1. Sepsis – What matters David Johnson 2014

2. Traditional care Early recognition Antibiotics Fluids Vasopressors Source control

3. Early Goal Directed Therapy Early goal-directed therapy in the treatment of severe sepsis and septic shock. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. N Engl J Med. 2001 Nov 8;345(19):1368-77 Early goal-directed therapy in the treatment of severe sepsis and septic shock. Single centre trial 263 patients Randomised in ED to standard care or EGDT EGDT resulted in lower lactate, lower base deficit, higher pH, higher mean SCVO2 AND lower mortality from 45% to 30% Note mortality from sepsis in Australian ICUs is around 20%

4. Sounds good…so what is it?

5. What is it? 500 mL crystalloid every 30 minutes till CVP 8-12 Vasopressors to keep MAP >65 CV line with O2 measurement Transfuse red cells to HCT >30 if SCVO2 <70 Dobutamine titrated to SCVO2 <70 after transfusion Aim is to maximise oxygen delivery to end organs

6. Problems Does anyone have a CV line that will measure O2 sats? Are they a good measurement? CVP?? Does central venous pressure predict fluid responsiveness?: a systematic review of the literature and the tale of seven mares. Marik PE, Baram M, Vahid B. Chest. 2008;134(1):172-178. Mortality in experimental group was still 30% vs 20% in Australian studies

7. But the basic story is the same Early recognition Antibiotics IV fluids (blood) (Measure some stuff) Vasopressors Source control

8. How much fluid The hardest question in sepsis. Maybe in medicine. Will this patient improve with further fluid or do we need to start vasopressors? Is the tank empty, are the pipes leaky or is the pump broken?

9. Measurements CVP – Probably no good Map/HR/Urine output/lactate/SVCO2 – fluid vs vasopressors? USS of IVC – as good as CVP IVC collapsibility change with leg raise – maybe Pulmonary artery catheter – should be good but it does not change outcomes Other things are coming, not here yet.

10. FEAST trial Maitland, K et al Fluid Expansion as Supportive Therapy (FEAST) N Engl J Med. 2011;364:2483- 2495 Trial of fluid bolus in sepsis in 3000 children in 6 African hospitals Fluid boluses increased mortality by 3% Most excess deaths due to cardiogenic shock, not fluid overload or respiratory failure.

11. Feast trial problems Africa – sick and dehydrated, walked for miles Kids Lots of malaria vs other sepsis

12. Why would fluid be bad? Why would it cause cardiovascular collapse, not fluid overload? The glycocalyx! Beyond the scope of this talk

13. Which fluid? Stop it! Crystalloids are fine Hydroxyethyl starches are worse for kidneys, provide no benefit Albumin – who knows, who cares. It is probably SAFE

14. Which vasopressors? Probably not dopamine – higher rates of supraventricular and ventricular arrhythmias without any benefit Noradrenaline if tachycardic Otherwise no good evidence Rivers uses norad then adds in dobutamine Remember metaraminol is indirect and uses patient’s own catecholamines – these will run out in a stressed state.

15. Anything else? Glucose – tight control must be better NICE-SUGAR study investigators. Intensive versus conventional glucose control in critically ill patients. N. Engl. J. Med. 360, 1283–1297 (2009) Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation Aiming for sugar of <11 vs 4.4-6.1 was associated with a 42% reduction in mortality This does not mean a sugar of 20 is OK!

16. Beta blockers? Morelli A, Ertmer C, Westphal M, et al. Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial. JAMA. 2013;310(16):1683-1691. Small study – 154 patients HR>95, high dose norad Esmolol to keep HR 80-94 Mortality 49% vs 80% ???

17. Steroids? Will not die! CORTICUS trial 2008 Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J: Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008, 358: 111–124 Despite claims of bias towards steroids, the authors found no mortality benefit Maybe worthwhile in shock refractory to vasopressors

18. Surviving sepsis campaign Expert group started in 2003 Much maligned for early embrace of activated protein C and sponsorship by industry Good literature review of everything to do with sepsis 3 hour and 6 hour “bundles” Worth knowing May change after PROCESS, ARISE, ProMISe all report

19. Surviving sepsis bundles TO BE COMPLETED WITHIN 3 HOURS: 1) Measure lactate level 2) Obtain blood cultures prior to administration of antibiotics 3) Administer broad spectrum antibiotics 4) Administer 30 ml/kg crystalloid for hypotension or lactate ≥4mmol/L TO BE COMPLETED WITHIN 6 HOURS: 5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg 6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥4 mmol/L (36 mg/dL): - Measure central venous pressure (CVP)* - Measure central venous oxygen saturation (ScvO 2 )* 7) Remeasure lactate if initial lactate was elevated*

20. Process Trial Multi-centre, 1341 patients Sepsis and hypotension refractory to initial 1 litre fluid bolus (or lactate >4 after bolus) Divided between EGDT, Protocol based standard therapy without CVP and usual care No difference in length of stay, mortality, need for organ support

21. What is usual care Fluid – 2-3 litres in first six hours Crystalloid Vasopressors – in about half Dobutamine? Only about 1% vs 8% for EGDT arm Tranfusion? 7-8% vs 14% in EGDT

22. What the trial tells us You don’t need to measure SVCO2 (other trials have said lactate is a good marker – very long discussion there) 2-3 litres (+1 to get into the study) of fluid is a good time to think about vasopressors Most of the time – 55% - you don’t need a central line You probably don’t need dobutamine You only need transfusion occasionally

23. What the trial doesn’t tell us Does not throw out the idea of early goal directed therapy Of course sepsis therapy should be early It should be goal directed – although the exact goals are not clear – clinical, lactate, SVC sats probably all reasonable. The mantra is still: Early recognition Antibiotics Fluids Vasopressors Source control