1. Ricard Ferrer
Intensive Care Department
Mutua Terrassa University Hospital
Barcelona. SPAIN

2. La sepsis es una de las enfermedades más
frecuentes pero menos reconocidas del
mundo
1. INTRODUCCIÓNMEDICINA INTENSIVA

3. Su incidencia está
aumentando de
forma
exponencial.
Los hospitalizados
por sepsis se han
duplicado en los
últimos 10 años.
1. INTRODUCCIÓNMEDICINA INTENSIVA

4. En un año, por cada
100.000 personas, 377
sufrirán sepsis, 135 su
forma grave o shock
séptico.
1. INTRODUCCIÓNMEDICINA INTENSIVA

6. Entre 20-30
millones de
personas en todo
el mundo son
afectadas cada
año. De las cuales
8 millones
mueren.
1. INTRODUCCIÓNMEDICINA INTENSIVA

7. Cada 4
segundos
alguien muere
por sepsis en el
mundo
1. INTRODUCCIÓNMEDICINA INTENSIVA

9. Crit Care Med 2009; 37: 1268–1274
Mortality (%)
ICU 15.5
Hospital 28.3
1 Year 40.9
2 Year 44.9
Quality of life (EuroQol-5D)=

10. Crit Care Med 2009; 37: 1268–1274

11. Crit Care Med 2009; 37: 1268–1274

12. Pillars of Sepsis Treatment
ABX Source Control EGDT
LactateRadiology
YOUR speed is LIFE!

13. Phase 1 Barcelona declaration
Phase 2 Evidence based guidelines
Phase 3 Implementation and education
Surviving Sepsis
Surviving Sepsis

14. Campaign Targets
•Mortality goal
•25% reduction in 5 years
•35% to 26%:
•72,000 lives saved in US
•500,000 worldwide

15. Phase 1 Barcelona declaration
Phase 2 Evidence based guidelines
Phase 3 Implementation and
Education
Surviving Sepsis

17. Phase 1 Barcelona declaration
Phase 2 Evidence-based guidelines
Phase 3 Implementation and education
Surviving Sepsis

18. SSC Phase III: Methodology
• Partner with Institute for Healthcare
Improvement (IHI)
–Develop sepsis “change bundles”
• Facilitate adoption of guidelines
– VAP, CLABSI
• 15 member panel
– Gap analysis

19. Surviving Sepsis Campaign: Timeline
Barcelona
Declaration
SSC
Guidelines
2010
Phase IV
Guidelines
And
bundles
Revision
2005
NEJM editorial
2004
2002
Guidelines
Revision
Phase III starts:
IHI partnership
2008 2012
Results
published
15,000 pts
20% RRR
2006 2012--

20. EDUSEPSIS es una organización
independiente de profesionales que
atienden al paciente crítico, tanto adulto
como pediátrico, cuyo objetivo es reducir la
mortalidad de la sepsis grave y el shock
séptico mediante la evaluación de la
eficacia y eficiencia de los tratamientos y la
transferencia del conocimiento científico.

21. Acciones
• Intervenciones de Transferencia del
Conocimiento en Sepsis.
– Adultos
– Pediatría
• Evaluaciones de la efectividad de los
tratamientos de la sepsis.
– Nacional
– Internacional: SSC
• Evaluaciones de costes y Coste-Efectividad.

22. Transferencia del
Conocimiento

23. Knowledge Transfer: Hype cycle

24. Knowledge Transfer in Critical Care
Fowler et al. CCM 2007;35:1696-1702

25. Variability in Clinical Practice
• Variability based on:
– Knowledge deficits
– Faulty application of knowledge
– Simple forgetting
– UANACCEPTABLE
• Variability based on
– Different weighting of relevant knowledge
– EXPECTED
• Performance measures, check-lists, bundles:
– Making the clinical decision-making process explicit
– Aids in identifying source of variability

26. Crit Care Med 2008; 36:2719–2725
Perception

27. PRE-INTERVENTION PROCESS-OF-CARE MEASURES
POST-INTERVENTION PROCESS-OF-CARE MEASURES
IMPROVE KWONLEDGE
CHANGE BEHAVIOUR
IMPROVE OUTCOME
EDUCATIONAL
STRATEGIES
STRUCTURE AND
ORGANIZATIONAL
STRATEGIES
Performance Improvement Interventions

28. Intensive Care Med 2008;34:17-60
SEPSIS RESUSCITATION BUNDLE
6H
SEPSIS MANAGEMENT BUNDLE
24H

29. Multifaceted Interventions
Intervention Effect
Interventions incorporating educational outreach Modest
Educational material + Educational meetings Small-Modest
Educational material + Audit and Feedback Modest
Educational material + Audit and Feedback +
Educational meetings
Small-Modest
Educational material + Educational meetings +
organizational interventions
Small-Modest
Reminders + Patient-directed interventions Moderate-Large
Remainders have a summative effect with other interventions

30. EDUCATIONAL
PROGRAMME
POST-EDUCATION
DATA COLLECTION
OCT-DEC JAN-FEB MAR-JUN
2005 2006
BASELINE
DATA COLLECTION
a before-and-after intervention study
2007
LONG-TERM
FOLLOW-UP
MAR-JUN
JAMA 2008;299(19):2294-2303
Study Timeline
PERCEPTION

31. Multifaceted Intervention
PI
Hospital
Manager
Interview
Physicians
Nurses
ICU
ED
Medical Ward
Surgical Ward
Graphic material:
distribution and display
Clinical training

32. 0
10
20
30
40
50
60
70
80
90%
Lactate Blood
Cultures
Antibiotics Fluids +
vasopresors
CVP>8 ScvO2>70 All
RESUSCITATION BUNDLE COMPLIANCE
Objective Subjective
Sepsis bundles: Audit vs Subjective Perception

33. 0
10
20
30
40
50
60
70
80
90%
Steroids aPC Glucose IPP All
MANAGEMENT BUNDLE COMPLIANCE
Objective Subjective
Sepsis bundles: Audit vs Subjective Perception

34. Resuscitation Bundle (6H)
0
10
20
30
40
50
60
70
80
90
%Compliance
Lactate Blood Cultures Antibiotics Fluids +
Vasopresors
CVP>8 SvcO2>70 All
Preintervention Intervention
* p<0.05
*
*
*
*
* *

35. Management Bundle (24h)
0
10
20
30
40
50
60
70
80
90
%Compliance
Steroids APC Glucose IPP All
Preintervention Intervention
* p<0.05
* * *
*

36. Educational Program and Mortality
44
39,7
36,4
31,1
0
10
20
30
40
50
%
Hospital Mortality ICU Mortality
Preintervention Intervention
p= .036 p= .01
Absolute reduction: 4.3%
Relative reduction 10%
28d Mortality: Kaplan-Meier curve
Absolute reduction: 4.3%
Relative reduction 10%
SSC objective was 25%!

37. Impact of Baseline Compliance
0
5
10
15
20
25
30
Pre-Intervention Post-Intervention
%
Cat 1 Cat 2 Cat 3
0
5
10
15
20
25
30
Pre-Intervention Post-Intervention
%
Cat 1 Cat 2 Cat 3
20
25
30
35
40
45
50
Pre-Intervention Post-Intervention
%
Cat 1 Cat 2 Cat 3
Resuscitation Bundle Management Bundle
Mortality
* p<0.05
*
*
*
*
*
Cat 1: < 4 tasks (n= 20)
Cat 2: 4-5 tasks (n= 19)
Cat 3: > 5 tasks (n= 20)

38. Resuscitation Bundle (6H)
0
10
20
30
40
50
60
70
80
90
%Compliance
Lactate Blood Cultures Antibiotics Fluids +
Vasopresors
CVP>8 SvcO2>70 All
Preintervention Intervention Long-term
Long-term follow up (23 centers) * p<0.05
* *
*
*
*

39. Time to Treatment
0
50
100
150
200
250
Minutes
Lactate Blood culture Antibiotics PVC >8 ScvO2>70
Preintervention Intervention Long-term
* p<0.05
*
Long-term follow up (23 centers)

40. Educational Program and Mortality
42,5
38,7
0
10
20
30
40
50
%
Hospital Mortality
Preintervention Intervention Long-term
38,0
Long-term follow up (23 centers)

41. PRE-INTERVENTION GUIDELINE IMPLEMENTATION
POST-INTERVENTION GUIDELINE IMPLEMENTATION
IMPROVE KWONLEDGE
IMPROVE OUTCOME
EDUCATIONAL STRATEGIES
Continuous Performance Improvement

42. Crit Care Med 2010; 38(2):367-374
n= 15.022

43. Crit Care Med 2010; 38(2):367-374

44. ABISS Edusepsis Study
Antibiotic Intervention in Severe Sepsis

45. Objectives
• Efficacy:
– Reduce time to empiric antibiotic in severe sepsis.
– Increase appropriateness of antibiotic treatment
– Reduce hospital mortality.
• Safety:
– Increase antibiotic deescalation.
By a multifaceted quality-improvement
intervention in patients with severe sepsis/septic
shock admitted to the Spanish ICUs.

46. Multifaceted Intervention
• Audit and Feed-back.
• Educational meetings: PP presentation.
• Interactive Sepsis simulation on-line.
• Posters and pocket material about initial TTM.
• Support for antibiotic prescription.
• Remainders by mail and SMS to all staff
assisting to educational meetings.

47. Remainders: SMSs

48. Audit and Feed-Back

49. 120 hospitals were invited to participate and received the
educational material:
-Poster “La Sepsis Mata”: 360
-Poster “Pilares del tratamiento de la Sepsis”: 360
-Poster “Juego interactivo”: 360
-Triptics “Pilares del tratamiento de la Sepsis”: 6000
Educational intervention:
-80 hospitals complete the educational intervention
-4567 doctors and nurses attend to the meetings and provide a
email address and/or mobile phone for remainders.
Educational Meetings

50. Educational Material

51. Prescription Support
• Local Guidelines of empiric antibiotic treatment
• Spanish Society of Intensive Care Guidelines of empiric
antibiotic treatment

52. Gamification

53. Remainder. SMSs
• En sepsis la administración del antibiótico adecuado es una
emergencia.Consulta tu guia local de tto antibiotico
empirico.TU VELOCIDAD ES VIDA.
• Los pilares del tratamiento de la sepsis son:antibióticoterapia,
control del foco y resucitación hemodinámica.¡COMPLETALOS
RAPIDAMENTE!
• Tardamos 3 horas en administrar antibiótico empírico en
sepsis con mortalidad 33%. Administrado en 1h la mortalidad
sería inferior!.
• Antes del tto antibiótico, recuerda tomar hemocultivos +
cultivos adicionales según foco de sepsis, después podrás
ajustar tu tto empírico!.

54. Results
• 72 hospitals in Spain.
• 2576 patients: PRE 1,325, POST: 1,251
• Age 64.1 ± 15.1 years, 54.1% male.
• CHARLSON 2.7 ± 2.2
• Septic Shock 67.6%, 32.4% severe sepsis.
• Bacteriemia: 33%
• APACHE-II 22 ± 8.
• SOFA 9 ± 3
• PCT 25 ± 35

55. Results: Blood Cultures
Microorganism n
Escherichia coli 299
Staphylococcus aureus MS and MR 78
Streptococcus neumoniae 75
Staphylococcus CN 60
Klebsiella spp 53
Pseudomonas aeuroginosa 42
Enterococcus spp 35
Streptococcus pyogenes 28
Enterobacter spp 25
Streptococcus other 22
Candida spp 21
Multiple microorganisms 19
Proteus mirabilis 16
Bacterioides fragillis 14
Acinetobacter baumanii 11
Clostridium 6
Neisseria meningitidis 5
Salmonella 5
Listeria monocytogenes 4
Serratia marcescens 4

56. Results: Source Control
Técnica n
Colectomía parcial/total 201
Colecistectomía 96
Resección intestino delgado 70
Desbridamiento piel-partes
blandas
77
Drenaje abdominal percutáneo 48
Nefrostomía 41
Cateterismo ureteral 37
Drenaje vía biliar 33
Drenaje torácico 24
Desbridamiento de absceso 19
Cirugía gástrica 19
Técnica n
Apendicectomía 17
Pancreatectomía parcial 13
Sutura úlcera 17
Cirugía hepática 9
Nefrectomía 7
Esofaguectomía 4
Desbridamiento cuello/mediastino 6
Histerectomía 3
Cirugía craneal 2
Cirugía de pulmón y bronquio 1
Cirugía valvular cardiaca 1
28,3% de los pacientes precisan una técnica de control del foco

57. Results
PRE POST P value
Age 64.3±15.3 63.9±15.0 0.480
Charlson 2.7±2.3 2.7±2.3 0.308
Leukocytes 14.4±11.5 15.9±11.0 0.290
CRP 27.1±24.8 25.0±24.5 0.055
PCT 25.1±35.2 25.6±34.5 0.804
Lactate (mmol/L) 3.5±3.1 3.6±2.8 0.247
APACHE II 22.6±8.1 21.4±8.0 <0.001
Number OF 3.0±1.4 3.0±1.4 0.897
SOFA 8.7±3.5 8.5±3.4 0.073

58. Results: Source Infection
p< 0.05

59. Results: Acquisition
p< 0.05

60. Results: Quality indicators
p< 0.05 p< 0.05 p< 0.05p= 0.58

61. Results: Source control
p= 0.611

62. Results: Antibiotics
p< 0.001 p= 0.020

63. Results
p= 0.002 p= 0.001

64. Results
p= 0.422 p= 0.182

65. ABISS Edusepsis
Pediatric

66. ABISS pediatric net
PICUs ABISS: 33

67. ABISS pediatric
ABISS PICUs characteristics:
• Total: 380 PICU beds
• Total admissions/month: 1460
• 100% of PICU with residents
• 94% public
• 83.3% medical and surgical, 25% pediatrics-
neonatal
• Protocols for sepsis management 100%
• Use of biomarkers: PCR 100%, PCT 64%
• Hemofiltration: 50%; ECMO: 20%

68. Preintervention results
• 198 cases
• 118 ♂ (59.6%)
• Median age (years) 2.9 ±4.6 ( 7 days-17.8 ys)
• Underlying diseases: 88 (44,4%)
• SOFA 6,74±3.71
• PRISM3 10.71± 7.21
• Biomarkers:
– PCT 36.97±52.25 ng/ml
– CRP 19.60±21.66 mg/dl

69. Preintervention results
• Global Mortality 15.6%
–Mortality Septic shock 26.2%
• Days of mechanical ventilation: 13.6±42.6
• Days of inotropic support: 5.77± 8.43
• PICU length of stay (days): 12.02±35.03
• Hospital length of stay (days): 26±45.09

70. Preintervention results
• Antibiotics previous to the onset of sepsis: 46
(23,2%)
• Evaluation of treatment: Change of ATB at 72
hs:

72. Evaluación Efectividad
de los Tratamientos
Eficacia Efectividad

73. Assessment of the Effects of Treatments
for Severe Sepsis on Mortality
Randomized
Control Trials
Observational
Studies

74. Randomized Control Trials in CCM
Pros:
• RCT is the standard
for generating
evidence.
• Bias are minimized.
• Confounders are
limited.
• Data about efficacy
and safety.
Cons:
• Lack of biomarkers:
Heterogeneous
groups of patients.
• Stringent eligibility
criteria.
• Difficult to
homogenize
treatments.
• Complex outcomes.
• Ethical constraints.

75. • Consistency:
– Biological plausibility.
– Confirmatory studies of single RCT.
– Multicentric confirmation of unicentric studies.
• Effectiveness studies in “real world scenario”.
– Patients excluded from RCT.
– Effect of combining several treatment.
– Feasibility of complex therapeutic
interventions/algorithms.
• Efficiency: Cost-effectiveness studies.
• Pharmacovigilance/Post-commercialization
studies: Safety
Knowledge Generation

76. Objective: To analyze the impact on hospital
mortality of severe sepsis treatments
included in the SSC guidelines in a
prospective multicenter observational
study (n= 2,796 adult patients with
severe sepsis in 77 Spanish ICUs).
Method: The effectiveness of each sepsis
treatment was estimated by using PS.
AJRCCM 2009;180:861–866.

77. TREATMENTS and MORTALITY
• Adjust for possible confounders:
–Clinical risks factors for mortality
–Other treatments and therapeutic
goals
–Propensity Score

78. Propensity Score. Antibiotics.

79. 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8
Odds ratio
OR and 95% CI
Broad spectrum AB:
Fluid challenge#
0-1 Hour
1-3 Hour
3-6 Hour
Previous AB
No AB first 6H
Steroids in septic shock
APC in MOF
Fluid challenge, only severe sepsis
Ferrer R et al. AJRCCM 2009;180:861–866
Effectiveness of APC in MOF
Final Model: All risk factors + Other TTMs + PS

80. time from hypotension onset (hrs)
fractionoftotalpatients
0.0
0.2
0.4
0.6
0.8
1.0 survival fraction
cumulative antibiotic
initiation
Early antibiotic treatment
Kumar A et al. Crit Care Med 2006;34:1589-96
• Retrospective
• Only septic shock
• Only adequate treatment

81. Time to Treatment. Antibiotics
Ferrer et al. ESICM 2011, Abstract 139; Annals Internal Medicine Submitted
25.089 patients with severe sepsis or septic shock
Predicted Mortality with 95% CI
0
.1
.2
.3
.4
HospitalMortality
0 1 2 3 4 5 6
Time to ABX, hours
Patient: North America, one baseline organ failure, and community acquired infection
Hospital Mortality by Time to ABX
Time to ABX,
hrs
OR 95% CI p-value
0 (ref) 1.00 --- --- ---
1 1.05 1.02 1.07 < 0.001
2 1.09 1.04 1.15 < 0.001
3 1.14 1.06 1.23 < 0.001
4 1.19 1.08 1.32 < 0.001
5 1.25 1.11 1.41 < 0.001
6 1.31 1.13 1.51 < 0.001

82. Time to Treatment. Antibiotics
25.089 patients with severe sepsis or septic shock
Predicted Mortality with 95% CI0
.1
.2
.3
.4
0 1 2 3 4 5 6
Time to ABX, hours
Severe sepsis Septic shock
Patient: North America, one baseline organ failure, and community acquired infection
Hospital Mortality by Time to ABX
Ferrer et al. ESICM 2011, Abstract 139; Annals Internal Medicine Submitted

85. Cox proportional hazard regression of PP < 30 cm H2O in patients without ALI
Cox proportional hazard regression of PP < 30 cm H2O in patients with ALI

86. Factores de Riesgo de Muerte
en Pacientes > 80 años
Hospital Mortality 48%
Multivariate Analysis

88. Coste y
Coste-Efectividad
Can it work?Efficacy
Does it work?Effectiveness
Efficiency Is it worth it?
Life year gained (LYG)
Quality adjusted life year (QALY)

89. 60.000 euros/LYG
30.000 euros/LYG
rechazo
?
adopciónADOPTION
+ EFFECTIVENESS
+COST
Cost-Effectiveness

90. Cost-Effectiveness Analysis
• Ratio of the cost of the intervention to a
relevant measure of its effect.
THERAPEUTIC
INTERVENTION
Expenditures
Outcome
Improvement in HealthCosts
Incremental Cost-Effectiveness Ratio (ICER)
Incremental Cost-Utility Ratio (ICUR)

91. 16935
18671
15000
16000
17000
18000
19000
20000
Euros
Hospital Costs
Preintervention Intervention
5.44
5.98
3.75 4.12
0
1
2
3
4
5
6
7
Years LYG QALY
Preintervention Intervention
Adjusted ICER 4,435 euros per LYG
Adjusted ICUR 6,428 euros per QALY

92. Distribution of mean costs per patient
12963
14018
3100
3773
820
826
54
52
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
Control group Treatment group
Costperpatient(Euros2006)
ICU Ward SSC protocol interventions Emergy Department

93. 60.000 euros/LYG
30.000 euros/LYG
rechazo
?
adopciónADOPTION
+ EFFECTIVENESS
+COST
SSC
Cost-Effectiveness

94. Premios
1. Premi a la millor comunicació presentada a la SOCMIC 2008, Badalona.
2. Mejores Ideas Diario Médico 2008 Política profesional por el Estudio
Edusepsis.
3. Accèsit a la millor comunicació mèdica presentada SOCMIC 2009.
4. Premi mutual médica Dr. Josep Font millor article científic 2008.
5. Award for the best abstract on sepsis (International Sepsis Forum):
Poster Award Winner 2009. 23rd Annual Congress ESICM.
6. Millor Comunicació Publicada SOCMIC 2010. AJRCCM.
7. Millor comunicació mèdica presentada SOCMIC 2010.
8. Premis Científics Capio – Hospital General de Catalunya, Edició 20.
Categoria Assistencial.
9. Mejor Comunicación XLVII CONGRESO NACIONAL DE LA SEMICYUC
10. Millor comunicació mèdica presentada SOCMIC 2013.

95. Conclusions
1. La sepsia greu continua teneint una elevada
incidència i mortalitat. El reconeixement
social encara és escàs.
2. La sepsia greu és una emergencia mèdica. Cal
que rebi una atenció multidisciplinar,
coordinada i precoç.
3. Pla Nacional de Sepsis. Indicadors de Qualitat.
4. Codi de Sepsis

97. 7 de Noviembre del 2013

98. rferrer@mutuaterrassa.es
Ricard Ferrer
Intensive Care Department
Mutua Terrassa University Hospital
Barcelona. SPAIN