Stakeholder Opinions: Sepsis - The Critical Care Community Gains Critical Mass

Introduction

The Critical Care Community is currently at its most organized, and motivated, and on a mission to improve outcomes in sepsis. This is driving a rigorous assessment of care strategies which is gathering speed and showing results. This will yield many opportunities for developing products, but current interventions' roles will change, with impacts on how they are measured, used and valued.

Report Highlights
Highlights

The critical care community's rigorous assessment of current management strategies is now gathering speed and showing results, gaining more converts and highlighting new perspectives on sepsis-related processes Current interventions used in sepsis are typically either repurposed from other disease areas, or based on nascent understandings of the processes in play Whilst this improved understanding may yield many new opportunities for developing new interventions, the understanding of the roles of current interventions may be turned upside-down, with implications for how they are measured, used, and indeed, valued in improving outcomes
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TABLE OF CONTENTS
ABOUT DATAMONITOR HEALTHCARE 2
About the Infectious & Respiratory Disease pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Objective of the analysis 3
Datamonitor insight into sepsis 3
A highly motivated Critical Care Community is gaining a singular momentum 4
Old dogs, new tricks? Current interventions meet new thinking 4
The new era: personalized medicine in infectious disease 5
Related reports 7
Upcoming related reports 7
CHAPTER 2 BACKGROUND 9
Catalyst 9
Scope 10
Acknowledgements 10
CHAPTER 3 DEFINITIONS 12
Sepsis defined - the lynchpin of progress 13
Matching definitions to working criteria for clinical inclusion 13
Taking an oncologist's view of sepsis: the PIRO model 16
CHAPTER 4 ORDER FROM CHAOS - THE IMPACT OF SEPSIS STAGING 19
P is for Predisposition and Prophylaxis targets 21
Age 24
Co-morbidities 26
Genetic predisposition 28
I is for Infection - a plethora of pathogens 30
The diagnostic shortfall 31
Anti-infectives: trialed for infection, not sepsis indications 36
Supply and demand: how do available anti-infectives stack up? 37
Too much of a gram-positive focus 38
Indication semantics - site of infection in sepsis 41
Matching infection indications to sepsis sites of infection 42
R is for Response to infection: when is too much and what to treat? 44
Multiple pathways 45
Beyond early goal directed therapy - current targets for new and novel therapeutics 47
Upstream versus downstream 49
Early versus late onset 49
Neither upstream, nor downstream 49
Sepsis, severe sepsis and clinical trials 50
Continuity of outcomes across progressive trials 50
Recruitment 52
Endpoints 54
O is for Organ dysfunction 55
Discrete organ dysfunction versus multiple organ dysfunction 57
Modeling sepsis-related organ failure 58
Measuring an outcome versus a target for intervention 61
Binary versus linear scales 61
With or without interventions 62
CHAPTER 5 CASE STUDY: THE SURVIVING SEPSIS CAMPAIGN 63
Mandate, leadership and direction 64
Singular view 69
Achievable principles versus specifics 69
Ethical responsibility 72
Legal liability 73
Coherence and continuous improvement - the evolution of SSC Guidelines 73
Backing 77
Creating a balance through non-industry grants 78
Diluting the ""Lilly-effect"" with more corporate sponsorship 79
Private foundations and government funding 79
New versus old guidelines 80
Balancing consistency with improvement 80
The big question: so what happened to Xigris recommendations? 81
Xigris, the data 82
Corticosteroids - CORTICUS prompts subtle changes 85
Glycemic controls and vasopressors 86
Vasopressin - more subtle changes, but why? 86
APPENDIX A - EPIDEMIOLOGY DATA 88
Sepsis by pathogen 88
Sepsis by deaths pathogen 90
Sepsis sites of infection 92
APPENDIX B - SSC GUIDELINE OUTLINES 93
Initial Resuscitation 93
Initial resuscitation (first 6 hours) 93
Diagnosis 94
Antibiotic Therapy 94
Source identification and control 95
Hemodynamic Support and Adjunctive Therapy 96
Fluid Therapy 96
Vasopressors 96
Inotropic therapy 97
Steroids 97
Recombinant human activated protein C (rhAPC) 98
Blood product administration 98
Mechanical ventilation of sepsis-induced acute lung injury (ALI)/Adult Respiratory Distress Syndrome (ARDS) 98
Sedation, analgesia, and neuromuscular blockade in sepsis 100
Glucose control 100
Renal replacement 100
Bicarbonate therapy 101
Deep vein thrombosis (DVT) prophylaxis 101
Stress ulcer prophylaxis 101
Consideration for limitation of support 101
APPENDIX C - PIPELINE DATA 102
Cell Signalling Targets 102
Coagulation Cascade Targets 103
Endotoxin Targets 104
Immodulation Targets 104
APPENDIX D 107
Bibliography 107
Definitions 107
Epidemiology 109
Websites 111
Clinical trial data 112
Contributing experts 115
Clinical 115
Industry 115
Report methodology 115
About Datamonitor 116
About Datamonitor Healthcare 116
About the Infectious & Respiratory Disease analysis team 117
About the Infectious Disease analysis team 117
Key therapy team members 118
Holger Rovini, Head of Respiratory and Infectious Diseases 118
Disclaimer 119
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Table 1: Evidence based preventative strategies for Septic Shock 23
Table 2: Candidate genes and severe sepsis 29
Table 3: Examples of microbial diagnostic tests 33
Table 4: Signs and symptoms of organ dysfunction 59
Table 5: Sponsors of the SSC Guidelines 66
Table 6: Relative frequency of sepsis by pathogen 89
Table 7: SOAP trial - mortality by pathogen type, and ICU/hospital attribution 91
Table 8: Site of infection in Sepsis Patients - SOAP study outcomes 92
Table 9: The Sepsis Pipeline: Cell-signaling targets by development stage 102
Table 10: The Sepsis Pipeline: Coagulation cascade targets by development stage 103
Table 11: The Sepsis Pipeline: Endotoxin targets by development stage 104
Table 12: The Sepsis Pipeline: Immunomodulation targets by development stage 104
Table 13: The Sepsis Pipeline: Specific Mediator targets by development stage 105
Table 14: The Sepsis Pipeline: Unknown targets by development stage 105

Figure 1: Defining Sepsis - the ACCP, SCCM, ATS, ESICM and SIS consensus conference 2001 14
Figure 2: The PIRO model 15
Figure 3: Increasing importance of the over 65s as a high risk group for sepsis, 1979-2001 24
Figure 4: Over 65s and sepsis - higher incidence, higher mortality rates 25
Figure 5: Co-morbidities in sepsis patients stratified by age 27
Figure 6: Pathogen, site, origin - the complexities of infection 31
Figure 7: Impact of timing of antimicrobial initiation on survival in sepsis 32
Figure 8: Diagnostic capabilities - different roles in assisting treatment strategy decisions 34
Figure 9: Stratifying diagnostic tools for sepsis 36
Figure 10: Top five marketed brand and pipeline coverage of antibiotics by indication, 2007 38
Figure 11: Site of infection in sepsis patients according to the onset from routine postoperative monitoring of sepsis 43
Figure 12: Stylized and simplified - sepsis progression 45
Figure 13: Main effector pathways for sepsis 46
Figure 14: The sepsis pipeline by target and stage of development, 2008 48
Figure 15: Theories of pathogenesis 56
Figure 16: Organ failure by type, 2000 58
Figure 17: SOFA, MODS and LODS - Parameters and scores used in assessing organ dysfunction 60
Figure 18: Key elements of the Barcelona Declaration 63
Figure 19: Can't comply, won't comply - barriers to uptake and facilitators of change 72
Figure 20: Early Goal Directed Therapy in Sepsis 74
Figure 21: Relative frequency of sepsis by pathogen 88
Figure 22: SOAP trial - mortality by pathogen type, and ICU/hospital attribution 90
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