Multi-center Clinical Trial of Lactate Clearance Goal-directed Fluid Resuscitation in Patients With Sepsis
Phase: NA
Conditions: Sepsis
Sponsor: Nanfang Hospital, Southern Medical University

The Protocol of
Multi-center Clinical Trial of Lactate Clearance Guided
Fluid Resuscitation in Patients With Sepsis
Sponsor:
Nanfang Hospital of Southern Medical
University
Central Contact Person:
Chen Zhongqing, Ph.D
Telephone:
+86 20 6164 1886
Email:
13503049103@163.com
Date:
2017-08-07

Brief Summary
Serum lactate level is depended on the balance between lactate production and
clearance. It is seen as a sensitive indicator reflecting not only the low systemic
perfusion but microcirculatory dysfunction which cause global or regional tissue
hypoxia (as a result of impaired mitochondrial oxidation). 2016 Surviving Sepsis
Campaign guideline stated “We suggest guiding resuscitation to normalize lactate in
patients with elevated lactate levels as a marker of tissue hypoperfusion”, with weak
recommendation and low quality of evidence. Several trials which evaluated the
resuscitation strategy included lactate clearance as a target while based on 2.0
diagnostic criteria for sepsis, finally showed conflicting results. The aim of this study
is to explore the feasibility of lactate clearance guide resuscitation in sepsis that
defined by The Third International Consensus Definitions for Sepsis and Septic shock
through multi-center, central-randomization clinical trial.
Background
Sepsis is a major public health concern which affects millions of people annually and
has a 28-day mortality rate of 14 to 50% depending on the patient population and the
study selection criteria. The exploration and discussion of sepsis has never stopped,
and it remains a great challenge for clinicians. In The Third International Consensus
Definitions for Sepsis and Septic Shock (Sepsis-3), Sepsis was defined as
life-threatening organ dysfunction caused by a dysregulated host response to infection.
The organ dysfunction was placed in a vital position instead of SIRS, and sepsis
shock was quantified by hypotension, need for vasopressor, and increased serum
lactate. All of these indicators indicate that sepsis-induced hypoperfusion exist. Early
effective fluid resuscitation is of critical importance to improve sepsis-induced tissue
hypoperfusion or septic shock.
Rivers et al proposed an explicit protocol in 2001 which targeted four goals: a central
venous pressure of 8 mm Hg or higher, the mean arterial pressure of 65 mm Hg or
higher, urinary output more than 0.5 ml/kg/h, and the central venous oxygen
saturation(ScvO2) was 70 percent or higher, called early goal-directed therapy
(EGDT). It showed significant benefits with respect to outcome in patients with
severe sepsis and septic shock. After that, EGDT was gradually accepted and used as
a conventional treatment for septic patients. The Surviving Sepsis Campaign (SSC)
has recommended EGDT since 2002 as the key strategy. However, three multicenter,
randomized trials, ProCESS, ARISE, ProMISe, demonstrated that the addition of
continuous ScvO2 monitoring and strict protocolization did not make EGDT better
than usual care. Reassess these four goals in EGDT protocol, we can tell that ScvO2
is the only indicator that reflects tissue oxygen metabolism. However, there are
studies confirmed that ScvO2 oriented EGDT cannot reduce the mortality of sepsis.
So it is important to find out a more effective indicator. Lactate is a product of
anaerobic metabolism of the body, lactate clearance has been found to effectively
predict the prognosis of sepsis. Few studies have shown that lactate clearance oriented
fluid resuscitation can be of benefit in patients with sepsis. Nevertheless, whether
lactate clearance could be combined with sepsis Bundle as a new marker to improve

the prognosis remains a problem. The objective of this study is to discuss the
feasibility of lactate clearance oriented sepsis treatment through multi-center clinical
trial.
Key words
Sepsis, lactate clearance, protocolized resuscitation
Aim
The objective is to compare the prognosis of setting different goals during
resuscitation of patients suffering from
sepsis with hyperlactacidemia (Lac≥
3mmol/L):(1)lactate clearance (Lac%)≥10%;(2) lactate clearance (Lac%)≥20%;(3)
central venous oxygen saturation (ScvO2) ≥70%, the Early goal-directed therapy
(EGDT) came up by Rivers et al in 2001 and recommended in international guidelines
for the resuscitation of patients presenting with sepsis.
Methods/design
This
trial
is
a
prospective,
multicenter,
single-blind,
parallel-group,
central-randomized, controlled trial in patients with sepsis and hyperlactacidemia
Patients will be stratified
by center,
age,
initial level
of lactate,
and
the
presence/absence of neurological diseases. Each participating unit department will go
through an educational program regarding study monitoring methods and study
reporting methods (including goal assessments and treatment attempts).
The recruitment begins after approval from local ethics committees.
Ethics committee approvals submission/approval
Medical Ethics Committee of Nanfang Hospital 5 June 2017
Hypothesis
We hypothesized that targeting the lactate clearance (Lac%) during the resuscitation
of patients suffering from sepsis will result in better prognosis as compared with those
patients who set central venous oxygen saturation (ScvO2)
as goal.
Diagnostic criteria
1.
Confirmed or suspected infection.
2.
QuickSOFA (qSOFA: respiratory rate of 22/min or greater, altered mentation, or
systolic blood pressure of 100 mm Hg or less) ≥2. (Have at least 2 of the
following clinical criteria that together constitute a new bedside clinical score
termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered
mentation, or systolic blood pressure of 100 mm Hg or less.)
3.
The increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA)
score of 2 points or more
4.
Septic shock can be clinically identified by a vasopressor requirement to maintain
a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater

than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia.
Inclusion criteria
1.
Older than 17 years old.
2.
Primary diagnosis is sepsis, means being confirmed or suspected infection while
have at least 2 points of qSOFA.
3.
Be transferred to intensive care unit (ICU) for the first time during this
hospitalization.
4.
Elevated lactate ≥3.0mmol/L.
Exclusion criteria
1.
Acute hemorrhage uncontrolled.
2.
Known to be pregnant.
3.
Known liver disease – Child-Pugh classes C, acute hepatic failure, severe
hepatopathy accompany with prominent portal hypertension.
4.
Known being in an immunosuppressive state:
1) Suffering from any disease that is unrelated with sepsis that severely inhibits
the immune to infection, such as: active hematological or lymphoma
malignancy, or during immunosuppressive therapy, such as chemotherapy or
radiotherapy.
2) Known human immunodeficiency virus (HIV) serology positive.
5.
Known chronic kidney disease.
6.
Suffering from any disease that affects lactate kinetics, such as mitochondrial
encephalopathy, congenital hyperlipidemia, Wernicke encephalopathy, etc. Or
other probable cause of hyperlactatemia.
7.
Took any drugs that affect lactate kinetics within the effective time window, such
as taking metformin or phenylephrine within 1 week.
8.
Suffering from any disease that restricts resuscitation, such as heart failure,
cardiac surgery, severe heart disease etc, or suffered from a cardio-pulmonary
resuscitation.
Participant withdrawal
Patients who meet any of the situation below are withdrawal from the protocol,
meanwhile the clinician should analyze and record expatiation.
1. Fail to obtain informed consent within 2 hours.
2. Surgery or RRT (renal replacement therapy) might be required within 6 hours.
3. Patients or their kin claim to withdraw from the protocol.
4. The investigator or sponsor claim that the patients should withdraw from the
protocol because of a proper therapy should be used or the patients cannot follow
the protocol strictly.
5. Severe adverse reactions (SARs) that need to stop or change the interventions of
protocol.
6. Loss to follow up.

Randomization
Randomization will be done by an independent team of statisticians using a
computer-based algorithm to realize central-randomized. It allow immediate and
concealed allocation to the intervention arm. The patient will be stratified according
to
the
age,
base-line
of
lactate,
place
that
patient
transferred
from,
and
presence/absence of central nervous system disease (with obtainable medical record).
Each patient will be allocated a unique patient ID-number. Randomization should be
performed within 2 hours after fulfillment of the inclusion criteria in the ICU.
Primary outcome measure
All-cause mortality at 28 days.
Secondary outcome measures
All-cause mortality at 90 days.
Length of stay in the intensive care unit (ICU)
Length of stay in hospital.
All-cause mortality at 90 days.
All-cause mortality during hospitalization.
All-cause mortality during ICU stay.
Administered treatments included: crystalloid volume, vasopressor administered,
dobutamine, RBC transfusion, mechanical ventilation, renal-replacement therapy.
Sequential Organ Failure Assessment (SOFA) at 24 hours.
Proportion of patients reporting treatment-emergent adverse events.
Blinding
This study follows the single-blind principle that patients do not know their own
allocation. The clinicians which should be in charge of patient’s administration will
be aware of the allocation during the intervention period. The clinicians should be
only aware of the patients’ base-line of lactate in control group, while patients’
base-line of ScvO2 should be available in lactate groups. After achieve the targets,
patients will be handed over to other clinician who is unaware of the patients’
allocation and continuing subsequent therapy.
Information on the primary outcome and other secondary outcomes will be provided
by the local investigators from patient charts, but the statistician doing the analyses
will be blinded to the allocation of patient.
Trial interventions
Once subjects are enrolled in the ICU, start systematic treatment of sepsis
immediately following Surviving Sepsis Campaign: International Guidelines for
Management International Guidelines for Management of sepsis and septic shock:
2016. The time point of taking blood sample is regarded as the beginning of research
(0h). MAP, CVP, urine output, ScvO2 and blood lactate (Lac) should be assessed
every 1 hour during 0 to 6h. Lactate clearance (Lac%) is defined as the percentage of
lactate reduction within every two hours. So we can get a Lac% per hour starting from

2h to the end of resuscitation.
Within first two hours, fluid should be administered to achieve the same goals from
EGDT in all subjects, which is still widely used in ICU, include MAP≥65mmHg,
CVP 8-12mmHg, Urine output ≥0.5ml/kg/h, ScvO2 ≥10%. Because that the
treatment of sepsis is time-dependent and many patients might be unconscious when
they enrolled in the ICU, the informed consent is allowed to be done within 2 hours.
Central- randomization should be done within 2 hours too, otherwise the subjects
considered to be withdrawn.
Starting from the third hour, all subjects will be treated according to the targets
(Appendix 1) of the allocated arm:
1. Intervention group – targeted lactate clearance (Lac%) care within 2 hours.
2. Control group – targeted central venous oxygen saturation (ScvO2) (EGDT)
standard care.
Appendix 1
The trial targets for the treatment arms.
Intervention group
Control group
– targeted lactate clearance care
– targeted central venous
oxygen saturation care
Lac%≥10% Group
Lac%≥20% Group
ScvO2 Group
①
MAP≥65mmHg
MAP≥65mmHg
MAP≥65mmHg
*②
CVP 8-12mmHg
CVP 8-12mmHg
CVP 8-12mmHg
③
Urine output≥0.5ml/kg/h
Urine output≥0.5ml/kg/h
Urine output≥0.5ml/kg/h
④
Lac%≥10%
Lac%≥20%
**ScvO2≥10%
*Central venous pressure (CVP) 12–15 mmHg in mechanically ventilated patients.
** ScvO2was measured by blood-gas analysis (BGA).
All interventions in each group will be given at the discretion of the clinician
according to the targets. The blood-gas analysis, blood lactate and the administration
will be registered per hour. In the control group lactate levels were not available for
the treatment team and patient during the treatment period. In the Intervention group
ScvO2 were not available for the treatment team and patient during the treatment
period. This endpoint was to be achieved by a resuscitation strategy as outlined in
Figure 1.
Statistical plan and data analysis
The statistical analysis will be done independently by the team of statistical experts.
The statistical analysis method is selected according to the purpose of the study, the
characteristics of the protocol and the nature of the observation data. Using the
chi-square test to study all-cause mortality at 28 days and 90 days, all-cause mortality
during hospitalization and ICU stay. The Kaplan-Meier survival curve was used to
observe the survival status of the three groups, and the log -rank method to compare
the survival of the three groups at 28 days and 90 days whether there is a difference.
The multivariate Cox proportional hazards regression model was used to stratify the
different factors (gender, age, antibiotic sensitivity, underlying disease type), adjust

covariates, and evaluate the confounding factors at the end of the study. In the sepsis
subjects,
set
three
variables
for
further
sub-group
analysis:
sepsis-induced
hyperlipidemia or not, combined adverse reactions，secondary adverse reactions. In
order to observe whether the different target-oriented treatment led to the overall
supportive treatment intensity and duration of the difference, use variance analysis to
analyze the intervention during 0-6h, 0-24h, 0-48h, 0-72h between three groups. If
three groups showed a statistical difference, then further comparison between two
should be done . In this study, the bilateral test used in the statistical test, α take 0.05,
this study using nQuery Adviser 7.0 statistical software.

Figure 1：