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 ??