Anthony Delaney, an Emergency Physician and Intensivist from Sydney gives an update on Sepsis Resuscitation in 2012. And he doesn't even talk about ARISE!

1. AN UPDATE ON SEPSIS
RESUSCITATION
Anthony Delaney MBBS MSc FACEM FCICM
Staff Specialist in Intensive Care, Royal North Shore Hospital
Senior Lecturer, Sydney Medical School, University of Sydney

2. A Big Topic
 Activated Protein C?
 Which Fluid?
 How much fluid?
 Resuscitation goals?

4. Drotrecogin alpha (activated) for adults
with septic shock
 Population:
 Adults, sepsis, hypoperfusion (BE <5mmol/L, HCO3<18
mmol/L, lactate >2.5 mmol/L) or renal or liver dysfunction,
and noradrenaline ≥5 g/min for 4 hours after 30ml/kg fluid
 May 2008 – August 2011 in 208 sites
 Intervention:
 Drotrecogin alpha activated 24mg/kg/hr for 96 hours
 Comparison:
 Placebo
 Outcome:
 Primary outcome: All cause mortality at 28 days

5. Drotrecogin alpha (activated) for adults
with septic shock
 Allocation concealment:
 Centralised randomisation system
 Blinding:
 Placebo controlled
 Complete follow-up:
 Not too bad
 Intention to treat analysis
 yes
 Baseline balance:
 Yes
 Treated equally apart from intervention:
 I think so

7. Drotrecogin alpha (activated) for adults
with septic shock

8. Drotrecogin alpha (activated) for adults
with septic shock
 Not so much

10. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study
 Population:
 Adults with severe sepsis
 Intervention:
 Hydroxyethyl starch 130/0.4 (Voluven)
 Comparison:
 0.9% Saline
 Outcome:
 Amount of study drug required to achieve a MAP
≥65mmHg for 4 hours + 2 of
 CVP 8-12
 u/o >2ml/Kg
 ScvO2 ≥70%

11. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study
 Allocation concealment:
 Not described
 Blinding:
 Yes, same as CHEST
 Complete follow-up:
 Unsure
 Intention to treat analysis:
 Yes, but….
 Baseline balance:
 Probably, but….
 Concomittant treatment:
 Not sure,
 Steroids and source control not mentioned

12. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study

13. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study

14. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study
 Excluded 12 in the HES group and 10 in the
NaCl group who never achieved
haemodynamic stability (?)

15. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study
 Mortality 28 days
 HES 31/100 (31.0%) v NaCl 24/95 (25.3%)
 RR = 1.1 (95% confidence limits 0.70 to 1.72)
 Mortality 90 days
 HES 40/99 (40%) v NaCl 32/95 (34%)
 RR = 1.2 (95% confidence limits 0.83 to 1.74)
 No difference in renal impairment
 Blood transfusion
 HES 29/100 (29.0%) v 20/96 (20.8%)
 P=0.25

16. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study
 Less HES was used to reach haemodynamic
stability compared to saline
 1379 ml v 1709 ml
 Difference of 300ml
 P=0.02
 No difference in time to haemodynamic
stability
 “No difference in mortality”???

17. Assessment of haemodynamic efficacy and safety of 6%
hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The
CRYSTMAS study
 Significantly less volume was required to
achieve haemodynamic stability for HES
compared to NaCl in patients with severe
sepsis
 No difference in surrogate measures of
renal function nor mortality
 Underpowered trial with methodologic
limitations, using surrogate endpoints to
draw conclusions

19. Hydroxyethyl starch 130/0.42 versus
Ringer’s acetate in severe sepsis
 Population:
 ≥18 yo with severe sepsis in the previous 24 hours
 SIRS + defined focus of infection + one organ
failure
 Intervention:
 Hydroxyethyl starch 130/0.42
 Comparison:
 Ringers acetate
 Outcome:
 Death or dependence on dialysis at day 90

20. Hydroxyethyl starch 130/0.42 versus
Ringer’s acetate in severe sepsis
 Allocation concealment:
 Centralised randomisation system
 Blinding:
 Yes
 Patients, clinicians, DSMC, Statistician, writing committee
 Complete follow-up:
 Not too bad
 Intention to treat:
 Pretty much
 Baseline balance:
 Yes
 Treated equally apart from intervention:
 I think so

25. Hydroxyethyl starch 130/0.42 versus
Ringer’s acetate in severe sepsis
 I think we should probably avoid
hydroxyethyl starch 130/0.42 in patients
with severe sepsis
 Await the results of CHEST (Crystalloid
versus hydroxy-ethyl starch) with interest
 HES 130/0.4!

27. Mortality after fluid bolus in African
Children with severe infection
 Population:
 Children 60 days to 12 years
 Kenya, Tanzania and Uganda
 Severe febrile illness, reduced LOC, respiratory distress, poor
perfusion
 Excluded those with severe malnutrition, gastroenteritis, non
infectious shock
 Intervention:
 20-40ml/Kg Albumin, 20-40ml/Kg saline,
 Comparison:
 Maintenance fluids only
 Outcome:
 Mortality at 48 hours

28. Mortality after fluid bolus in African
Children with severe infection
 Intervention (all trial participants):
 General paediatric ward
 Training to staff in paediatric life support
 Basic infrastructure: NIBP and O2 sats
 2.5-4.0 ml/Kg/Hr maintenance fluids, antibiotics,
antimalarials, glucose, 20ml/Kg blood if Hb <5
 Increased sample size due to lower than
anticipated overall mortality

29. Mortality after fluid bolus in African
Children with severe infection
 Allocation concealment:
 Opaque sealed numbered envelopes
 Blinding:
 Not really
 End-point review committee blinded to treatment allocation
 Complete follow-up:
 Very good considering
 Intention to treat:
 Yes
 Baseline balance:
 Yes
 Treated equally apart from intervention:
 I think so

35. Mortality after fluid bolus in African
Children with severe infection
 DUDE!!
 Care with fluid boluses next
time you are resuscitating kids
with ? Sepsis in Africa
 Question some dogma

37. Positive fluid balance and elevated CVP
in septic shock
 Retrospective analysis of data from VASST
 778 patients
 Analysis stratified by quartiles using cox
proportional hazards models
 Age, APACHE II score, dose of noradrenaline

38. Positive fluid balance and elevated CVP
in septic shock

39. Positive fluid balance and elevated CVP
in septic shock

40. Positive fluid balance and elevated CVP
in septic shock
It might just be worthwhile
thinking about the dogma that
more fluid is better for you?

42. Lactate clearance vs central venous oxygen
saturation as goals of early sepsis therapy
 Population:
 > 17 years old
 Severe sepsis or septic shock
 BP < 90 after 20ml/Kg fluid OR lactate > 4mmol/L
 Intervention:
 Quantitative resuscitation guided by lactate clearance
(10% per hour)
 Comparison:
 Quantitative resuscitation guided by ScvO2 (ScvO2
>70%)
 Outcome:
 In-hospital mortality

43. Lactate clearance vs central venous oxygen
saturation as goals of early sepsis therapy
 Allocation concealment:
 Opaque sealed envelopes
 Blinding:
 No, …
 Subsequent staff were
 Complete follow-up
 Yes
 Baseline balance:
 It appears so
 Concomitant therapy:
 Probably

46. • In- hospital mortality
• Estimate of in-hospital mortality 25% in the
ScvO2 group
• Sample size non-inferiority: 10% boundary,
=0.05 (one-sided), =0.71

47. Lactate clearance vs central venous oxygen
saturation as goals of early sepsis therapy
 It may be more important to pay attention
to ensuring that the patient is resuscitated
adequately, rather than the specific goals.

48. QUESTIONS ??