What works in sepsis. Topics. EGDT: Severe Sepsis/ Shock. Sepsis

Transcription

1 What works in sepsis Eric Schmidt, MD Denver Health Medical Center University of Colorado School of Medicine Topics Understanding and early goal directed therapy (EGDT) Protein C should we use it? Vasopressor agents in sepsis which ones to use? Sepsis EGDT: Ra@onale Organ Failure Severe Sepsis/ Sep@c Shock Hospital mortality Mackenzie I, Lever A BMJ 2007;335:

2 1 st 6 hours (in ER) VOLUME RESUSCITATE OPTIMIZE BP Randomize Crystalloid or colloid to CVP 8 12 mm Hg Vasopressors or vasodilators to MAP mm Hg Transfer to ICU MAXIMIZE O 2 DELIVERY If ScvO 2 < 70%... Transfuse PRBC un@l HCT > 30 If ScvO 2 s@ll < 70%... Start inotropes Success rates in 1 st 6 hours? Goal Usual care Interven8on VOLUME RESUSCITATE CVP 8 12 mm Hg 10.5 ± 6.8 mm Hg 11.7 ± 5.1 mm Hg OPTIMIZE BP MAP mm Hg 81 ± 16 mm Hg 88 ± 16 mm Hg MAXIMIZE O 2 DELIVERY ScvO 2 > 70% 65.4 ± 15.5 % 71.6 ± 10.2 % Mean ± SD In hospital mortality 28 day mortality 60 day mortality EGDT outcomes? Usual care Interven8on 46.5% 30.5% 49.2% 33.3% 56.9% 44.3% p < 0.05 p < 0.05 p < 0.05 Conclusion: A protocol aimed at op@mizing volume status, blood pressure, and oxygen delivery early in sepsis improves survival

3 What do we remember re: EGDT? Incremental improvements to EGDT What s the ideal measurement oxygen delivery? ScvO 2 As oxygen delivery extrac@on relaxes, leading to normaliza@on of ScvO 2 Requires specialized central line or serial VBG s Lactate clearance As oxygen delivery improves, an ini@ally elevated venous lactate normalizes Goal? >10% decrease in lactate amer 2 hours of resuscita@on Performed similarly to ScvO 2 in EGDT (Jones et al. JAMA 2010) Incremental improvements to EGDT What s the ideal measurement of volume status? Does CVP adequately predict preload reserve? increase in cardiac index > 15% amer a 500 cc colloid bolus Michard et al AJRCCM 2000

4 Change in pulse pressure? = (PPmax PPmin)/(mean of PPmax and min) If > 13%, pa@ent is dry Requires regular rhythm, 10 volume on ven@lator Michard et al AJRCCM 2000 Ac8vated Protein C and Sepsis Ac@vated Protein C (APC) has mul@ple func@ons An@coagulant An@ inflammatory Fibrinoly@c During sepsis, endogenous levels of APC are decreased (Bernard et al. NEJM 2001) Magnitude of reduc@on correlates with mortality PROWESS (Bernard et al NEJM 2001) 1,690 pa@ents with severe sepsis randomized to APC x 96 hours vs placebo Survival (%) Placebo APC p = % risk of major bleeding (p = 0.06) FDA, based on their own subgroup analysis of risk:benefits, approved APC for APACHE II 25 ( 2 organ failure)

5 ADDRESS (Abraham et al NEJM 2005) FDA mandated follow up study (2640 pts) Does APC benefit with APACHE II < 25 (single organ failure)? Survival (%) APC Placebo Trial stopped early for Increased risk of major bleeding (3.9% vs. 2.2%, p < 0.05) Increased mortality in post opera@ve pa@ents ENHANCE (Vincent JL et al. Crit Care Med 2005) Open label observa@onal study of 268 pa@ents treated with APC for sepsis Significantly higher bleeding risk than what was noted in PROWESS and ADDRESS Major bleeding: 6.2% (3.5% in PROWESS) Intracranial hemorrhage: 1.5% (0.2% in PROWESS) What to do with APC? Risks uncertain, but appreciable No benefit to the less sick APACHE II < 25 or single organ failure Probably a benefit to the most sick PROWESS SHOCK (Finfer et al. Intensive Care Med 2008) Currently enrolling pa@ents with Sep@c shock APACHE II > 25 Greater than 1 organ failure

6 Vasopressors in sepsis Vasopressors keep blood pressure up α1 receptors (catecholamines) V1 receptors (vasopressin) Inotropes improve oxygen delivery β1 receptors (dobutamine, dopamine, catecholamines, phosphodiesterase inhibitors) β2 receptors (dobutamine, phosphodiesterase inhibitors, epinephrine) L-tyrosine Which catecholamine to use? L-DOPA Phenylephrine Less tachycardia, but drop in stroke volume (negative inotrope) Dopamine Norepinephrine Recommended first-line agents by Surviving Sepsis Campaign (Dellinger et al. Intensive Care Med 2008) Epinephrine Associated with increased lactate, more tachycardia p = 0.07 No survival difference between DA and NE in management of shock (regardless of type)

7 Which is bezer in shock? Increased frequency of arrhythmia with DA De Backer et al NEJM 2010 Vasopressin Vasopressin levels rise during sepsis Prolonged sepsis? Vasopressin levels inappropriately normalize ( rela@ve vasopressin deficiency ) Fixed, low dose vasopressin as a catecholaminesparing agent? VASST trial (Russell et al. NEJM 2008) Norepinephrine vs. Norepinephrine /Vasopressin No difference in survival rates in sep@c shock (778 pts) Subgroup analysis: vasopressin may have benefit in the less sick (on lower doses of NE of randomiza@on) Conclusions? EGDT: Early ini@a@on of a protocol aimed at op@miza@on of volume, BP, and oxygen deliver improves outcomes. APC: No benefit in less sick pa@ents; stay tuned for role in sicker pa@ents Pressors? Norepinephrine slightly favored over dopamine. Consider adding fixed low dose vasopressin in the less sick.