Post on 07-May-2015
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AN UPDATE ON SEPSIS RESUSCITATION
Anthony Delaney MBBS MSc FACEM FCICM
Staff Specialist in Intensive Care, Royal North Shore HospitalSenior Lecturer, Sydney Medical School, University of Sydney
A Big Topic
Activated Protein C? Which Fluid? How much fluid? Resuscitation goals?
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 ≥5mg/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
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
Drotrecogin alpha (activated) for adults with septic shock
Drotrecogin alpha (activated) for adults with septic shock
Not so much
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%
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
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
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
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 (?)
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
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”???
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
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
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
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!
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
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
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
Mortality after fluid bolus in African Children with severe infection DUDE!! Care with fluid boluses next
time you are resuscitating kidswith ? Sepsis in Africa
Question some dogma
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
Positive fluid balance and elevated CVP in septic shock
Positive fluid balance and elevated CVP in septic shock
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?
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
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
• In- hospital mortality• Estimate of in-hospital mortality 25% in the
ScvO2 group• Sample size non-inferiority: 10% boundary, a=0.05 (one-sided), b=0.71
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.
QUESTIONS ??