1. ARISE (Australian Resuscitation In Sepsis Evaluation)*
James Hayward
* = At least they included the “I”

2. ARISE – EGDT does not reduce mortality
Multi-centred RCT to evaluate the effect of early goal directed therapy (EDGT) on patients with early sepsis
Primary end-point was 90-day all-cause mortality
No difference (significant, clinical or actual) in 90 day mortality.
Also no difference in survival time, in-hospital mortality, duration of organ support, length of stay.

3. But I thought EGDT saved lives…….

4. Rivers (2001) suggested a huge mortality benefit.
2001 – Rivers – EGDT in sepsis and septic shock
Single centre
263 patients
Inclusion criteria
2 out of 4 SIRS criteria
Systolic <90mmHg (after 20-30ml/kg stat challenge)
Or lactate >4mmol/L
In-hospital mortality EGDT vs “normal” - 30% vs 46%
Temp <36 or >38
HR>90
RR>20 or PaCO2<4.3kPa
WCC <4 or >12 X 109/L
Rivers argued that normal physiological parameters are not good indicators of ongoing tissue hypoxia, instead arguing that central venous oxygenation can be used as a proxy for cardiac index. Prior studies had enrolled up to 72 hours following admission therefore Rivers looked specifically at the effect of early intervention.
Excluded: less than 18 years, pregnancy, or the presence of an acute cerebral vascular event, acute coronary syndrome, acute pulmonary oedema, status asthmaticus, cardiac dysrhythmias (as a primary diagnosis), contraindication to central venous catheterization, active gastrointestinal haemorrhage, seizure, drug overdose, burn injury, trauma, a requirement for immediate surgery, uncured cancer (during chemotherapy), immunosuppression (because of organ transplantation or systemic disease), DNAR

5. The EGDT protocol differed from standard in terms of attaining SvO2

6. The target SvO2 was attained through transfusion and inotropes

7. But Rivers’ standard targets were discretionary
All patients (irrespective of group) had central venous and arterial access.
Standard group (133 patients)
Treated at clinician’s discretion according to a protocol
Antibiotics given at discretion of lead clinician
EGDT group (130 patients)
CVC with continuous saturation monitoring
Remained in the ED for 6 hours
All targets adhered to
All patients went on to be looked after by critical care physicians who did not know which group the patients had been randomised to.

8. The groups seemed well matched
EGDT group:
More CHF (36% vs 30%)
More COPD (18% vs 13%)
Fewer patients received abx in first 6hrs (86% vs 92%)
No difference in 0-hour physiology

9. There were considerable difference between interventions
Standard group received 1.5l less fluid to start with, then 2l more, but nearly the same in total
Standard group received less RBC in initial phase, more in the second phase
More patients in the standard group received vasopressors , but fewer received inotropes
More patients in the standard group got ventilated post resuscitation – why?
12% more patients in the standard group had a PA catheter inserted

10. During these interventions there were some physiological differences
The initial lactates were very high
Subsequently lactate higher in standard group (but less than 1.0 difference)
HR and CVP same between groups throughout
BP lower in standard group (15mmHg at 6hrs, 6mmHg by 72hrs)
60% of the standard group, 90% of the intervention group achieved SvO2 of 70% or higher but small difference in means
Large difference in BE – why?
Small difference in haematocrit (1-2%)
Small difference in PT (17 vs 15)
Combined haemodynamic goals were achieved in 86.1% of the standard group and 99% of the EGDT group.
Patients in the standard group had significantly lower SvO2 (66% vs 77%) and larger BE (8.0 vs 4.7).

11. And the resultant mortality difference was large

12. But the Power calculation raised a few eyebrows
Assumed a potential 15% reduction in mortality from EGDT
Assuming a rate of refusal or exclusion of 10 percent, a two-sided type I error rate of 5 percent, and a power of 80 percent, we calculated that a sample size of 260 patients was required

13. IF a study is underpowered but finds significance…
The difference is likely to be falsely elevated
Because the calculation of p-value involves “n”, to detect small differences larger study populations are required. Conversely, if the sample size is small – the difference would have to be large to reach statistical significance. IF the study is also underpowered the type 1 error will be much larger.
when studies are underpowered, the literature is likely to be inconsistent and often misleading

14. Rivers has been criticised for other reasons
Single centre
Very few clinicians
Non-blinded
Very high initial lactates (?particularly sick population)
Considerable evidence of harm in the interventions that were implicated as beneficial by Rivers
No attempt to isolate individual intervention
Much higher both group mortality than any other contemporaneous literature suggesting possible selection bias
ProCESS – US multi-centred trail (showed no effect)

15. So Rivers concludes that early intervention and SvO2 targeting are key

16. Back to ARISE – it deliberately mimics Rivers but adds power
51 hospitals, tertiary, urban and rural
Multi centred
1600 patients
Used 90-day all cause mortality as primary end-point
Designed in parallel with ProCESS and ProMISe
Similar inclusion criteria
EGDT according to similar methodology
?Power calculation
?Better end-point
2 of 4 SIRS criteria, refractory hypotension or lactate >4.0mMol/L

17. The standard interventions were discretionary, the EGDT interventions were strictly guided by a team
In the standard group a SvO2 was not permitted
The EDGT interventions were guided by a specific team
The algorithm was followed for 6 hrs
Non-blinded

18. The power calculation had a very different conclusion
Assume intervention effect of 7.6%
Assumed in-hospital rate of death in the usual-care group of 28% with an increment of 10% for the rate of death at 90 days
1600 patients
A lower standard mortality than in the Rivers EGDT group
Half the projected effect of River’s
6X study population

19. Group base line characteristics were well matched

20. The EGDT protocol was based on Rivers’ protocol
Arterial line and a central venous catheter capable of continuous ScvO2 measurement was inserted within 1 hour after randomisation
Supplemental oxygen titrated to achieve SpO2 > 93%
500mls bolus at least every 30 minutes until CVP > 8mmHg (self ventilating) or > 12mmHg (NIV or invasive ventilation)
Vasopressors to achieve MAP of 65–90mmHg
ScVO2 >70% once CVP and MAP targets achieved
If ScVO2 < 70% and HCT < 30% → PRBC transfusion
If ScVO2 remains < 70% despite HCT >30% or Hb > 100g/dl → dobutamine 2.5–20mcg/kg/min
If ScVO2 still < 70% → increase oxygen → NIV → Mechanical ventilation
Sedative and paralysing agents used if mechanically ventilated

21. Those patients in the EGDT group received more i. v
Those patients in the EGDT group received more i.v. fluids, RBC, vasopressors and dobutamine (0-6hrs)
Less than HALF the volume given in Rivers.
100% vs 62% CVC
1964mls vs 1713mls
13.6% vs 7.0% received RBC transfusion
66% vs 57% vasopressor
15.4% vs 2.6% received dobutamine
EDGT group in ARISE received LESS blood than the standard group in Rivers
More than double the proportion in Rivers
About the same!!

22. The survival curve does not even hint at a difference, nor does subgroup analysis
No difference in adverse incidents between groups
EDGT spent 36minutes fewer in ED
No difference in secondary or tertiary endpoints

23. Thoughts? Is Rivers a Type 1 error as a result of underpowering?
Is Rivers false?
Did Rivers have a huge effect primarily BECAUSE it was single centre and they could implement the protocol accurately and consistently?
Has Rivers found a population which would benefit from EGDT?
Despite a nearly identical protocol they had vastly different interventions as a result of that protocol – WHY?
Detail

24. So where does that leave us?1

25. Thanks!

26. ARISE - Summary
Multi-centred RCT to evaluate the effect of early goal directed therapy (EDGT) on patients with early sepsis
1600 patients
796 EGDT
804 “normal” therapy
Primary end-point was 90-day all-cause mortality
EGDT
Approx 200mls more fluid (1.9l vs 1.7l)
8% more underwent vasopressor therapy (66% vs 58%)
More RBC transfusions (14% vs 7%)
Dobutamine (15% vs 3%)
No difference (significant, clinical or actual) in 90 day mortality.
Also no difference in survival time, in-hospital mortality, duration of organ support, length of stay.