The ProCESS trial found no significant difference in mortality between patients receiving protocol-based early goal-directed therapy (EGDT), protocol-based standard therapy, or usual care for early septic shock. While the EGDT group received fluid resuscitation more consistently, there were no differences in outcomes like mortality, organ failure, or length of stay. This prompted review by the Surviving Sepsis Campaign. They concluded that early diagnosis and treatment remain important. ProCESS did not assess patients with severe sepsis without shock. It also showed improved usual care since 2001, with mortality dropping from 46.5% to 18%, so key bundles should still be followed.

1. Critical care 1
Topic : Protocol based care for early septic
shock trial May 2014
Surviving Sepsis Campaign 2012
Response of SSC to ProCESS
Dr. Ankur Gupta
J.L.N.Medical College,Ajmer

3. Why the need ??
ProCESS trial was conducted to determine
whether the findings of EGDT Trial, in which
intravenous fluids, vasopressors, inotropes,
and blood transfusions were adjusted to reach
central hemodynamic targets, were
generalizable and whether all aspects of the
protocol were necessary.

4. METHODS
Study oversight
Multicenter, randomized trial at 31 hospitals in the United
States.
Sites and Patients
Patients in the emergency department in whom-
• sepsis was suspected according to the treating physician,
• ≥ 18 years of age,
• who met ≥2 criteria for SIRS or refractory hypotension,
• serum lactate level of ≥4 mmol/liter .

5. Patients
Study duration - March 2008 through May 2013.
1341 patients for the analysis:
• 439 in the protocol based EGDT group,
• 446 in the protocol-based standard-therapy group
• 456 in the usual care group.

7. Study Interventions
Patients were randomly assigned, as 1:1:1
Protocol based EGDT group: The protocol
prompted placement of a central venous
catheter.
Protocol-based standard group set of 6-hour
resuscitation instructions, but the components
were less aggressive than those used for EGDT
group.
Usual-care group, the bedside providers directed
all care, with the study coordinator collecting
data but not prompting any actions.

8. Outcome Measures
Primary outcome -- Rate of in-hospital death from
any cause at 60 days.
Secondary outcomes -- Rate of death from any
cause at 90 days and cumulative mortality at 90
days and 1 year.
Other outcomes –
• Duration of acute cardiovascular failure ,
• Acute respiratory failure,
• Acute renal failure,
• The duration of the stay in the hospital and ICU,
• Hospital discharge disposition

10. Statistical Analysis
• Analysis done according to the intention to-treat
principle.
• For the primary outcome, design tested
sequentially whether protocol-based
resuscitation was superior to usual care and,
if it was, whether protocol- based EGDT was
superior to protocol-based standard therapy.

11. Resuscitation
• During the first 6 hours, the volume of IV
fluids administered differed significantly
among the groups (2.8 liters in the protocol-based
EGDT group, 3.3 liters in the protocol-based
standard-therapy group, and 2.3 liters
in the usual care group (P<0.001).

12. • Patients in the protocol-based standard-therapy
group received the greatest volume initially and
overall, patients in the usual care group received
the least volume of fluid, and patients in the
protocol-based EGDT group received fluid at the
most consistent rate.
• More patients in the two protocol-based groups
than in the usual-care group received
vasopressors

13. Outcomes
• By day 60, mortality was-
92 patients in the protocol based EGDT group
(21.0%),
81 in the protocol based standard-therapy
group (18.2%),
86 in the usual-care group (18.9%).
• There is no significant difference in 90-day
mortality or in the time to death up to 90 days
and 1 year

15. • The incidence of acute renal failure was
higher in the protocol-based standard therapy
group than in the other two groups (6.0% in the
protocol-based standard-therapy group vs. 3.1% in the protocol-based
EGDT group and 2.8% in the usual-care group, P = 0.04).
• The rate of admission to the intensive care
unit was higher in the protocol-based EGDT
group than in the other two groups.
• There were no significant differences in the
incidence and duration of cardiovascular /
respiratory failure,length of stay / the
discharge disposition.

16. CONCLUSION
• No significant advantage, with respect to
mortality or morbidity, of protocol-based
resuscitation over bedside care that was
provided according to the treating physician’s
judgment.
• No significant benefit of the mandated use of
central venous catheterization and central
hemodynamic monitoring in all patients.

18. International Guidelines for
Management of Severe Sepsis and
Septic Shock 2012

21. Initial Resuscitation and Infection Issues

22. Protocolized, quantitative resuscitation of
patients with sepsis- induced tissue
hypoperfusion (1C)
Goals during the first 6 hrs of resuscitation:
a) Central venous pressure (CVP) 8–12 mm Hg
b) Mean arterial pressure (MAP) ≥ 65 mm Hg
c) Urine output ≥ 0.5 mL/kg/hr
d) Central venous (superior vena cava) or mixed
venous oxygen saturation 70% or 65%,
respectively

23. Diagnosis
Cultures as clinically appropriate before
antimicrobial therapy if no significant delay (> 45
mins ) (1C)
Use of the 1,3 beta-D-glucan assay (2B), mannan
and anti-mannan antibody assays (2C)
Imaging studies performed promptly to confirm a
potential source of infection (UG).

24. Antimicrobial Therapy
Initial empiric anti-infective therapy of one or
more drugs that have activity against all likely
pathogens (bacterial and/or fungal or viral)
and that penetrate in adequate
concentrations into tissues presumed to be
the source of sepsis (1B).
Antimicrobial regimen should be reassessed
daily for potential de-escalation (1B).

25. Source Control
A specific anatomical diagnosis of infection
requiring consideration for emergent source
control be sought and diagnosed or excluded
as rapidly as possible, and intervention be
undertaken for source control within the first
12 hr after the diagnosis is made, if feasible
(1C).

26. Hemodynamic Support and Adjunctive
Therapy

27. Fluid Therapy of Severe Sepsis
Crystalloids as the initial fluid of choice in the
resuscitation of severe sepsis and septic shock
(1B).
Against the use of hydroxyethyl starches for
fluid resuscitation of severe sepsis and septic
shock (1B).

28. Fluid Therapy of Severe Sepsis
Initial fluid challenge in patients with sepsis-induced
tissue hypoperfusion with suspicion
of hypovolemia to achieve a minimum of 30
mL/kg of crystalloids (a portion of this may be
albumin equivalent).
More rapid administration and greater
amounts of fluid may be needed in some
patients (1C).

29. Vasopressors
Vasopressor therapy initially to target a mean
arterial pressure (MAP) of 65 mm Hg (1C).
Norepinephrine as the first choice vasopressor
(1B).
Epinephrine (added to and potentially substituted
for norepinephrine) when an additional agent is
needed to maintain adequate blood pressure
(2B).

30. Mechanical Ventilation of Sepsis-
Induced ARDS
Target a TV of 6 mL/kg predicted body weight in
patients with sepsis-induced ARDS ( 1A vs. 12
mL/kg).
Plateau pressures upper limit goal for plateau
pressures in a passively inflated lung be ≤30 cm
H2O (1B).
PEEP be applied to avoid alveolar collapse at end
expiration (atelectotrauma) (1B).

31. Mechanical Ventilation of Sepsis-
Induced ARDS
Head of the bed elevated to 30-45 degrees to
limit aspiration (1B).
A conservative rather than liberal fluid
strategy for patients with established sepsis-induced
ARDS who do not have evidence of
tissue hypoperfusion (1C).

32. Mechanical Ventilation of Sepsis-
Induced ARDS
weaning protocol be in place when patients satisfy the
following criteria:
a) arousable
b) hemodynamically stable (without vasopressor
agents)
c) no new potentially serious conditions;
d) low ventilatory and end-expiratory pressure
requirements and
e) low Fio2 requirements which can be safely delivered
with a face mask or nasal cannula.
If the spontaneous breathing trial is successful,
consideration should be given for extubation (1A).

33. Sedation, Analgesia, and
Neuromuscular Blockade
Continuous or intermittent sedation be
minimized in ventilated sepsis patients (1B).
Neuromuscular blocking agents (NMBAs) be
avoided if possible in the septic patient
without ARDS. If NMBAs must be maintained,
either intermittent bolus as required or
continuous infusion with train-of-four
monitoring (1C)

34. Glucose Control
Commencing insulin dosing when 2
consecutive blood glucose levels are >180
mg/dL ,targeting an upper blood glucose ≤180
mg/dL (1A).
Blood glucose values be monitored every 1–2
hrs until glucose values and insulin infusion
rates are stable and then every 4 hrs
thereafter (1C).

35. Deep Vein Thrombosis Prophylaxis
Patients with severe sepsis receive daily
pharmaco prophylaxis (1B), with
subcutaneous low-molecular weight heparin
(LMWH) or UFH.
If creatinine clearance is <30 mL/min, use
dalteparin (1A) or another form of LMWH that
has a low degree of renal metabolism (2C) or
UFH (1A).

36. Stress Ulcer Prophylaxis
Stress ulcer prophylaxis using H2 blocker or
proton pump inhibitor be given to patients
with severe sepsis/septic shock who have
bleeding risk factors (1B).

37. Setting Goals of Care
Discuss goals of care and prognosis with
patients and families (1B).
Incorporate goals of care into treatment and
end-of-life care planning, utilizing palliative
care principles where appropriate (1B).

38. SURVIVING SEPSIS CAMPAIGN BUNDLES
TO BE COMPLETED WITHIN 3 HOURS:
1) Measure lactate level
2) Obtain blood cultures prior to administration of antibiotics
3) Administer broad spectrum antibiotics
4) Administer 30 mL/kg crystalloid for hypotension or lactate 4mmol/L
TO BE COMPLETED WITHIN 6 HOURS:
5) Apply vasopressors (for hypotension that does not respond to initial
fluid resuscitation) to maintain a mean arterial pressure (MAP) 65 mm Hg
6) In the event of persistent arterial hypotension despite volume
resuscitation (septic shock) or initial lactate 4 mmol/L (36 mg/dL):
- Measure central venous pressure (CVP)*
- Measure central venous oxygen saturation (ScvO2)*
7) Remeasure lactate if initial lactate was elevated*
*Targets for quantitative resuscitation included in the guidelines are CVP of 8
mm Hg, ScvO2 of 70%, and normalization of lactate.

39. Surviving Sepsis Campaign Responds
to ProCESS Trial
(1) The ProCESS trial reflects the consensus
that early diagnosis of septic shock is
essential. Notably, all groups in the study
received on average more than 2 liters of fluid
prior to randomization and more than 75%
received antibiotics prior to randomization--
both elements of the 3-hour Surviving Sepsis
Campaign bundle.

40. (2) ProCESS does not address the protocolized
management of patients with severe sepsis
without septic shock, a group of patients for
whom early detection and treatment remain
critical.
Further, the ProCESS results have no impact
on the 3-hour bundle

41. (3) The 18% mortality rate in the “usual care”
arm of ProCESS illustrates a dramatic change
in the management and outcomes of patients
with septic shock.
In comparison, septic shock
mortality was 46.5% in the 2001 early goal-directed
therapy trial by Rivers.