Current issues in the management of adult sepsis Jon Cohen MRF London Nov 2007

Current controversies Low dose steroids Intensive insulin therapy – tight glycaemic control Activated protein C Goal directed therapy

Effect of steroids on 28 day mortality Favours treatmentFavours control RR 0.88 (0.78 to 0.99) p = 0.03 Annane et al, BMJ :480

Effect of steroids on shock reversal Favours treatmentFavours control RR 1.6 (1.27 to 2.03) p < Annane et al, BMJ :480

CORTICUS International, prospective double-blind RCT of hydrocortisone in patients with moderate – severe septic shock HC 50 mg q6h for 5 d then tapering to d 11. No fludrocortisone. Primary EP 28 d mortality in nonresponders Approx 500 patients enrolled, study closed Nov 2005

CORTICUS - Results No effect on 28 day mortality in whole population or pre-identified subgroups Did not reverse shock in whole population or pre-identified subgroups Did reduce the time to shock reversal No significant problem with super- infection Sprung et al., 2007

Intensive insulin therapy in critically ill patients Van den Berghe et al, NEJM :1359 Tight glycaemic control= mg/dl ( mmol/l)

Intensive insulin therapy in medical patients on ICU Van den Berghe et al, N Engl J Med :449

Intensive insulin therapy in medical patients on ICU for > 3 days ICU mortality In hospital mortality ARR (%)OR (95% CI)P value Δ 6.8% Δ 9.5% 0.69 ( ) ( )0.003 OR and p value corrected for type & severity of illness Van den Berghe et al, N Engl J Med :449

Growing concerns about tight glycaemic control Uncertainty about feeding regimen and highly selected pt population in first NEJM study. Single centre study. Failure of second NEJM study to confirm clear survival benefit German VISEP study terminated because of XS hypoglycaemia & no survival benefit

PROWESS – Drotrecogin alfa (activated) [activated protein C] in sepsis P value Absolute reduction in risk (%) aPCPlacebo mortality (%) All treated pts stratified All randomised pts Bernard et al, N Engl J Med :699

Drotrecogin alfa – UK NICE guidelines Drotrecogin alfa (activated) is recommended for use in adult patients who have severe sepsis that has resulted in multiple organ failure (that is, two or more major organs have failed) and who are being provided with optimum intensive care support. The use of Drotrecogin alfa (activated) should only be initiated and supervised by a specialist consultant with intensive care skills and experience in the care of patients with sepsis NICE Technology appraisal 84; September 2004

Drotrecogin alfa (activated) is not effective in adults with severe sepsis and a low risk of death*, and is associated with an increased rate of serious bleeding Abraham et al, NEJM : ADDRESS trial group * APACHE II < 25 or Single organ failure

Meta-analysis of 28d mortality outcomes in the two RCTs of drotrecogin alfa Costa et al, BMC Anesthesiol 2007; 7:5

PROWESS – Continuing debate Is there confidence in the baseline comparability of the populations – especially the subpopulations? There are variable outcomes depending on the severity marker used (IL6, APII, SOFA) There is no confirmatory study ADDRESS severe subgroup did not show benefit

Haemodynamic monitoring in sepsis – Background Long standing “discussions” about how to measure/quantify shock Clinical and laboratory biomarkers poorly defined Role of invasive monitoring uncertain Shoemaker develops “goal directed therapy” based on CI, DO 2 & VO 2, but clinical studies fail to support this approach

Recent recommendations on haemodynamic monitoring in shock Shock now defined on the basis of tissue dysoxia Hypotension not a requirement Lactate only useful biomarker Routine measurement of CO not required PAC not helpful Support for Early Goal Directed Therapy Antonelli et al, International Consensus Conference, Intensive Care Med :

Early Goal Directed Therapy ER admissions with severe sepsis/shock treated for 6 h before ICU transfer Protocol designed to achieve: –CVP ≥ 8 – 12 mmHg –MAP ≥ 65 mmHg –ScvO 2 ≥ 70% –Urine output ≥ 0.5 ml/kg.hr Rivers et al, N Engl J Med :

Early goal-directed therapy in sepsis Standard therapy n=133 Active therapy n=130 p In hospital mortality (%) All patients Severe sepsis Septic shock Rivers et al, N Engl J Med :1368 But…. Unexpectedly high placebo mortality Unusual (ER) population Single centre study

Current controversies Low dose steroids ? / Not confirmed Intensive insulin therapy ? / Not confirmed Activated protein C ?/ Requires confirmation Goal directed therapy ?/ Requires confirmation

Updated version, 2008, in press

Experimental & Investigational Agents, 2007 Statins Cytokines –Polyclonal anti-TNF –MIF –HMG-B1 Cholinergic pathway –JCI :289 Coagulation pathway –TFPI –AT Anti-TLR strategies –TAK 242 –Eritoran

TAK-242 Novel small molecule signal transduction inhibitor Effective when given up to 4 h after LPS challenge in mice Phase I human studies confirm broad inhibition of cytokines Excellent safety profile

TAK-242 exhibits a TLR4-specific mode of action

E5564 inhibits LPS-induced TLR4-mediated NF-kB reporter activity Mullarkey et al, J Pharmacol Exp Ther :1093 HEK293 cells stably transfected with TLR4, MD-2, and a luciferase reporter gene driven by an NF-kB-dependent promotor

Mean change in heart rate from baseline among healthy volunteers with experimental endotoxemia who received E5564 or placebo Lynn et al, J Infect Dis :631

Phase II study of Eritoran (E5564) in sepsis Placebo Low dose High dose 28 d mortality (%)RRR (%)p N = 293 Eisai, press release, Aug 2005

Phase II study of Eritoran (E5564) in sepsis High risk subgroup Placebo Low dose High dose 28 d mortality (%)RRR (%)p Eisai, press release, Aug N = 162

Cuban Hospital, 1898 Greetings from ICU at Brighton General Hospital !

A role for statins in sepsis? Pleiotropic anti-inflammatory effects Prevents lethal sepsis in mice used either as prophylaxis or therapy (Merx, Circulation :117) Beneficial in human LPS-challenge model (Steiner, Circulation :1841) Clinical observational studies suggest statins reduce risk of complications/death in pts admitted with sepsis (Almog, Circulation :880) (Kruger, Intensive Care Med :75)

Statin use and mortality after bacteraemia Statin use YES NOMRRp Death (%) Risk period 0 – 30 d n = Thomsen et al, Crit Care Med :1080

Statin use and mortality after bacteraemia Statin use YES NOMRRp Risk period 31 – 180 d Death (%) < 0.05 Thomsen et al, Crit Care Med :1080

Statins reduce infection-related mortality in patients with atherosclerosis, independently of other comorbidities Almog et al, Crit Care Med :372

Modlin & Cheng, Nature Med :1173

TAK-242 has a broad suppressive effect on LPS induced inflammatory mediators Yamada et al, J Med Chem :7457

Early initiation of antimicrobial therapy is critical Kumar et al, Crit Care Med :1589

Impact of antibiotic choice on survival of community-acquired BSI Vallés et al, Chest :1615