mergenhagen, S. M . Wahl ) 523

T u m o r Necrosis Factor A l p h a Inhib i t s Hepatocyte M i t o c h o n d r i a l Respiration and Induces Release of Cytoplasmic Enzymes (J. Stadler, Β. G. Bentz, J. M . Langrehr, R. D . Curran , T. R. Bi l l iar , B. G . Harbrecht, R. L . Simmons) 527

M o d u l a t i o n of Hepatic M i t o c h o n d r i a l Fat Ox ida t ion and Hepatic Gene Transcr ip t ion by T u m o r Necrosis Factor (R. A. Barke, P. S. Brady, L . J. Brady) 531

X I V Contents

Increased Leukocyte Adhesion in Liver Sinusoids F o l l o w i n g Superior Mesenteric Ar tery Occlusion in the Rat (V. Bühren , Β. Maier , R. Hower , Μ . D . Menger, I . Marz i ) 539

Section 7

Cytokines and Modulation of Cytokine Action

Gene K n o c k o u t : New Approach to the Physiology of Cytokines (F. F. Csaikl , IJ . N . Csaikl , S. K . D u r u m ) 547

The Role of Inter leukin-1 and Other Macrophage-Derived Cytokines in Macrophage-T-Cell Interactions ( L . S. Davis, P. E. Lipsky) 5 5 7

Inter leukin-1-Induced Hypotension and the Effect of an Inter leukin-1 Receptor Antagonist (C. A. Dinare l lo) 5 7 1

Interleukin-8 (Neu t roph i l -Ac t iva t ing Peptide-1) and Related Chemotactic Cytokines ( M . Baggiolini) 5 7 7

Cellular and Molecu la r Mechanisms that Regulate the Produc t ion of Interleukin-8: The Potential Role of Chemotactic Cytokines in Acute Respiratory Distress Syndrome and M u l t i p l e Organ Failure (S. L . Kunke l , S. W . Chensue, T. J. Standiford. R. M . Strieter) 583

Generat ion and Properties of Neu t roph i l -Ac t iva t ing Peptide 2 (NAP-2) (A. Walz, F. M e l o n i , R. Zwahlen, I . Clark-Lewis , B. Car) 593

Soluble and Ce l l Surface Receptors for T u m o r Necrosis Factor ( H . Engelmann, D . Aderka, Y . Nophar , O. Kemper , C. Brakebusch, Η . H o l t m a n n , D . Wallach) 5 9 9

Regulat ion o f C y t o k i n e Synthesis T h r o u g h Cyclic Nucleotides (S. Endres, H . J . Fü l le , Β. Sinha, D . Stoll , R. Gerzer) 609

Removal of C i r cu l a t ing Cytokines by Hemodialysis Membranes I n V i t r o ( G . Lonnemanm, R. Schindler, C. A. Dinare l lo , Κ. M . K o c h ) 613

M o d u l a t i o n o f M o n o k i n e Product ion I n V i t r o by H u m a n Intravenous

I m m u n o g l o b u l i n (J. P. Andersson, S. Nagy, U . G. Andersson) 625

Contents XV

Trans forming G r o w t h Factor ß \ Upregulates the Inter leukin-2 Receptor α Promoter (C. S. Cocanour, F. M . Orson, D . Thomas, S. Rich) 6 2 9

Section 8

Cytokines in Acute Phase States and Trauma

Interact ions of Immunopa tho log ica l Mediators (Tumor Necrosis F a c t o r - α , - / i , Prostaglandin E 2 ) i n Traumatized Individuals ( C L . Mi l le r -Graz iano , G . Szabo, K . Kodys, B. Mehta) 637

I n V i t r o Product ion and Secretion of Interleukin-1 by H u m a n Monocytes After Surgical T r a u m a ( M . L . V u o t t o , E. Bresciano, D . Manc ino , Μ . T. Ielpo, M . R. Mos t i , G . De M a r t i n o , A. Barbarisi) 651

The Biological Characteristics of Cytokines and Their Interactions w i t h Prostaglandins F o l l o w i n g Hemorrhagic Shock (W. Ertel , E. Faist, I . H . Chaudry) 655

The Response of Inter leukin-1 and Inter leukin-6 i n Patients Undergoing M a j o r Surgery (R. J. Baigrie, P. M . Lamont , M . J. Da l lman , P. J. Mor r i s ) 665

Possible Role of Cytokines in the Stress Response of the Hypo tha lamo-P i tu i t a ry -Adrena l Axis D u r i n g Upper A b d o m i n a l Surgery (Y. N a i t o , S. Tamai , K . Shingu, K . Shindo, T. Shichino. T. Matsu i , O. Ebisui , J. Fukata, K . Yone, K . M o r i ) 673

The Synthesis of Stress Proteins i n Cul tured Cardiac Myocytes Is Induced by the Interleukins and T u m o r Necrosis Factor ( I . L ö w - F r i e d r i c h , D . Weisensee, P. M i t r o u , W . Schoeppe) 677

Effects o f T u m o r Necrosis Factor on the Hypotha lamic-P i tu i t a ry-Adrena l Axis ( K . Mea ly , B. G . Robinson, J. A. Majzoub, D . W . Wi lmore ) . 681

In te r leukin-2-Modula ted Cy tok ine Secretion in Thermal ly Injured Patients (J. Teodorczyk-Injeyan, B. Sparkes, W. Peters) 687

X V I Contents

Cytokine Treatment of Radiat ion-Induced Hemopoiet ic Suppression: Results of Inter leukin-6 and Granulocyte Colony-St imula t ing Factor in a M u r i n e Radia t ion M o d e l ( M . L . Patchen, T. J. Mac Vi t t ie , Β. D . Solberg, R. Fischer, L . M . Souza) 693

Circula t ing T u m o r Necrosis Factor i n Active Inf lammatory Bowel Disease (K . R. Gardiner, Μ . I . Hal l iday, F. L l o y d , S. Stephens, B. J. Rowlands) . 699

Interleukin-1 and T u m o r Necrosis F a c t o r - α Suppress Hypoxia- Induced Product ion of Ery thropoie t in I n V i t r o ( M . Wolff, W . Jelkmann, J. Fandrey) 705

Neopterin, Interferon-?, and Immunodeficiency States (D . Fuchs, Α. Hausen, G . Reibnegger, G . Weiss, E. R. Werner. G. Werner-Felmayer, H . W ä c h t e r ) 715

Systemic Cytokine Response to Strenuous Exercise ( H . Northoff , Μ . W. Baumstark, W. Α. Flegel, A. Berg) 719

Section 9

The Mediator Role of T N F in Sepsis

Act iva t ion of Neutrophi ls by T u m o r Necrosis F a c t o r - α D u r i n g Sepsis (G. Rothe, W. Kel lermann, J. Briegel, B. Schaerer, G . Valet) 727

Dist inct Subpopulations of H u m a n Peripheral B lood Monocytes Characterized by Absence of the C D 14 Surface M a r k e r , and Distinguished by H i g h or L o w Intracellular Glu ta th ione (R. L . Rabin, F. J. Staal, M . Roederer, M . M . Beiber, L . A. Herzenberg, Ν . Η . Teng) 737

The Role of Endotoxins in Burns: Anomalies in Cy tok ine Regulat ion of I m m u n i t y (R. A. Winchurch , D . Z h o u , A. M . Munster) 743

Role of T u m o r Necrosis Factor on Pseudomonas Aeruginosa Infect ion and on A n t i t u m o r A c t i v i t y i n Relation to Arachidonic Cascade ( N . Satomi, A. Sakurai, R. Haranaka, K . Haranaka) 751

Contents X V I I

Survival f rom Cecal L iga t ion and Puncture and the F o r m a t i o n of Fibrous Adhesions in the Peritoneal Cavi ty Depend on Endogenous T u m o r Necrosis Factor (B. Echtenacher, W . Falk, D . N . M ä n n e l , P. H . Krammer ) 755

The Cellular Mechanisms of T u m o r Necrosis Factor-Induced M o r t a l i t y : A Possible Role for Platelet Act iva t ing Factor and/or the Eicosanoids (J. M . Moore , M . Hubbard , M . Earnest, P. Wi l l iams, A . DiSimone, N . Abumrad , J. R. Fletcher) 759

Section JO

Endotoxin—Mechanisms of Action and Protection from Shock

Molecula r Mechanisms of Lipopolysaccharide-Induced Cytokine Product ion by Monocytes (R. R. Schumann, J. C. Math i son , P. S. Tobias, R. J. Ulevi tch) 767

Na tu ra l Endotoxic Shock Protect ion by Soluble C D 1 4 (C. Schutt, C. K r ü g e r , W . Schönfe ld , U . Grunwa ld , T. Schilling) 773

Use of M o n o p h o s p h o r y l L i p i d A as a Prohylactic for Sepsis and Shock (J. A. Rudbach, J. T . U l r i c h , Κ. Β. von Eschen, D . Beatty) 779

Hemodynamic and Pulmonary Response to Treatment w i th On-L ine Adsorp t ion on Po lymyx in Β D u r i n g Endotoxemia in Pigs (B. Stri t tmatter , W . Schneider, K . Massarrat, A. Eckhardt , Β. U . von Specht) 783

Apo l ipopro te in A - I Enriched L ipopro te in Attenuates T u m o r Necrosis Factor Product ion and Shock in an Anesthetized Rabbit Endotoxemia M o d e l (Α. P. H ü b s c h , J. E. D o r a n , P. G . Lerch, G . Hodler , J. J. Morgenthaler , H . -J. Heiniger) 789

Escherichia Co/Mnduced Septic Shock in the Baboon: A n A n i m a l M o d e l for the Evalua t ion of Neutral is ing M o n o c l o n a l Antibodies to Phospholipase A 2

(R. Buchta, J-A, Green, G . M . Smith, C. Gabelish, D . Cairns, C. Salom, M . Conte, P. Mackie , R. Sublett, F. B. Taylor , I . A . Rajkovic, K . F. Scott) 792

X V I I I Contents

Leukotriene I n h i b i t o r and Antagonist Prevent Endo tox in Lethal i ty i n Carrageenan-Pretreated Mice (O. Masanor i , K . Masayuki , Y. Shin-Ichi , M . Yasuo, A. Shigematsu). . . 799

Effect of Type-Specific Ant iserum on the Pulmonary Hypertensive Response to G r o u p Β Streptococcus i n Piglets (J. B. Philips, M . Chwe, J. X . L i , Β. M . Gray, D . G. Pr i tchard, J. R. Oliver , K . Gran tham, W . Mena) 803

Detect ion of I g E Reactive w i t h Lipopolysaccharide in Plasma of Traumat ica l ly Injured Patients (J. T. D i Piro, R. G . H a m i l t o n , T. R. Howdieshell , D . Callaway, N . F. Adkinson) 807

Altered Guanine Nucleotide Protein Funct ion: Potential Role in Endo tox in Tolerance ( K . Coffee, P. V. Halushka, W . C. Wise, J. A. Cook) 811

Section 11

Clinical Aspects of Multiple Organ Failure

The Pattern of Organ Failure F o l l o w i n g Severe T r a u m a — A Postmortem Study ( H . C. Pape, G . Regel, Kleemann, J. A. Sturm, H . Tscherne) 823

Hyper tonic Volume Therapy: A Feasible Regimen to Cont r ibute to the Prevention of M u l t i p l e Organ Failure? ( U . Kreimeier, L . Frey, A. Pacheco, K . Messmer) 831

A New Sepsis Scale for Burns: Corre la t ion w i t h Endo tox in and Host Response (A. M . Munster , Μ . Meek, R. A. Winchurch , C. Dickerson) 843

M u l t i p l e Organ Failure: Cl inical Characteristics of G u t - O r i g i n Septic States (J. R. Border) 851

Intraperi toneal Infections and M u l t i p l e Organ Failure (T. Hau) 857

The Role o f Empi r ica l Laparo tomy i n the Management of Sepsis and Mul t i sys tem Organ Failure ( H . C. Polk, P. Burgess, W . G . Cheadle) 863

Contents ΧΪΧ

Management of the W o u n d as Therapy for M u l t i p l e Organ Failure ( L . F l in t ) 867

Aggressive Enteral N u t r i t i o n Reduces Sepsis i n the Hypercatabolic In jured Patient (Ε. E. M o o r e , F. A. Moore ) 871

Cl in ica l -Media to r Correlat ions of M u l t i p l e Organ Failure and Preventive/Therapeutic Strategies: T o Block Stimulate, or Replace? Tha t is the Question (A. E. Baue) . 881

Section 12

The Pathophysiologic Impact of Bacterial Translocation and Strategies for Its Prevention

Bacterial Translocation F o l l o w i n g M a j o r Thermal Injury in Rats, Sheep, and Mini -P igs ( D . N . Herndon, S. T. Zeigler, T. C. Rutan, R. Saydjari, S. E. M o r r i s , G . I . Beerthuizen, R. Tokyay , C. M . Townsend) 893

Does Early Portal Bacteremia/Endotoxemia Prime for Postinjury M u l t i p l e Organ Failure? (F. A. Moore , Ε. E. Moore , R. S. Poggetti, O. J. McAnena) 899

Prevention of Bacterial Translocat ion w i t h Ear ly Enteral Feeding—A Feasible Approach? (J. W. Alexander) 903

Gut -Der ived Infectious-Toxic Shock Syndrome: Therapeutic Chances w i t h Polyspecific Immunoglobu l ins ( H . Cottier, A. Häss ig , R. Kraf t ) 911

Maintenance of Gastrointest inal In tegr i ty After Burn In jury w i t h Specific Dietary Supplementation and Epidermal G r o w t h Factor (R. L . Zapata-Sirvent, J. F. Hansbrough, M . G Cox, P. W o l f ) 917

Selective Decontaminat ion of the Digestive Tract: Open Questions and Controversies (L . L . Dever, W. G . Johanson Jr.) 925

XX Contents

Selective Decontamina t ion o f the Digestive Tract (SDD): Review of Available Cl in ica l Studies (C. P. Stoutenbeek, Η . K . van Saene) 931

Nonselective G u t Decontaminat ion for Avoidance of Bacterial Translocat ion i n Shock (J. Brand, A. Ekkernkamp. A. Helbig , G . M u h r ) 939

Section 13

Antibiotic Interactions with Host Defenses

Antibiot ics and Phagocytic Cell Func t ion : A Cri t ical Review (P. van der Auwera, M . Bonnet, Μ Husson, F. Jacobs) 945

Interaction of Ant ib io t ics w i t h the Phagocyte Oxidat ive Burst (Μ. T. Labro , J. El Benno) 953

Intraphagocytic Cell Penetration and Intracellular Bioact iv i ty of Ant ibiot ics (A. Pascual) 965

Extraphagocytic K i l l i n g of Bacteria i n the Presence o f Ant ib io t ics (P. J. van den Broek) 971

Cell W a l l Inh ib i tors and Bacterial Susceptibility to Phagocytosis (A. M . Cuffini , N . A. Carlone, V. T u l l i o , G . Cavallo) 979

Protein Synthesis Inh ib i tors and Bacterial Susceptibility to Phagocytosis (C. G. Gemmell) 987

Section 14

The Role of Nutrition in Host Defense

Augmenta t ion of Host Defense Reactivity w i th Special Nutr ients (J. W. Alexander) 995

The Role of Structured Lip ids in Host Defense Interactions (R. A. Forse, G. L . Blackburn , B. R. Bistr ian) 1003

Contents X X I

M a n i p u l a t i o n of Cytokine Synthesis T h r o u g h Dietary Lipids (S. Endres, S. N . Meydani , C. A. Dinare l lo ) 1013

Die tary Fish O i l Prevents Postischemic Leukocyte /Endothel ium Interact ion Through Inh ib i t i on of Leukotr iene Biosynthesis ( H . A. Lehr, D . Nol te , C. H ü b n e r , Κ. Messmer) 1017

Die tary Requirement for Preformed Purine and Pyr imidine Bases for Intact Funct ion of Cellular Immune Response: A Review (L . G . Kabbash, A. R. Forse) 1023

Relationship of Plasma Acute-Phase Prote in to A m i n o Ac id Levels D u r i n g High-Dose Branched Chain A m i n o Acid Support i n Sepsis (C. Chiarla , I . Giovannin i , J. H . Siegel, Μ . Castagneto) 1029

Section 15

New Insights into the Mechanisms of Wound Healing

W o u n d Management and the Stress Response (D. N . Herndon, R. L . Rutan, T. G Rutan , J. M . M l a k a r ) 1037

The Role of the W o u n d in Posttraumatic Immune Dysfunction ( M . C. Regan, A. Barbul) 1043

The Role of G r o w t h Factors in the Regulat ion of W o u n d Repair ( D . R. K n i g h t o n , V. D . Fiegel, G. D . Phil l ips) 1051

A n Adverse W o u n d Environment Reduces Leukocyte Phagocytosis and Protein Synthesis (B. R. Moelieken, S. J. Mathes, A. Amerhauser, D . C. Price, Τ. Κ Hunt ) 1065

Basic Fibroblast G r o w t h Factor Inh ib i t s the Release of Oxygen Radicals by H u m a n Granulocytes (W. Macheiner, C. O i smül le r , W. Pohl , Μ . Micksche) 1079

The Influence of Liver Regeneration o n Skin W o u n d Heal ing and Lymphocyte G r o w t h Features ( N . Zarkovic , I . Stipancic, M . Hrzenjak, Z . I l ic , S. Kis , I . Vuckovic , M . Jurin) 1085

X X I I Contents

Section 16

Therapeutic Immunomodulatory Approaches: Prevention

Therapy of Secondary T-Cel l Immunodeficiencies w i t h Biological Substances and Drugs: A n Update (J. W . Hadden, Ε. M . Hadden) 1097

Progress in Antiinfective Perioperative I m m u n o m o d u l a t o r y Therapy w i t h Simultaneous Admin i s t r a t ion of Blocking and Enhancing Agents (E. Faist, A. Markewi tz , S. Endres, D . Fuchs, L . H ü h n e r , S. Lang) . . . 1109

Effect of I m m u n o m o d u l a t i o n of Skin Test Reactivity F o l l o w i n g Trauma (W. Browder, D . Wil l iams, G . Ol ivero , P. M a o , A. Franchello, F. Enrichens) 1131

Therapeutic Use of Cytokines: A n i m a l Models ( M . L . Rodr ick, Ν . Μ . Moss, D . Β. Gough , P. G . Horgan , Β. M . Crowley, M . G. O 'Riorda in , R. G . M o l l o y , J. A. Mann ick ) 1135

The Rationale for Gamma-Interferon Admin is t ra t ion in T r a u m a Patients ( H . C. Polk, Jr., S. Galandiuk , G. Sonnenfled, W. G . Cheadle) 1145

Immunomodula to r s of the Thermal In jury Response (J. M . Mlaka r , J. P. Waymack) 1153

Section 17

Endotoxin Neutralization with IV-Immunoglobulins and Monoclonal Antiendotoxin Antibodies

Antiendotoxic Therapy wi th Polyclonal and Polyvalent Immunoglobul ins : I n V i t r o and I n V i v o Studies ( D . Berger, S. Schleich, Μ . Seidelmann, Η . G . Beger) 1163

The Use of Polyvalent I m m u n o g l o b u l i n G in Patients w i t h Sepsis and M u l t i p l e Organ Failure (G. Pilz, Κ. Werdan), 1175

Cl in ica l Effects of I m m u n o g l o b u l i n Admin i s t r a t ion in Patients w i t h M a j o r Burn Injury (A. M . Munster) 1187

Contents X X I I I

Treatment of Gram-Negat ive Septic Toxic Diseases w i t h an I m m u n o g l o b u l i n Preparat ion Conta in ing I g G , I g M , and IgA: A Prospective Randomized Cl in ica l T r i a l ( I . Schedel, U . Dreikhausen, B. Nentwig , M . H ö c k e n s c h n e i d e r , D . Rauthmann, S. Bal ikc ioglu , R. Coldewey, Η . Deicher) 1193

Immunotherapeut ic Strategies for Passive Immuniza t ion Against Pseudomonas aeruginosa (L . Saravolatz, J. K i l b o r n , J. Pennington) 1205

Bind ing Characteristics of the Ant i endo tox in A n t i b o d y Xomen-E5 to Bacterial Whole-Cel l Antigens (K . J. Gorel ick, D . M . W o o d , J. B. Parent, E. L i m , Κ. D . Knebel , D . Μ . Fishwi ld , D . T. Reardan, P. W . T r o w n , P. J. Conlon) 1211

Immunotherapy w i t h H u m a n Ant iendo tox in Antibodies in the Treatment of Gram-Negat ive Sepsis: Practical Considerations (C. H . Worte!) 1219

The Use of A n t i b o d y Specificity and Affini ty i n Determining the Protectiveness of H u m a n M o n o c l o n a l Antibodies Against Fatal Infections w i t h Nosocomia l Gram-Negat ive Bacteria ( U . Bruderer, A. B. Lang, B. By l , A. Crusiaux, J. Deviere) 1223

Section 18

Interventional Strategies in the Therapy of Septic Shock

Potential Benefits of Platelet Ac t iva t ing Factor Receptor Antagonists in Endotoxemia/Sepsis (J. R. Fletcher, J. A. M o o r e , A. G . DiSimone, N . Abumerad, P. Wi l l i ams , J. Pol lard , J. Coll ins , E. Graves) 1229

Phospholipase A 2 : A New Target for M o n o c l o n a l A n t i b o d y Therapy i n Sepsis (K . F. Scott, G . M . Smith , J. A. Green, C. Salom, C. Gabelish, D . Cairns, A. Tseng, P. Mackie , R. Buchta, R. Lee, I . A. Rajkovic) . . . 1237

Admin i s t r a t ion o f Antiadhesion Molecules: A Feasible Approach? (R. K . W i n n , S. R. Sharar, W J. Mi lesk i , C. L . Rice, J. M . Har lan) . . . 1243

Local Admin i s t r a t i on o f Inter leukin-2 Protects Mice from Lethal In t r a -Abdomina l Bacterial Sepsis (R. Richards, D . R. Green) 1251

X X I V Contents

M u r i n e In t raabdomina l Abscess: Immune M o d u l a t i o n w i t h Interferon-y (S. Galandiuk, S. Appel , J. D . Pietsch, W . G . Cheadle, H . C. Polk, Jr.) . 1257

Acute Resuscitation and An t iox idan t Therapy (Β. E. Hedlund. P. E. Hal laway) 1263

Cl inical Indications for the Admin i s t r a t i on of Oxygen Radical Scavengers (J. H i l l , T. Lindsay, C. R. Valer i , D . Shepro, Η . B. Hechtman) 1271

First Experiences w i t h Recombinant H u m a n Superoxide Dismutase Therapy in Polytraumatized Patients ( I . M a r z i , V . B ü h r e n , Α. Schü t t l e r , Ο . Trentz) 1279

Subject Index 1285

Diagnostic Role of New Mediators and Markers of Inflammation in Multiple Injured Patients

D. N a s t - K o l b 1 , C. Waydhas 1 , M . J o c h u m 2 , M . Spannagl 3 , W . M a c h l e i d t 4 , K . H . D u s w a l d 1 , and L . Schweiberer 1

Introduction

The major cause of late death after severe b lun t t rauma is (multiple) organ failure (OF) , w h i c h is a direct consequence of mediators released dur ing pr imary tissue damage and c i rcula tory shock. T o further elucidate the role of inf lammat­ory mediators i n the development o f O F we performed a prospective study in severely in jured patients. I n a second step we examined the early prognostic value o f objective biochemical markers for death and the development o f O F compared to the In ju ry Severity Score (ISS).

Patients and Methods

I n the per iod 1986-1989, t raumat ized patients a r r iv ing at our emergency r o o m were included i n the prospective study i f a l l o f the fo l lowing criteria were met: (a) severe injuries o f at least t w o body regions (head/brain, thorax, abdomen, skeletal system) or three major fractures, (b) age between 16 and 70 years, and (c) less than 6 h between accident and admission to the emergency department. A to ta l o f 69 p r i m a r y surv iv ing patients entered the study. The mean ISS was 36 (range, 13-66). Between days 4 and 28, 11 patients died (median survival t ime, 19, days). O f survivors, 29 suffered f rom O F , and 29 had an event-free recovery. Three groups were formed: g roup 1, lethal O F (n = 11); group 2, reversible O F (n = 29); g roup 3, no O F (n = 29).

L a b o r a t o r y testing and recording o f c l inical data was started w i t h i n 30 m i n after a r r iva l of the patient in the emergency department and continued on a 6-h basis. After 48 h the in terva l was extended to 24 h for a period of 14 days. After 2

1 Chirurgische K l i n i k und Poliklinik, K l in ikum Innenstadt der Universität München, Nußbaumstr . 20, 8000 Munich 2, FRG

2 Abteilung für Klinische Chemie und Klinische Biochemie, Chirurgische Klinik und Poliklinik, K l in ikum der Universität München , Nußbaums t r . 20, 8000 Munich 2, FRG

3 Medizinische Kl in ik , K l in ikum Innenstadt der Universität München, Nußbaumstr . 20, 8000 Munich 2, F R G

4 Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie der Universität München , Goethestr. 3, 8000 Munich 2, FRG

Host Defense Dysfunction in Trauma, Shock and Sepsis Eds. Faist/Meakins/Schildberg C Springer-Verlag, Berlin Heidelberg 1993

222 D. Nast-Kolb et al.

weeks the clinical course was recorded un t i l either transfer to a general ward or death. The biochemical markers studies are shown in the Fig . 1.

The fo l lowing definitions were used: Respiratory failure: need of mechanical vent i la t ion and p 0 2 / F i 0 2 < 280 or

positive end-expiratory pressure > 8 m m H g for at least 24 h

Renal failure: creatinine > 177 μηιοΐ/ΐ for at least 48 h Liver failure: b i l i r ub in > 51 μηποΐ/ΐ for at least 48 h Disseminated intravascular coagulation: (a) thrombocytes < 1 0 0 x l 0 9 / l or

fall o f > 30% in 24 n, (b) part ial th romboplas t in t ime > 50 s for 24 h, (c) 22 reptilase t ime > 22 s for 24 h

Neopterin Elastase Cathepsin Β

PMN Granulocytes Macrophages >̂ Cellular Systems <̂

Phospholipase Α P S T I C R P Lactate Cell Membrane traumatic cel l Metabolism

hemorrhagic SHOCK

Cascade Systems Kallikrein-Kinin -

System ^ Clotting

Sys tem Fibrinolysis

System Prokall ikrein ci- Inhibi tor

Prothrombin Antithrombin III

Plasminogen alpha-2-Antiplasmin

Factor VIII Antigen Protein C

t-PA. t -PA Inhibitor DD Fragment

Fig. 1. Biochemical markers in traumatic hemorrhagic shock

Table 1. Complications {n = 69)

Incidence (n)

Multiple organ failure 29 Sepsis 20 Respiratory Failure 42

Adult respiratory distress syndrome 17 Liver failure 42 Renal failure 17 Gastrointestinal failure 7 Disseminated intravascular coagulation 7 No complications 32

Diagnostic Role of New Mediators and Markers of Inflammation 223

Gl failure: endoscopically confirmed ulceration wi th bleeding, acalculous cholecystitis

MultipleOF: Failure of two or more organ systems at the same t ime

The complications of the 69 patients are shown in Table 1. Statistical testing was done w i t h the non parametric W i l c o x o n test for two

samples. Differences were considered significant w i t h ρ values below 0.05.

Lactate

1 2 3 L 5 6 7 8 9 10 11 12 13 14 days

Fig. 2. Lactate, P M N elastase, and cathepsin Β in groups 1 ( * ) , 2 (O) , and 3 ( + )

224 D. Nast-Kolb et al.

Results

The release o f mediators and indicators of inf lammatory reactions i n the three outcome groups is displayed in Figs. 2 -4 for those markers wh ich showed clinical relevance. The fo l lowing differences proved to be significant. A higher

20 +

mg/dl

10 +

C-Reactive Protein

ο 1 §k4 ' 1 I I I I I I I I I I I

DD Fragment

2 3 U 5 6 7 8 9 10 11 12 13 U days

Fig. 3. C-reactive protein, D D fragment, and neopterin in groups 1 ( * ) , 2 (O), and 3 ( +

Diagnostic Role of New Mediators and Markers of Inflammation 225

accumulation of lactate (Fig. 3) was observed in non survivors (group 1) compared to survivors w i t h organ failure (group 2) throughout 14 days of observation. The level of polymorphonuclear leukocyte ( P M N ) elastase (Fig. 2) showed a highly significant difference in groups 1 and 2 versus group 3 throughout the whole observation period and in group 1 versus group 2 after the

Antithrombin III

I I J I I 1 I I I I I J I

Prothrombin

-s—£—£—£"

0 1 ι ι ι ι ι ι ι ι ι ι ι ι ι 1

t-PA 10 +

U/ml

5 +

1 2 3 4 5 6 7 8 9 10 11 12 13 14 days

Fig. 4. Antithrombin I I I , prothrombin, and t-PA in groups 1 ( * ) , 2 (O), and 3 ( + )

226 D . Nast-Kolb et al.

3rd day. Cathepsin Β (Fig. 2) dist inguished patients wi th O F (groups 1 and 2) from those w i t h uneventful recovery (group 3) w i t h i n the first 4 days. The produc t ion of C-reactive protein; (CRP; F i g 3) was different among a l l outcome groups starting on the 3rd day after t rauma. The D-dimer fragment (Fig. 3) o f group 3 differed from that o f groups 1 and 2 at arr ival , and the levels of a l l three groups differed between days 3 and 5. Neop te r in (Fig. 3 ) was higher i n group 1 (nonsurvivors) compared to survivors (groups 2 and 3) f rom the 2nd day onwards and between groups 2 versus 3 after the 4th post traumatic day. A n t i t h r o m b i n I I I (Fig. 4) showed a lower inh ib i to ry act ivi ty i n groups 1 and 2 versus group 3 al l the t ime and between groups 1 and 2 (nonsurvivors versus survivors w i th O F ) after the 1st week. A t arr ival , p r o t h r o m b i n and tissue plasminogen activator ( t-PA; F ig 4) distinguished between patients devoloping O F (groups 1 and 2) and those having an uneventful recovery (group 3). I n the 2nd week p ro th rombin differed between survivors and nonsurvivors.

As O F often started on the 1 day, predict ion o f later O F was possible at hospital arr ival , whereas a lethal outcome could be predicted w i t h i n the first 3 days. The demonstrated mediators showed a reasonable accuracy in predic­t ing O F and death w i t h a higher va l id i ty than the ISS Table 2. The combina t ion of the four factors w i t h prognostic value for death ( P M N elastase, CRP,

Table 2. Prognostic value for lethal outcome at hospital arrival 3 and at day 4

ACC Sens Spec PPV NPV

Lactate 3 ( > 45 mg/dl) 88% 60% 93% 60% 93% Elastase ( > 500 ng/ml) 90% 73% 93% 67% 95% CRP ( > 20 mg/dl) 88% 67% 98% 86% 95% Neopterin ( > nmol/1) 86% 75% 93% 67% 95%

ISS ( > 50) 80% 36% 88% 36% 88%

ACC, Accuracy; Sens, sensitivity; Spec, specifity; PPV, positive, predicitive value; NPV, negative predictive value. Prognostic value at hospital arrival for lactate only.

Table 3. Prognostic value for organ failure at hospital arrival

ACC Sens Spec PPV NPV

Cathepsin B ( > 190 U/ l ) 90% 63% 86% 86% 62% Elastase ( > 200 ng/ml) 67% 84% 42% 68% 65% Antithrombin I I I ( < 80%) 66% 7 1 % 58% 7 1 % 58% Prothrombin ( < 70%) 6 1 % 7 1 % 60% 73% 58% D-dimer fragment ( > 12 000 ng/ml) 6 1 % 62% 6 1 % 70% 52% t-PA ( > 8 ng/ml) 57% 62% 54% 68% 48%

ISS ( > 30) 6 1 % 70% 48% 65% 54%

ACC, Accuracy; Sens, sensitivity; Spec, specifity; PPV, positive, predicitive value; NPV, negative predictive value,

Diagnostic Role of New Mediators and Markers of Inflammation 227

Table 4. Prognostic value of the combination of four para­meters for lethal outcome: elastase, CRP, neopterin, lactate

(minimum of pathological factors)

3 2 1

Sensitivity 53% 73% 93% Specifity 99% 87% 67% PPV 89% 50% 34% NPV 92% 95% 98% Accuracy 92% 85% 6 1 %

PPV, Positive predictive value; NPV, negative predicitve value.

neopterin, lactate) further improved the accuracy of predict ion. M o r e than three pathological results showed a very h igh risk of death; normal release of al l mediators indicated survival (Table 3, 4).

Summary

Biochemical mediators showed a significant difference between t raumatized patients wi th lethal, reversible, and no organ failure. These objective parameters of inf lammat ion might give a more accurate description of injury severity and al low a better estimation of risk for O F than many t rauma severity scores.