“Surviving Sepsis” Barcelona declaration (ESICM congress, 2002) Surviving Sepsis Campaign Guidelines (CCM & ICM, 2004) SSC guidelines Version 2 Crit Care Med 2004; 32: 858-73. Intensive Care Med 2004 ; 30 : 536. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Potential conflicts of interest « The challenges involved in producing first-rate guidelines and performance standards are only exacerbated by the intrusion of marketing strategies masquerading as evidence-based medicine. » Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Population-adjusted Incidence of Sepsis, USA, 1979-2000 240 83 Severe Sepsis: 34% France: Choc septique 9% Severe Sepsis: 34% G.Martin et al, NEJM 2003; 348: 1546-54. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

1. Identification & initial assessment Recommandations SFAR – SRLF 2006 “Surviving Sepsis” ? 1. Identification & initial assessment

SIRS and Organ Dysfunction Criteria SIRS: Conventional criteria Fever / hypothermia Tachypnea Tachycardia Leukocytosis / leukopenia Others Biomarkers: Elevated PCT, .. Organ dysfunctions lactates > 4 mmol/l - SBP < 90 mm Hg - PaO2/FiO2 < 300 - Oliguria, creatinine > 176 mmol/L - INR > 1,5 / PT > 60 sec - thrombocytopenia < 100 000/mm3 bilirubin > 34 µmol/l Glasgow coma score ≤ 13 But < 50% of patients with SIRS have documented infection Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Infection/Sepsis: Initial assessment Tachycardia Tachypnea Fever or hypothermia Skin perfusion Neurologic status Arterial pressure Urine output Lactate Sev Sepsis? Evaluation of sepsis Biochemistry Hematology And coagulation Initial assessment (H0-H3) Recommandations SFAR – SRLF 2006 Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Algorithm for disposition of patients in ED Suspected Severe Sepsis Monitoring HR, RR, AP, Urine Oxygen to SpO2>95% Biochemistry (lactate) & microbiology Cristalloids (500 ml/15 min) to mAP >65 Call referent intensivist Organ failure? YES No Clinical Hypoperfusion ? mAP <65 ? Lactate >4 ? Comorbidity ? Etiology at risk ? YESI YES Acute care area Maintain non-invasive monitoring + urine output No Urine < 0,5 ml/kg/h ? mAP < 65 ? YES ICU Admission Recommandations SFAR – SRLF 2006 Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Infection/Severe Sepsis: initial steps Source Control: Drainage? Surgery? Re-assessment of organ dysfunctions Antibiotics Blood cultures + site samples Fluid Challenge Imaging? Sev Sepsis ? 0 – 3 hrs Recommandations SFAR – SRLF 2006 Sino-Fr Symposium - Oct 07 C. Brun-Buisson

“Surviving Sepsis Campaign” 2. Recommendations and Guideline Revision (2006-07) Sponsored exclusively by supporting societies

Impact on survival of early antibiotic administration Kumar et al, Crit Care Med 2006; 34: 1589-96 Sino-Fr Symposium - Oct 07 C. Brun-Buisson

The premise of early goal directed therapy was not rocket science. In contradistinction of previous studies we examined patients with clinical evidence of global tissue hypoxia (high risk) and at the most proximal stages of the disease presentation. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

E. Rivers, 2001 - EGT Sino-Fr Symposium - Oct 07 C. Brun-Buisson

EGT – Mortality rates * RR = 0.58 0.58 0.67 P = 0.01 0.01 0.03 Looking at mortality, there was difference in in-hospital mortality of 16% (statistically significant). This 16% improvement in the treatment group was maintained at 28 days, and also 12% at 60 days. RR = 0.58 0.58 0.67 P = 0.01 0.01 0.03 E. Rivers et al, NEJM 2001 Sino-Fr Symposium - Oct 07 C. Brun-Buisson

EGT - Volume of fluid infused * P<0.01 * * Looking at fluid administration, the EGT-treated patients got almost 3.5 Liters more fluids within the first 6 hours. This was reversed in the subsequent 72 hours. Understand that your intensivist was reacting to some events during these hours and blinded to what had happened in the first 6 hours. Overall, these patients only an 60 mL difference in fluid administration. Overall, they got almost 14 L fluids, but only 60 mL difference, so our blinding was effective. Thus, it is the timing, not the amount of fluid administered which made the difference. E. Rivers et al, NEJM 2001 Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Supportive Care: Glucose Control Fluid Therapy We recommend fluid resuscitation with either natural/artificial colloids or crystalloids. There is no evidence-based support for one type of fluid over another. 1B Supportive Care: Glucose Control Recommend glucose control with intravenous insulin after initial stabilization 1B Suggested glucose target: Normal and < 150 mg/dL 2C Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Potential conflicts of interest Pour un moratoire sur l’utilisation des hydroxyéthylamidons L. Brochard1, F. Schortgen1, C. Brun-Buisson1, D. Dreyfuss2, J.-J. Rouby3, J. Chastre4, D. Robert5, G. Hilbert6, D. Payen7, E. L’Her8, C. Richard9, M. Gainnier10, J. Pugin11, J.-C. M. Richard12. Conclusion Les données dont nous disposons actuellement suggèrent fortement que la balance entre les bénéfices attendus et les risques observés avec l’administration des hydroxyéthylamidons est défavorable. Dans ces conditions, il ne parait pas justifié de continuer à utiliser ces produits pour le remplissage vasculaire en réanimation, alors que des alternatives moins toxiques (et moins coûteuses) sont disponibles. Il ne s’agit pas à notre sens d’une querelle d’experts, et nous suggérons à titre protecteur qu’un moratoire soit mis en place sur l’utilisation des hydroxyéthylamidons dans le remplissage vasculaire chez les patients de réanimation, dans l’attente de nouveaux essais démontrant de manière convaincante leur avantage et leur innocuité. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Vasopressors We recommend either norepinephrine or dopamine as the first choice vasopressor agent to correct hypotension in septic shock (administered through a central catheter as soon as one is available) (1C) We suggest that epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock (2C). Norepinephrine or dopamine, as combined inotrope/vasopressors (to match the sepsis-induced decrease in contractility and systemic vascular resistance) are considered equal choices as the initial vasopressor of choice. It is important to remember that vasopressors should be utilized not only when fluid resuscitation fails to reverse hypotension, but also during fluid resuscitation to maintain minimally adequate blood pressure while fluid resuscitation is administered in attempts to decrease vasopressor requirement. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

SSC: Objectives for the first 6 hours Mesure arterial lactate level Obtain blood cultures before administering antibiotics Prescribe within 3 (1) hrs broad-spectrum empiric antibiotic therapy If hypotension (PAS < 90 mmHg or mAP < 70mmHg) or hyperlactatemia (lactate > 4 mmol/l) : Start fluid loading with cristalloïds (or equivalent colloïd) 20-40 ml /kg estimated ideal body weight. Administer vasopressors to maintain mAP ≥ 65 mmHg, if persisting hypotension despite adequate fluid loading. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

SSC: Objectives for the first 6 hours If persisting hypotension or hyperlactatemia (> 4 mmol/l) despite initial fluid loading, measure PVC and ScvO2 (or SvO2), and: Maintain CVP at 8 - 12 mmHg. Consider inotropic therapy and/or RBC transfusion if hematocrit is ≤ 30 % when ScvO2 is < 70 %, or SvO2 < 65 % and CVP ≥ 8 mmHg. (2B) Recommandations SFAR – SRLF 2006 Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Low-dose Steroids: 28 d survival Non-Responders HR = 0.67 p=0.023 Responders D. Annane & al, JAMA 2002;288: 862-871. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Low-dose Steroids We suggest intravenous hydrocortisone be given only to adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy 2C We recommend corticosteroids not be administered for the treatment of sepsis in the absence of shock. 1D A final option for steroid therapy of septic shock includes the addition of fludrocortisone (a pure mineralocorticoid) . Fludrocortisone was utilized in the Annane study, but not in the Bollaert or Briegel studies. Hydrocortisone does have significant mineralocorticoid activity, although fludrocortisone is a pure mineralocorticoid. (See next slide.) Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Low-dose Steroids ACTH stimulation test (250-g) not recommended (2B) Variability in assay Variability in response on same day Free versus protein bound measurement Fludrocortisone optional (2C) Dexamethasone only if hydrocortisone not available (2B) The use of ACTH stim test to define non-responders (post-stimulation cortisol 9 g/dl) as those who will have steroids continued is optional. If this approach is taken, steroid therapy is discontinued in responders.

Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Recombinant Human Activated Protein C (rhAPC) Suggest use in patients with clinical assessment of high risk of death due to sepsis induced organ dysfunction, typically with APACHE II ≥25 or multiple organ failure (2B) And no absolute contraindications Weighing the risk/benefit of relative contraindications We recommend that adult patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC (1A ) The SSC recommendation lists four patient findings that would be linked to high risk of death for which rhAPC is recommended. In addition to no absolute contraindications, relative contraindications should also be weighed. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

3. Experience with implementation of the guidelines Surviving Sepsis 3. Experience with implementation of the guidelines

Probability of survival of patients with septic shock managed before or after (open circles) the implementation of standardized hospital order set Micek S. Crit Care Med 2006; 34: 2707. Sino-Fr Symposium - Oct 07 C. Brun-Buisson

Many “Leaks” from research to practice Aware Accept Target Doable Recall Agree Done Valid Research If 80% achieved at each stage then 0.8 x 0.8 x 0.8 x 0.8 x 0.8 x 0.8 x 0.8 = 0.21 Sino-Fr Symposium - Oct 07 C. Brun-Buisson