4. BACKGROUND
● Intravenous fluids and vasopressor agents are commonly used in
early resuscitation of patients with sepsis.
● Vasopressor therapy also comes with risks that include
vasoconstriction resulting in tissue ischemia, increased cardiac
workload, and arrhythmias.
6. STUDY QUESTION
P: Patients with sepsis-induced hypotension
I: Restrictive fluid strategy with early vasopressor use
C: Liberal fluid strategy
O: Primary outcome: Death from any cause before discharge
home by day 90
=> On patients with sepsis-induced hypotension, does restrictive
fluid strategy with early vasopressor use reduce death from any
cause before discharge home by day 90 when compared to a
liberal fluid strategy?
7. HYPOTHESIS
All-cause mortality before discharge home by day 90 (primary
outcome) would be lower with a restrictive fluid strategy than with
a liberal fluid strategy.
9. STUDY DESIGN
Multicenter Patients were recruited from 60 centers, including EDs, ICUs and
other acute care areas of the PETAL Network Clinical Centers
Prospective Patients were monitored during the first 24-hour intervention
and up to 90 days after hospital discharge.
Phase 3 RCT Interventional trial of fluid treatment strategies in the first
24 hours for patients with sepsis-induced hypotension.
Superiority Whether a restrictive fluid strategy is potentially
superior to a liberal fluid strategy.
Conflict of Interest Funded by National Institutes of Health National
Heart, Lung, and Blood Institute (NHLBI).
11. EXCLUSION CRITERIA
Previous receipt
of fluid
03
Previous receipt of more than
3000 ml of intravenous fluid during
this episode.
Elapse of more than 24
hours
02 Since presentation to the hospital
Elapse of more than 4
hours
01 Since meeting inclusion criteria
despite at least 1000 mL of fluid
Fluid overload
04 Pulmonary edema or clinical signs
of new fluid overload
Severe volume
depletion
05 Severe volume depletion from non-
sepsis causes.
13. INTERVENTION
Randomization
(within 4 hours from
hospitalization)
Restrictive
(vasopressors)
Liberal
(crystalloid fluid)
Additional 500 mL bolus
after each assessment
2000 mL of fluid
Adjust norepinephrine or
add vasopressors after
each assessment
Limit all fluids, give
norepinephrine
SPB < 100 mmHg or MAP < 65 mmHg after 1-3L
crystalloid
RESCUE FLUID RESCUE VASOPRESSOR
14. MEASUREMENTS
• Demographic data
• Blood pressure and antibiotic administration to detect subject meeting
trial criteria
• Clinical and laboratory at the baseline and after randomization
• Ultrasound, chest X-ray and clinical features monitored for volume
overloads
• ABG, creatinin kinase serum, ECG, SOFA score for assessing
secondary outcomes
• Measurement of adverse events: Poisson regression
• Primary outcome: Kaplan Meier, forest plots.
• Study power 90%, CI 95%, two-side alpha level of 0.5 => powered
sample size: 2320.
• Risk difference, mean, percentage difference, relative risk, ARR, NNT.
15. PRIMARY OUTCOMES
The death from any cause before discharge home by day 90:
includes deaths from all causes following randomization in any
heathcare facility prior to discharge home until study day 90.
Study subjects still in a health care facility at study day 91 are
considered alive for this endpoint.
16. SECONDARY OUTCOMES
EFFICACY OUTCOMES SAFETY OUTCOMES
28-day measures of the number of days free
from:
- Organ Support
- Ventilator
- Renal Replacement Therapy
- Vasopressor
- ICU
- Hospital
- Initiation of mechanical ventilation to day
28
- Initiation of renal replacement to day 28
- Change in creatinine-based KDIGO
stage
- Change in SOFA score
- 90-day all-cause mortality at any location
- Development of ARDS within 7 days
- Supraventricular/ventricular tachycardia
(SVT/VT) or new onset atrial
fibrillation/flutter (AF) to day 28
24. SERIOUS ADVERSE EVENTS
Adverse events during hospitalization:
Blood And Lymphatic System Disorders
Cardiac disorders
Gastrointestinal Disorders
General Disorders And Administration Site Conditions
Hepatobiliary Disorders
Infections And Infestations
Metabolism And Nutrition Disorders
Musculoskeletal And Connective Tissue Disorders
Nervous System Disorders
Renal And Urinary Disorders
Respiratory, Thoracic And Mediastinal Disorders
Vascular Disorders
P = 0.75
26. CONCLUSION
Among patients with sepsis-induced hypotension, a restrictive
fluid strategy (with earlier vasopressor use) did not result in
significantly lower (or higher) mortality before discharge home
by day 90 than a liberal fluid strategy.
28. STUDY STRENGTHS
● Randomised
● Multi-centre trial with broad inclusion criteria means
results applicable to ED and early ICU practice where
patients present in undifferentiated manner.
○ The caveat to this is that sepsis is a heterogeneous
process and different causes of sepsis may respond
differently to fluid.
● Excellent design with high internal validity that helps
answer an important and frequently occurring question with
prior limited evidence base.
29. STUDY STRENGTHS
● High level of adherence to protocol:
○ 97% adherence in restrictive group and 96% in liberal
group (within audited sample).
● Achieved separation in fluid administered in first 24 hours.
● Almost identical amounts of fluid administered in both
groups following the intervention to day 7.
● Excellent safety outcome reporting including on peripheral
vasopressor administration.
● Funded by the National Heart, Lung, and Blood Institute and
ClinicalTrials.gov (not by any pharmaceutical companies)
30. STUDY LIMITATIONS
● Unblinded
● Single country may limit external validity.
● Underpowered study (estimated total sample = 2320
patients > enrolled participants = 1563 patients)
● No group in which clinicians received no guidance.
● Early cessation of intervention
● Patients may not have been that unwell at baseline
(median SBP > 90, an ICU admission rate of ~63% and only
~60% patients in restrictive group required vasopressors).
31. STUDY LIMITATIONS
● No dynamic methods used to assess fluid
responsiveness.
● The fluid regimes don’t account for patient weight/size –
2L in a 50 kg patient is likely to have a different physiological
response to that in a 100 kg patient.
● Significant amounts of the study were left to individual
clinician preference, introducing bias.
32. POTENTIAL BIASES
- Selection bias:
+ The subgroups of patients with different diagnosis or
different coexisting conditions who might have responded
differently to either of the strategy.
+ Patients may not have been that unwell at baseline
(median SBP > 90, low lactate levels, an ICU admission rate of
~63% and only ~60% patients in restrictive group required
vasopressors).
33. POTENTIAL BIASES
- Selection bias
The uneven number of patients within the subgroups such as
kidney failure and ICU admission.
34. POTENTIAL BIASES
- Information bias:
+ Unblind => group assignment may have influenced the
ascertainment and reporting of adverse events
+ Measurement: The groups used common clinical
characteristics and routine assessments to trigger protocol-
directed actions for vasopressor and fluid administration.
+ No dynamic methods used to assess fluid responsiveness
+ The fluid regimes do not account for patient weight / size.
35. POTENTIAL BIASES
- Information bias:
+ Specific variations: some patients assigned to the restrictive
fluid group received more fluid with vasopressors given later
than intended. Similarly, some patients assigned to the liberal
fluid group received lower fluid volumes with earlier use of
vasopressors.
+ Misclassification: 1-3 liters of fluid is quite wide range ->
may result in different reactions.
36. CONFOUNDING
The study is well-controlled of controllable confoundings
(regarding the conduct of randomization, stratification,
matching and large sample size).
38. GENERALIZABILITY TO OUR PATIENT POPULATION
- The study was conducted in predominantly White Caucasian
populations.
- The trial was clearly not powered to look at those different
subgroups and they enrolled patients very early when they
presented to emergency department.
39. VALIDITY OF RESULTS & MAGNITUDE OF EFFECTS
- This trial was a very timely trial and very well conducted.
- We do not have any direct answers from this trial because
there was no significant difference in both statistic and clinical
outcomes.
- It might not going to change our practice very much but add
a significant body of evidence to the current literature.
- Allowing the initial administration of vasopressor agents
through peripheral intravenous catheters.
40. PREVIOUS FINDING
The Conservative versus Liberal Approach to Fluid Therapy of
Septic Shock in Intensive Care (CLASSIC) trial compared a
restrictive fluid protocol with a standard fluid approach that
resulted in greater volumes of fluid administration among patients
who had already been admitted to the ICU after initial
resuscitation; this trial showed no difference in 90-day all-cause
mortality.
41. THE INFLUENCE OF RESEARCH RESULTS IN
MANAGEMENT OF THIS PATIENT POPULATION
- 40% of patients are able to avoid taking any vasopressor while
not receiving a much of fluid => some patient might not need
vasopressor at all.
- The duration use of vasopressor should not last longer period
of time to avoid complications.
- The key point: stand at the bedside and see the
responsiveness to amount of fluid that we’re giving to the patient.
- Monitoring devices looking at a trajectory of the patient and
using the multi-modal approach to resuscitation is the best
practice now rather than sticking to one fixed approach.
