1. A Randomised Trial of Protocol-Based Care for Early Septic Shock
The ProCESS Investigators

2. Middle Ages
“The physicians say it happens in hectic fever, in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning it becomes easy to detect but difficult to cure”

3. Rivers 2001
Protocolized early goal directed therapy initiated in the ED in severe sepsis and septic shock patients improved resuscitation parameters and reduced mortality
263 patients – severe sepsis or septic shock
SBP <90 despite 30ml/kg fluid
Lactate >4mmol/L
Randomised to standard of care vs. EGDT
Central venous pressure and central venous oxygen saturation to guide the use of IV fluids, vasopressors, packed red cell transfusions and dobutamine in order to achieve pre-specified physiological targets
EGDT
Central line for ScvO2
Maintain CVP 8-12mmHg
Map > 65
ScvO2 >70%
HCT >30%
Primary endpoint (hospital mortality) lower with EGDT 30.5% vs. 46.5%

5. Rivers Trial Launched the EGDT era of sepsis management Encouraged
Coordinated efforts
Earlier identification of septic shock
Increased earlier larger volume resuscitation
ProCESS trial allows refinement of the EGDT approach to fluid administration by defining lower boundaries that are associated with equivalent outcomes and setting limits that are needed to avoid the twin problems of renal failure and pulmonary dysfunction

6. Research Question
Is protocol based cared (EGDT and standard-therapy groups combined) superior to usual care
Is protocol based (EGDT) superior to protocol-based standard therapy

7. Study Design Multicentre vs. Rivers Randomised protocolased study
31 hospitals in the US
All academic hospitals
> yearly admissions
Funded by national institute of general medical sciences
Centres had to use the measurement of serum lactate levels as the method for screening for shock and had to adhere to the surviving sepsis campaign guidelines but could not have routine resuscitation protocols and couldn’t use continuous Scvo2 catheters

8. Study subjects
31 emergency departments in the US March 2008 – May 2013
In the emergency department in whom sepsis was suspected according to the treating physician
>18
Refractory hypotension OR lactate >4mmol
SBP <90 or required vasopressor to maintain 90mmHg even after IV fluid challenge >20ml/kg over 30min, in April changed to a challenge of 1000ml or more administered over 30min
Patients randomly assigned to (1341)
Protocol based EGDT (439)
Protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotrope, blood transfusions (446)
Usual care (456)
Randomisation was performed with the use of a centralised web-based program

10. Interventions Randomly assigned 1:1:1
Protocol based EGDT
Protocol based standard therapy
Usual care
Same physician led team implemented both the protocols
One physician who was trained in the protocol guided resuscitation interventions
Study coordinator – monitored adherence to protocols
Bedside nurse
All study physicians were trained in emergency medicine or critical care medicine and had completed a web based certificate examination
Therapy could be continued outside of emergency

12. All 3 arms No arterial line Did not specify type of fluid
Did not specify type of inotrope

13. Protocol based standard therapy
6 hour resuscitation instruction
Designed on bases of review of literature, 2 independent surveys of emergency physician and intensivist practice world wide
Consensus feedback from investigators
Adequate peripheral access
Administration of fluids and vasoactive agents to reach goals for SBP and shock index (ratio of HR to SBP) and to address fluid status and hypoperfusion which were assessed clinically at least once an hour
PRBC only if Hb <75
Administration of IVF until the team leader decided fluids were replete

14. Usual care group
Bedside providers directed all care with the study provider collecting data but not prompting any actions
Lead investigators could not serve as the bedside treating physician for patients in this group

15. Outcome variables Primary end point: 60 day in hospital mortality
Secondary outcomes
Longer term mortality (1 year)
Duration of cardiovascular failure - need for vasopressors
Duration of respiratory failure – need for ventilation
Duration of acute renal failure – need for dialysis

16. Statistical analysis
With a sample of 1950 patients, study would have at least 80% power to detect a reduction in mortality of 6-7%, assuming mortality of 30-46%
Mortality on half way analysis – 20% - re-analysed would need 1350 patients

17. Patients well matched at baseline

19. 60 days
92 deaths in EGDT (21%)
81 deaths in the protocol-based standard therapy (18.2%)
86 deaths in the usual group (18.9%)

20. No significant differences in 60 day mortality or 1 year mortality

21. No difference in duration of organ support

22. Renal failure - Higher in protocol based standard therapy group
Rate of admission to ICU higher in EGDT group
No significant difference in incidence and duration of cardiovascular failure or respiratory failure
No differences in the length of stay in hospital or discharge disposition

23. Resuscitation Volume of fluids 2.8L EGDT 3.3L protocol based group
2.3L in usual care group
96% crystalloids
Vasopressors 54.9% 52.2% Vs. 44.1% P=0.003
Dobutamine 8% 1.1% 0.9% p<0.001
PRBC 14.4%, 8,3%, 7.5% p=0.001

24. Use of antibiotics, glucocorticoids and APC was similar

25. Antibiotics
76% of patients received antimicrobial agents by the time they underwent randomisation – mean of 3 hours
97% had received antibiotics by mean 9 hours
Ongoing role of early recognition of sepsis and antibiotic treatment for sepsis in improving survival (kumar – duration of hypotension before initiation of effective antimicrobial therapy)

26. Need for central monitoring in managing sepsis guidelines?
In the non EGDT 56.5% and 57.9% had a CVC inserted but later then the EGDT , and CVC used for monitoring in only 4% in other groups Use of central hemodynamic and oxygen-saturation monitoring in the EGDT group did not result in better outcomes than those achieved with clinical assessment of the adequacy of circulation

27. Limitations Adherence to protocols
Enrolled patients who were recognised to be in septic shock – does not address extent to which any of these strategies offer advantages in settings where septic shock is not recognised promptly
Septic shock occurs in a heterogeneous population and care before randomisation can be variable
Limited power to address whether particular strategies were more effective in specific subgroups
Two ongoing multicentre trials
ARISE
ProMIse
In hospital mortality amongst patients requiring life support is strongly influenced by varying practices regarding withdrawal of care

28. Rivers
Process
Arise
Promise
Study
Single center, EGDT vs. Standard therapy
Multi center, EGDT vs. protocol based standard therapy vs. standard therapy
Mute center, RCT of the effect of EGDT, compared to standard care
Multi center RCT of the clinical and cost-effectiveness of EGDT, protocoled resuscitation for septic shock
Design
Central line – continuous ScvO2 and protocoled care to maintain
CVP 8-12
MAP >65
ScvO2 >70%
HCT >30%
EGDT and Protocol based VS standard therapy
EGDT vs. Protocol based therapy
EGDT 6 hours vs.
Standard care
Effect of EGDT, protocoled resuscitation vs. usual care at 90days
To compare the incremental cost effectiveness at one year
Power
263 patients
1341 patients
1600 patients over 2.5 years
Outcome
Difference at 72 hours of APACHE II score
Mortality at 28 and 60 days
60 day in hospital mortality
90 day mortality
Cost effectiveness
Inclusion criteria
Suspected or confirmed infection
AND the presence of 2 or more
Core T <36 or >38
HR >90
RR >20
WCC >12 <4
AND
Hypoperfusion – SBP <90mmHg despite 30mL/kg fluid bolus or lactate >4
Hypoperfusion – SBP <90mmHg despite 30mL/kg fluid bolus (later changed to 1L) or lactate >4
Evidence of either refractory hypotension or hypoperfusion
SBP <90 after 1L IVF OR
Lactate >4
First dose of IV Abs commenced prior to randomization
Exclusion criteria
Age <18
Pregnancy
ACS
Acute Cerebrovascular event
APO
Contraindication to CVL
Active GIT haemorrhage
Seizure
Drug overdose
Burn
Trauma
Requirement for surgery
Uncured cancer
Immunosuppression
Limitation therapy order
Contraindication to blood products
Inability to fulfill EGDT
Haemodynamic instability due to active bleeding
Inpatient transfer
Underlying disease with life expectancy <90 days
Limitation of therapy order
Death is deemed imminent
Contraindication to CVC insertion

29. So, why and where are the differences coming from?
So, why and where are then the differences coming from…..?
So, why and where are the differences coming from?

30. Difficulty replicating a study
Statistics can be milked to get desired answers

31. Why rivers worked? Comparing famine with feast
Mean initial ScVo2 49% but measured pre fluid administration in new study measured after fluids
Managing sepsis guidelines 2002

32. Why ProCESS didn’t work
Early recognition of sepsis and antimicrobial agents as specified in the surviving sepsis campaign guidelines was incorporated into all groups
Low tidal volume ventilation
Moderate glycaemic control
Clinical assessment of the adequacy of circulation

33. ProCESS versus rivers - TIME
Advances in care of critically ill
Use of lower Hb levels
Lung protection studies
Use of tighter control of BSL
Publication of managing sepsis guidelines 2002
May have helped lower mortality and reduced the marginal benefit of alternative resuscitation strategies

34. ProCESS versus rivers - ADHERENCE
100% Adherence to protocol in Rivers vs. 88.1% in ProCESS

35. ProCESS versus rivers - POPULATION
Enrolled populations differed
Rivers – slightly older, higher rates of pre-existing liver and heart disease, higher initial serum lactate

36. Patients managed without a protocol had same outcome as those managed with a protocol
Refinement of EGDT approach to fluid administration by defining lower boundaries that are associated with equivalent outcomes and setting limits to avoid too little fluid (renal failure) vs. fluid overload (pulmonary dysfunction)

37. Early recognition of sepsis
Early antibiotics
Adequate volume resuscitation
Clinical assessment of the adequacy of circulation

38. QUESTIONS