Early Goal Directed Therapy Using a Physiological Holistic View. A Multicenter Study in Latin America: The ANDROMEDA-SHOCK Study
Phase: NA
Conditions: Septic Shock, Hyperlactatemia, Peripheral Perfusion
Sponsor: Pontificia Universidad Catolica de Chile

Hernández et al. Ann. Intensive Care  (2018) 8:52 
https://doi.org/10.1186/s13613-018-0398-2
RESEARCH
Early goal-directed therapy  
using a physiological holistic view:  
the ANDROMEDA-SHOCK—a randomized 
controlled trial
Glenn Hernández1*, Alexandre Biasi Cavalcanti2, Gustavo Ospina-Tascón3, Fernando Godinho Zampieri2, 
Arnaldo Dubin4, F. Javier Hurtado5, Gilberto Friedman6, Ricardo Castro1, Leyla Alegría1, Maurizio Cecconi7, 
Jean-Louis Teboul8 and Jan Bakker1,9,10,11The ANDROMEDA-SHOCK Study Investigators
Abstract 
Background: Septic shock is a highly lethal condition. Early recognition of tissue hypoperfusion and its reversion 
are key factors for limiting progression to multiple organ dysfunction and death. Lactate-targeted resuscitation is the 
gold-standard under current guidelines, although it has several pitfalls including that non-hypoxic sources of lactate 
might predominate in an unknown proportion of patients. Peripheral perfusion-targeted resuscitation might provide 
a real-time response to increases in ﬂow that could lead to a more timely decision to stop resuscitation, thus avoiding 
ﬂuid overload and the risks of over-resuscitation. This article reports the rationale, study design and analysis plan of 
the ANDROMEDA-SHOCK Study.
Methods: ANDROMEDA-SHOCK is a randomized controlled trial which aims to determine if a peripheral perfusion-
targeted resuscitation is associated with lower 28-day mortality compared to a lactate-targeted resuscitation in 
patients with septic shock with less than 4 h of diagnosis. Both groups will be treated with the same sequential 
approach during the 8-hour study period pursuing normalization of capillary reﬁll time versus normalization or a 
decrease of more than 20% of lactate every 2 h. The common protocol starts with ﬂuid responsiveness assessment 
and ﬂuid loading in responders, followed by a vasopressor and an inodilator test if necessary. The primary outcome 
is 28-day mortality, and the secondary outcomes are: free days of mechanical ventilation, renal replacement therapy 
and vasopressor support during the ﬁrst 28 days after randomization; multiple organ dysfunction during the ﬁrst 72 h 
after randomization; intensive care unit and hospital lengths of stay; and all-cause mortality at 90-day. A sample size 
of 422 patients was calculated to detect a 15% absolute reduction in mortality in the peripheral perfusion group with 
90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle.
Conclusions: If peripheral perfusion-targeted resuscitation improves 28-day mortality, this could lead to simpliﬁed 
algorithms, assessing almost in real-time the reperfusion process, and pursuing more physiologically sound objec-
tives. At the end, it might prevent the risk of over-resuscitation and lead to a better utilization of intensive care unit 
resources.
Trial registration ClinicalTrials.gov Identiﬁer: NCT03078712 (registered retrospectively March 13th, 2017)
Keywords: Septic shock, Resuscitation, Peripheral perfusion, Lactate, Fluid responsiveness
© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License 
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, 
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, 
and indicate if changes were made.
Open Access
*Correspondence:  glennguru@gmail.com 
1 Departamento de Medicina Intensiva, Facultad de Medicina, Pontiﬁcia 
Universidad Católica de Chile, Diagonal Paraguay 362, Santiago, Chile
Full list of author information is available at the end of the article

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Hernández et al. Ann. Intensive Care  (2018) 8:52 
Background
Septic shock is a potentially lethal condition associated 
with a mortality risk of up to 30–60% [1, 2]. Early recog-
nition of tissue hypoperfusion and its reversion are key 
factors for limiting progression to multiple organ dys-
function and death [1–6].
Hyperlactatemia has been traditionally considered as a 
hallmark of ongoing tissue hypoxia and anaerobic metab-
olism [7, 8]. A recent study targeting a decrease in lac-
tate levels as a resuscitation goal in critically ill patients 
showed a signiﬁcant improvement in organ failure and 
outcomes associated with this endpoint [9]. Therefore, 
normalization of lactate levels has been recommended 
as a resuscitation target by current guidelines [10]. How-
ever, other non-hypoperfusion-related causes of hyper-
lactatemia might predominate in an unknown number 
of patients [11, 12]. In that setting, sustained eﬀorts to 
increase cardiac output (CO) with ﬂuids or vasoactive 
drugs could lead to detrimental eﬀects of over-resusci-
tation [13, 14]. In addition, lactate exhibits a biphasic 
recovery rate even after a successful resuscitation [15], 
introducing an important confounder for practitioners.
Monitoring peripheral perfusion is particularly attrac-
tive because of its easy clinical accessibility and more 
importantly, because it could reﬂect the adequacy of 
intraabdominal visceral organ perfusion [16, 17]. The 
skin territory lacks auto-regulatory ﬂow control, and 
therefore, sympathetic activation impairs skin perfusion 
during circulatory dysfunction [17], a phenomenon that 
could be evaluated by peripheral perfusion assessment. A 
robust body of evidence conﬁrms that abnormal periph-
eral perfusion after initial resuscitation is associated with 
increased morbidity and mortality [18–23], whereby it 
could be used as a potential resuscitation goal [24]. In 
fact, the presence of a cold clammy skin, mottling or pro-
longed capillary reﬁll time (CRT) has been suggested as 
indicators to initiate ﬂuid resuscitation in patients with 
septic shock [17]. Interestingly, CRT was the ﬁrst param-
eter to be normalized in patients surviving from septic 
shock and predicted lactate normalization at 24 h [18]. 
A recent pilot study suggests that targeting peripheral 
perfusion during septic shock resuscitation is safe and 
associated with less ﬂuid administration and organ dys-
functions [25]. Therefore, the excellent prognosis associ-
ated with CRT recovery, its rapid-response time to ﬂuid 
loading, its relative simplicity, its availability in resource-
limited settings and its capacity to change in parallel with 
perfusion of physiologically relevant territories such as 
the hepatosplanchnic region [16] constitute strong rea-
sons to evaluate the usefulness of CRT to guide resuscita-
tion in septic shock patients.
Consequently, we decided to conduct a rand-
omized controlled trial (RCT) comparing peripheral 
perfusion-targeted resuscitation (PPTR) versus lactate-
targeted resuscitation (LTR) in patients with septic shock, 
hypothesizing that resuscitation aimed at peripheral 
perfusion will be associated with lower mortality rates. 
We also hypothesize that patients assigned to PPTR 
will require less volume of ﬂuids with subsequent lower 
positive ﬂuid balances. Accordingly, PPTR should be 
associated with less organ dysfunctions, especially at res-
piratory, renal and gastrointestinal levels.
Methods
Primary objective
To determine if PPTR is associated with lower mortality 
rates at 28 day than a LTR in patients with septic shock.
Secondary objectives
To determine if a PPTR is associated with less severe 
multiple organ dysfunction; more mechanical ventila-
tion (MV) free days; and less vasopressor load and renal 
replacement therapies (RRT) than a LTR strategy in 
patients with septic shock.
Outcomes
Primary outcome will be all-cause mortality at 28-day.
Secondary outcomes:
  •
Free days of MV, RRT and vasopressor support dur-
ing the ﬁrst 28 days after randomization;
  •
Multiple organ dysfunction during the ﬁrst 72 h after 
randomization [26];
  •
Intensive care unit (ICU) and hospital lengths of stay;
  •
All-cause mortality at 90-day.
Tertiary outcomes:
  •
Amount of resuscitation ﬂuids at 8 and 24-hours;
  •
Total ﬂuid balance at 8, 24, 48 and 72-h;
  •
Occurrence of intraabdominal hypertension (IAH) 
during the ﬁrst 72 h after randomization (%);
  •
Use of RRT (%)
  •
In-hospital mortality
Study design
ANDROMEDA-SHOCK is a prospective, multicenter, 
parallel-group, randomized trial aimed to compare an 
8-h protocol of PPTR vs. LTR in patients with septic 
shock [27].
Patients
Consecutive adult patients (≥ 18 years) with septic shock 
will be considered eligible. Septic shock is deﬁned as 
suspected or conﬁrmed infection, plus hyperlactatemia 
(≥ 2.0 mmol per liter) and vasopressor requirements due 

Page 3 of 10
Hernández et al. Ann. Intensive Care  (2018) 8:52 
to refractory hypotension [27]. This latter is character-
ized as a systolic blood pressure (SBP) < 90 mmHg or a 
mean arterial pressure (MAP) < 65 mmHg after an intra-
venous ﬂuid load of at least 20 ml/kg, administered over 
the course of 60 min.
Patients will be excluded in case of:
  •
pregnancy;
  •
anticipated surgery or dialysis procedure during the 
ﬁrst 8 h after septic shock diagnosis;
  •
Do-Not-Attempt-Resuscitation status;
  •
active bleeding;
  •
acute hematological malignancy;
  •
concomitant severe acute respiratory distress syn-
drome (ARDS);
  •
more than 4 h after the onset of septic shock criteria.
An active daily screening for potentially eligible 
patients will be performed at all the participating ICUs.
Randomization
Eligible patients will be randomly allocated to PPTR or 
LTR groups. PPTR will be aimed to normalize CRT, while 
LTR will target lactate normalization or a decreasing 
rate > 20% per 2 h of lactate levels during the 8 h of the 
study period (Fig. 1).
A randomization sequence with an allocation of 1:1 
will be generated by a computer program. Study-group 
assignment will be performed by means of randomized 
permuted blocks of eight. Allocation concealment will 
be maintained by means of central randomization. 
Investigators at the sites will call a representative of the 
Study Coordinating Center (SCC) available 24 h/7 days 
through a dedicated phone number. The group to which 
the patient is allocated will only be disclosed after the 
information is recorded by the SCC. Such a measure 
prevents the investigator and the medical team from 
predicting to which treatment group the patient will be 
allocated.
Interventions
General management protocol
Both study groups will be treated with a common gen-
eral management protocol. Sepsis source identiﬁcation 
and control, and antimicrobial therapy will be given at 
the discretion of the treating physician. A central venous 
catheter (CVC) and an arterial line will be inserted in all 
cases, while the use of CO monitoring (pulmonary artery 
catheter or transpulmonary thermodilution techniques) 
is recommended for patients with a past medical history 
of heart failure or concomitant ARDS but leaving deci-
sion at discretion of the attending physician. Echocardi-
ography will be performed routinely as soon as possible 
after admission to evaluate basal cardiac function, and 
to add in assessing ﬂuid responsiveness (FR) [28]. Other 
dynamic predictors of response to ﬂuids such as pulse 
pressure variation (PPV), stroke volume variation (SVV) 
or end-expiratory occlusion test (EEOT) will be used 
whenever applicable (see below) [28, 29]. MV will be pro-
vided (when needed) under light sedation (midazolam, 
propofol or dexmedetomidine) and analgesia (fenta-
nyl, alfentanil, morphine); tidal volume (Vt) will be lim-
ited to 6–8 mL/kg and positive-end-expiratory-pressure 
(PEEP) will be set according to individual requirements 
[10]. Glycemic control will be adjusted to maintain glu-
cose levels < 150 mg/dL. Norepinephrine (NE) will be the 
vasopressor of choice, and its dose will be adjusted to 
maintain a MAP ≥ 65 mmHg in all patients. Hemoglobin 
concentrations will be maintained at 8 g/dL or higher to 
optimize arterial  O2 content. The use of other therapies 
such as epinephrine, vasopressin analogues, steroids or 
diﬀerent blood puriﬁcation techniques like high-volume 
hemoﬁltration (HVHF) will be provided according to the 
usual practice at the involved centers in patients evolv-
ing with refractory septic shock. Finally, stress ulcer and 
venous thrombosis prophylaxis will be managed accord-
ing to international recommendations [10].
Study protocol
A sequential approach to resuscitation will be followed 
in both groups as shown in Fig. 2. After fulﬁlling inclu-
sion criteria and discarding all exclusion conditions, an 
informed consent will be obtained. Basal measurements 
including hemodynamics and blood sampling will be 
Fig. 1 Pre-randomization phase assessments and interventions. CVC 
central venous catheter

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Hernández et al. Ann. Intensive Care  (2018) 8:52 
performed at Time 0 (T0) representing the starting point 
just after randomization. The intervention period will be 
extended for 8 h. All other treatments, during the inter-
vention period and after, will be at the discretion of the 
treating clinicians according to their local usual clinical 
practices.
Tests and procedures during the study period
Capillary refill time assessment
CRT will be measured by applying ﬁrm pressure to 
the ventral surface of the right index ﬁnger distal pha-
lanx with a glass microscope slide. The pressure will be 
increased until the skin is blank and then maintained for 
10 s. The time for return of the normal skin color will be 
registered with a chronometer. A CRT > 3 s will be con-
sidered as abnormal [30].
Lactate measurements
A lactate value ≥ 2.0  mmol per liter will be considered 
as abnormal. Arterial lactate levels will be measured at 
each center, either at point of care or central laboratories 
(point of care: GEM 4000, Instrumentation Lab, IL, USA; 
central laboratories: Cobas b221, Roche Diagnostics 
International; Basel, CH).
Fluid responsiveness (Fig. 3)
FR will be assessed using a structured approach out-
lined in Fig. 2. Dynamic predictors of FR will be evalu-
ated depending on the individual status, i.e., considering 
if under MV or spontaneous breathing, Vt, respiratory 
rate (RR), respiratory system compliance and the pres-
ence of arrhythmias. The protocol for patients under MV 
is shown in Fig. 3 [28, 29].
Fig. 2 Resuscitation protocol for both groups. The ﬁgure describes the sequential approach to resuscitation. The process starts with ﬂuid loading 
according to the status of ﬂuid responsiveness. If the goal is not obtained, the second step is a vasopressor test, and then an inodilator test. CRT, 
capillary reﬁll time

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Hernández et al. Ann. Intensive Care  (2018) 8:52 
Fluid challenges
In  FR+ patients, the ﬁrst resuscitation step will be to 
administer a ﬂuid bolus (FB) of 500  ml of crystalloids 
every 30 min until normalizing CRT in the PPTR group. 
In the LTR group, FB will be stopped if at 2 h lactate is 
normalized or has decreased > 20%, or previously if after 
any of the ﬂuid boluses, central venous pressure (CVP) 
has increased ≥ 5  mmHg or the patients have become 
ﬂuid unresponsive  (FR−).
Safety measures during fluid challenges
CVP and FR will be reevaluated after any ﬂuid chal-
lenge. If CVP increases < 5  mmHg and FR is still +, 
another FB will be administered and so on while the 
perfusion (CRT or lactate) goal are not attained. If CVP 
increases ≥ 5 mmHg or FR is or become negative, ﬂuids 
will be stopped and the patient will be moved to the next 
step.
Vasopressor test
An open-label vasopressor test will be performed 
increasing MAP up to 80–85 mmHg by using progressive 
incremental doses of NE in patients with previous history 
of chronic hypertension and persistently abnormal CRT 
or unfulﬁlled lactate goals accompanied by a ﬂuid unre-
sponsive state. Parameters will be reassessed 1 h after in 
the PPTR and 2 h after in the LTR. If after the vasopres-
sor test, CRT improves, and lactate goals are achieved in 
PPTR and LTR, respectively, NE will be titrated to main-
tain this new MAP goal throughout the study period. If 
goals are not achieved despite increasing MAP, or NE 
dose surpasses 0.8  mcg/kg/min or adverse eﬀects are 
observed (heart rate (HR) > 140 ppm, arrhythmias or evi-
dent cardiac ischemia), NE dose will be reduced to the 
level before the vasopressor test, and the protocol will 
move to the next step.
Inodilator test
An open-label test of dobutamine at ﬁxed 5  mcg/kg/
min or milrinone at ﬁxed 0.25  mcg/kg/min doses (at 
discretion of the attending physician) will be started in 
patients with persistent abnormal CRT or non-achieved 
lactate goals, and negative FR status. CRT and lactate 
goals will be rechecked such as in the vasopressor test. 
If such resuscitation goals are not reached, drugs will be 
discontinued and no further action will be taken dur-
ing the study period, except for rechecking FR every 
hour and restart ﬂuid challenges if the patient gets again 
FR + . Dobutamine or milrinone doses will be maintained 
throughout the study period in those favorably respond-
ing to the open-label inodilators test. As a safety measure, 
Fig. 3 Assessment of ﬂuid responsiveness during the study period. The ﬁgure describes an algorithm for assessing ﬂuid responsiveness in diﬀerent 
settings depending on the presence or not of mechanical ventilation, arrhythmias or other conditions. Diﬀerent tests are proposed with the respec-
tive cutoﬀ values. ARDS acute respiratory distress syndrome; PLR passive leg rising; CO cardiac output; EEOT end-expiratory occlusion test; CI cardiac 
index; VTI velocity time integral; Vt tidal volume, PBW predicted body weight; PPV pulse pressure variation; SVV stroke volume variation, IVC inferior 
vena cava; SVC superior vena cava

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Hernández et al. Ann. Intensive Care  (2018) 8:52 
inodilators will be stopped if HR increases > 15%, or 
arrhythmias, ischemia or hypotension develop.
Management of peripheral perfusion-targeted 
resuscitation
As a safety measure, if signs of inadequate macrohemo-
dynamics persist such as HR > 120 BPM or unstable MAP 
with increases in vasopressors during the last hour, resus-
citation will be continued even if CRT is normal.
After CRT normalization at any step, it will be reas-
sessed hourly during the study period. If at any point it 
turns abnormal again, the resuscitation sequence will be 
restarted (Fig. 2)
Management of lactate-targeted resuscitation
Lactate will be assessed every 2 h during the 8-h study 
period. If after achieving lactate goals, it becomes again 
abnormal or the decrease rate slow down under 20%/2 
h at any of the following controls, the resuscitation 
sequence will be restarted (Fig. 2).
Safety measures
The protocol can be stopped at any moment for safety 
considerations during the 8-h study period if the attend-
ing intensivist considers that the patient has developed 
unexpected and severe complications or evolves into 
refractory shock, conditions that under his judgment 
require liberalization of management. This action has 
to be reported on the case report form (CRF), and the 
patient will be followed up with major outcomes, and 
included in the intention-to-treat (ITT) analysis. Speciﬁc 
safety measures for ﬂuid administration, vasopressor test 
and inodilator use are speciﬁed above.
Suspected unexpected serious adverse reactions (SUSAR)
Any adverse event that occurs in a clinical trial subject, 
which is assessed by the study investigator as being unex-
pected, serious and as having a reasonable possibility of 
a causal relationship with the study procedure will be 
reported. Reports of these reactions are subject to expe-
dited submission to health authorities. SUSAR’s will be 
analyzed by both the SCC and the data safety monitoring 
committee (DSMC).
Blinding
Since the intervention will be administered to critically ill 
patients (mostly sedated), blinding of these patients is not 
necessary. Because this is a non-pharmacological inter-
vention, blinding of the medical team is not feasible.
Data collection and management
Study follow-up and the variables that will be collected 
are described below.
Baseline
Demographics, comorbidities, acute physiology and 
chronic health evaluation (APACHE) II [31], sepsis 
source and treatment
pre-ICU resuscitation and ﬂuid balance
Sequential Organ Failure Assessment (SOFA) [26] + and 
Acute Kidney Injury Network (AKI) criteria [32]
Hemodynamics: HR, SBP, diastolic blood pressure (DBP), 
MAP, CVP, FR status, intraabdominal pressure (IAP), NE 
levels, diuresis.
Perfusion: lactate, central venous  O2 saturation  (ScvO2), 
central venous arterial  pCO2 gradient (P(cv-a)CO2), Hb, 
central venous and arterial blood gases, CRT, mottling 
score.
Evolution
SOFA and AKI criteria at 8, 24, 48 and 72 h
Hemodynamics hourly up to 8 h
Fluid administration and balance at 8, 24, 48 and 72 h
Complete perfusion assessment when the targeted 
parameter is normalized and then at 8, 24, 48 and 72 h
Register of vasoactive drugs and dobutamine/milrinone 
use
Register of MV and RRT
Source control re-analysis at 4 h
Rescue therapies: HVHF, vasopressin, epinephrine, ster-
oids, others.
Echocardiography at least once during the study period
Follow-up till 28 days for use of MV, RRT and vasopres-
sors
All-cause mortality at hospital discharge, 28 and 90 days
Cause of death.
Quality control
Several procedures will assure data quality, including (1) 
all investigators will attend a training session before the 
start of the study to standardize procedures, including 
data collection (2) the investigators may contact the SCC 
to solve issues or problems that may arise; (3) CRFs pro-
vided by the centers will be subjected to various checks 
by members of the SCC for missing data, plausible, pos-
sible or non-permitted value ranges, and logic checks on 
a weekly basis. (4) centers will be notiﬁed of the incon-
sistencies or missing data as queries and asked to correct 
them; (5) the SCC will review detailed reports on screen-
ing, enrollment, follow-up, inconsistencies and com-
pleteness of data. Immediate actions will follow to solve 
problems that arise; (6) only after the CRFs are cleared by 
the SCC, data will be entered in the ﬁnal electronic data-
base by the data digitizer.

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Hernández et al. Ann. Intensive Care  (2018) 8:52 
Sample size
Mortality in patients with increased lactate levels in cir-
culatory dysfunction has been shown to exceed 40% 
[9]. In addition, several studies have shown that abnor-
mal peripheral perfusion is associated with a mortality 
exceeding 40% as well, whereas a normal CRT in the early 
phase of septic shock has been associated with a less than 
10% mortality [19, 30].
A total sample size of 420 patients (210 per group), 
analyzing the data using the ITT principle, is expected to 
provide approximately 90% power to detect a reduction 
in 28-day mortality from 45 to 30%, considering logistic 
regression, with a two-sided alpha level of 5%. We con-
sider a decrease of 15% in mortality to have direct clini-
cal implementation eﬀect. Similar eﬀects on mortality 
have been shown in early resuscitation studies. In addi-
tion, limiting ﬂuid administration in patients with septic 
shock and normal peripheral perfusion has been shown 
to decrease organ failure, which is the leading cause of 
death in these patients [25].
However, if a smaller decrease in mortality (such as 
10%) is observed at interim analyses, our initial calcu-
lated sample size would have only a 57% power to detect 
beneﬁt. Therefore, we will use an adaptive approach [33] 
that will allow for a sample-size re-estimation at a pre-
planned interim analysis after 75% of the sample has 
been recruited. The sample-size re-estimation will be 
conducted by the DSMC only if the size eﬀect observed 
in the interim analysis is between 10 and 15% absolute 
reduction in mortality [32].
Statistical analysis plan
We will report a detailed statistical analysis plan in a sep-
arate document.
Brieﬂy, all analysis will follow the intention-to-treat 
principle.
Primary outcome
We will assess the eﬀect of PPTR compared to LTR 
on the primary outcome using time-to-event analy-
sis. Results of our main analysis will be calculated with 
Cox proportional hazards models, with adjustment for 
ﬁve pre-speciﬁed baseline covariates. APACHE II score, 
SOFA score, lactate level, CRT and source of infection, 
as ﬁxed (individual-level) eﬀects. Results will be reported 
as hazard ratios with 95% conﬁdence intervals (CI) and p 
values. We will also present Kaplan–Meier curves.
Secondary outcomes
We identiﬁed several secondary outcomes. First, binary 
outcomes will be compared through Chi-squared tests, 
and we will present the results risk ratios (RR), with 95% 
CI and p values.
Continuous outcomes with normal distribution will be 
analyzed with t test and reported as mean diﬀerence 95% 
CI and p value. Continuous outcomes with asymmetri-
cal distribution will be analyzed using bootstrapping 
techniques and reported as absolute diﬀerence between 
medians, 95% CI and p values.
Subgroup analyses
We will analyze the eﬀects of resuscitation strategies on 
the primary outcome in the following subgroups:
(a) Patients with lactate > 4.0 mmol/L as set by SSC [10]
(b) Patients without a conﬁrmed source of infection (as 
this could increase the translation of the study to 
other critically ill).
(c) Patients with low APACHE II/SOFA scores
(d) Patients with a more than 10% diﬀerence in lactate 
levels between the very ﬁrst one measured and the 
baseline when starting the study.
Ethical aspects
Each investigator center will submit the study protocol to 
its Institutional Review Board (IRB). The study will start 
only after being approved by the IRB. Written informed 
consent will be obtained from a legal representative of all 
participants. This study is in compliance with local and 
international declarations.
Trial organization and management
Study Coordinating Center
A team based on the Departmento de Medicina Inten-
siva, Facultad de Medicina of Pontiﬁcia Universidad 
Católica, Chile, will manage the trial on a day-to-day 
basis. The SCC is comprised by the chief and co-chair 
investigators, four project managers, a statistician and a 
data digitizer. The statistician is based on the Research 
Institute HCor, São Paulo, Brazil.
The responsibilities of the SCC include:
1. Planning and conducting the study designing the pro-
tocol; designing the CRF; designing the operation 
guide; managing and controlling data quality; design-
ing, testing and maintaining the electronic database; 
data quality control; assisting the steering committee;
2. Managing the research centers selecting and train-
ing the research centers; helping the centers prepare 
a regulatory report to be submitted to the IRBs and 
assisting the centers with the submission; monitoring 
recruitment rates and the actions to increase recruit-
ment; monitoring follow-up and implementing 
actions to prevent follow-up losses; auditing; sending 
study materials to the research centers; producing 

Page 8 of 10
Hernández et al. Ann. Intensive Care  (2018) 8:52 
a monthly study newsletter; developing supporting 
material for the study;
3. Statistical analysis and research reporting complete 
statistical analysis; helping to write the ﬁnal manu-
script.
Trial Steering Committee
The Trial Steering Committee (TSC) is responsible for 
the overall study supervision, assisting in developing 
the study protocol and preparing the ﬁnal manuscript. 
All other study committees report to the TSC. The TSC 
members are investigators trained in designing and con-
ducting randomized clinical trials in critically ill patients.
Study centers
The study centers for ANDROMEDA-SHOCK were 
selected through a rigorous process. This started with a 
survey of professional and technical resources as well as 
processes of care. Centers were contacted trying to make 
this process representative across public, private and uni-
versity hospitals, diﬀerent countries and cultures, and 
hospital size.
At the end, 34 centers were selected and all applied for 
IRB approval, leaving ﬁnally 26 active centers to start on 
March 1, 2017, in 5 countries. Brazil is still pending
Details of the centers which accepted to participating 
in the trial at the time of this manuscript submission are 
given in the Appendix.
Publication policy
The ANDROMEDA-SHOCK study success depends on 
all its collaborators. Therefore, the primary results of the 
trial will be published under the name of ANDROM-
EDA-SHOCK Investigators. The contributions of all col-
laborators, their names and respective institutions, will 
be acknowledged in the manuscript. To safeguard the 
scientiﬁc integrity of the study, data from this study will 
be submitted to publication only after the ﬁnal approval 
from the TSC.
Data Safety Monitoring Committee
The DSMC is set up with independent epidemiologists 
and intensivists. The DSMC is in charge of providing 
recommendations for the SCC of continuing the study 
as planned or discontinuing the recruitment based on 
evidence that the intervention causes increased mortal-
ity in the experimental group (PPTR) as compared to the 
control group (LTR). Interim analyses will be conducted 
after recruitment of the ﬁrst 100 patients and at 75% of 
the sample.
In addition, the DSMC will discuss and potentially rec-
ommend a re-estimation of the sample size according 
to the interim analysis after recruitment of 75% of the 
patients. A sample-size re-estimation design is a ﬂexible, 
adaptive design with the primary purpose of allowing 
sample size of a study to be reassessed in the mid-course 
of the study to ensure adequate power.
Discussion
ANDROMEDA-SHOCK is a relevant study in septic 
shock for several reasons: (1) it determines the value of 
a simple, bedside, universally available parameter to be 
used as a resuscitation goal in early septic shock; (2) it 
proposes an early goal-directed resuscitation strategy 
based on a holistic physiological view of the reperfusion 
process; (3) it challenges the gold-standard parameter of 
lactate since this latter is not universally available and has 
many interpretation diﬃculties.
If our hypothesis proves to be correct, resuscitation 
algorithms might be simpliﬁed, assessing almost in real-
time the reperfusion process, and in pursuing more 
physiologically sound objectives through a peripheral 
perfusion-based strategy, it could prevent the risk of 
over-resuscitation and lead to a better utilization of ICU 
resources.
Study status
ANDROMEDA-SHOCK study started recruiting on 
March 1 in 26 centers from ﬁve countries. At the submis-
sion of this manuscript, already 388 patients have been 
recruited.
Abbreviations
CO: cardiac output; CRT: capillary reﬁll time; RCT: randomized controlled 
trial; PPTR: peripheral perfusion-targeted resuscitation; LTR: lactate-targeted 
resuscitation; MV: mechanical ventilation; RRT: renal replacement therapy; 
ICU: intensive care unit; IAH: intraabdominal hypertension; SBP: systolic blood 
pressure; MAP: mean arterial pressure; SCC: Study Coordinating Center; CVC: 
central venous catheter; FR: ﬂuid responsiveness; PPV: pulse pressure variation; 
SVV: stroke volume variation; EEOT: end-expiratory occlusion test; Vt: tidal vol-
ume; PEEP: positive-end-expiratory-pressure; NE: norepinephrine; HVHF: high-
volume hemoﬁltration; RR: respiratory rate; VTI: aortic velocity time integral; 
PLR: passive leg raising; HR: heart rate; CRF: case report form; ITT: intention-
to-treat; DSMC: data safety monitoring committee; APACHE: acute physiology 
and chronic health evaluation; AKI: acute kidney injury network; DBP: diastolic 
blood pressure; SUSAR: suspected unexpected serious adverse reactions; IAP: 
intraabdominal pressure; ScvO2: central venous oxygen saturation; P(cv‐a) 
 CO2: central venous‐arterial  PCO2 gradient; IRB: Institutional Review Board; TSC: 
Trial Steering Committee.
Authors’ contributions
JB and GH are guarantors of the entire manuscript; JB, JLT, GH, GOT, AD, GF, 
MC, JH, AC, RC, LA designed the study; All the authors will help in the data 
interpretation and the ﬁnal manuscript draft. All authors read and approved 
this ﬁnal manuscript.
Author details
1 Departamento de Medicina Intensiva, Facultad de Medicina, Pontiﬁcia Uni-
versidad Católica de Chile, Diagonal Paraguay 362, Santiago, Chile. 2 Research 
Institute HCor, Hospital do Coração, R. Des. Eliseu Guilherme, 147 - Paraíso, São 
Paulo, Brazil. 3 Department of Intensive Care Medicine, Fundación Valle del 
Lili, Universidad ICESI, Carrera 98 # 18-49, Cali, Colombia. 4 Servicio de Terapia 
Intensiva, Sanatorio Otamendi y Miroli, Azcuénaga 894, Ciudad Autónoma de 

Page 9 of 10
Hernández et al. Ann. Intensive Care  (2018) 8:52 
Buenos Aires, Argentina. 5 Centro de Tratamiento Intensivo, Hospital Español, 
Escuela de Medicina, Universidad de la República, Avda. Gral. Garibaldi, 1729 
esq. Rocha, Montevideo, Uruguay. 6 Departamento de Medicina Interna, 
Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, R. Ramiro 
Barcelos 2350 – Santa Cecilia, Porto Alegre, Brazil. 7 St George’s University 
Hospitals NHS Foundation Trust, Rd, London SW17 0QT, UK. 8 Service de 
Réanimation médicale, Hôpitaux universitaires Paris-Sud, Assistance Publique-
Hôpitaux de Paris, Paris, France. 9 Division of Pulmonary, Allergy and Critical 
Care Medicine, Columbia University Medical Center, 630 W 168th St, New York, 
USA. 10 Department Intensive Care Adults, Erasmus MC University Medical 
Center, Rotterdam, CA, The Netherlands. 11 Division of Pulmonary, and Critical 
Care Medicine, New York University-Langone, New York, USA. 
Acknowledgements
We acknowledge the support from the Departamento de Medicina Intensiva, 
Facultad de Medicina, Pontiﬁcia Universidad Católica de Chile.
Competing interests
The authors declare that they have no competing interests.
Funding
The study is ﬁnanced in part by an internal grant from the Departamento de 
Medicina Intensiva, Facultad de Medicina, Pontiﬁcia Universidad Católica de 
Chile.
Ethics approval and consent to participate
Each investigator center will submit the study protocol to its Institutional 
Review Board (IRB). The study will start only after being approved by the 
IRB. Written informed consent will be obtained from a legal representative 
of all participants. This study is in compliance with local and international 
declarations.
ANDROMEDA–SHOCK Investigators consists of: Writing and Steering 
Committee
Glenn Hernandez (chair), Gustavo Ospina-Tascón, Alexandre Cavalcanti, 
Arnaldo Dubin, Javier Hurtado, Gilberto Friedman, Ricardo Castro, Leyla 
Alegría, Jean-Louis Teboul, Maurizio Cecconi, Fernando Zampieri, Lucas Petri 
Damiani, Jan Bakker (co-chair). Study Coordinating Center: Glenn Hernan-
dez, Leyla Alegría, Giorgio Ferri, Nicolás Rodriguez, Patricia Holger, Natalia Soto, 
Mario Pozo, Lucas Petri Damiani, Jan Bakker. Data Safety Monitoring Com-
mittee: Deborah Cook, Jean-Louis Vincent, Andrew, Rhodes, Bryan Kavanagh, 
Phil Dellinger, Wim Rietdijk. Study Centers: Chile: Pontiﬁcia Universidad 
Católica de Chile, Santiago: David Carpio, Nicolás Pavéz, Elizabeth Henriquez, 
Sebastian Bravo, Emilio Daniel Valenzuela; Hospital Barros-Luco Trudeau, San-
tiago: Maria Alicia Cid, Ronald Pairumani, Macarena Larroulet, Edward Petruska, 
Claudio Sarabia; Hospital San Juan de Dios, Santiago: David Gallardo, Juan 
Eduardo Sanchez, Hugo González, José Miguel Arancibia, Alex Muñoz, Ger-
mán Ramirez, Florencia Aravena; Hospital Dr. Sótero del Río, Santiago: Andrés 
Aquevedo, Fabián Zambrano; Hospital Del Salvador, Santiago: Milan Bozinovic, 
Felipe Valle, Manuel Ramirez, Victor Rossel, Pilar Muñoz, Carolina Ceballos; 
Hospital Herminda Martinez, Chillán: Christian Esveile, Cristian Carmona, Eva 
Candia, Daniela Mendoza; Hospital San Juan de Dios, Curicó: Aída Sanchez; 
Hospital Guillermo Grant Benavente, Concepción: Paula Fernández, Daniela 
Ponce, Jaime Lastra, Bárbara Nahuelpán, Fabrizio Fasce; Hospital Clínico 
Universidad de Chile, Santiago: Cecilia Luengo, Nicolas Medel, Cesar Cortés. 
Argentina: Clínica La Pequeña Familia, Junín: Luz Campassi; Sanatorio Ota-
mendi y Miroli, Buenos Aires: Arnaldo Dubin, Paolo Rubatto, Brenda Nahime 
Horna, Mariano Furche; Hospital Provincial del Centenario, Rosario: Juan Carlos 
Pendino, Lisandro Bettini; Sanatorio Parque, Rosario: Carlos Lovesio, María 
Cecilia González, Jésica Rodruguez; Hospital Interzonal San Martín, La Plata: 
Elisa Estenssoro, Héctor Canales, Francisco Caminos; Sanatorio Allende Nueva 
Córdoba: Cayetano Galletti, Estefanía Minoldo, María José Aramburu, Daniela 
Olmos; Uruguay: Hospital Español Juan J Crottogini, Montevideo: Javier 
Hurtado, Nicolás Nin, Jordán Tenzi, Carlos Quiroga, Pablo Lacuesta, Agustín 
Gaudín, Richard Pais, Ana Silvestre, Germán Olivera; Hospital de Clínicas, Mon-
tevideo: Gloria Rieppi, Dolores Berrutti. Ecuador: Hospital Universitario del Rio, 
Cuenca: Marcelo Ochoa, Paul Cobos, Fernando Vintimilla; Hospital Eugenio 
Espejo, Quito: Vanessa Ramirez, Milton Tobar, Manuel Jibaja, Fernanda García, 
Fabricio Picoita, Nelson Remache; Hospital San Francisco de Quito, Quito: 
Vladimir Granda, Fernando Paredes, Eduardo Barzallo, Paul Garcés; Hospital 
Carlos Andrade Marín, Quito: Fausto Guerrero, Santiago Salazar, German Torres, 
Cristian Tana, José Calahorrano, Freddy Solis; Hospital IESS Ibarra, Ibarra: Pedro 
Torres, Luís Herrera, Antonio Ornes, Verónica Peréz, Glenda Delgado, Alexei 
Carbonell, Eliana Espinosa, José Moreira; Hospital General Docente Calderón, 
Quito: Diego Barahona, Blanca Salcedo, Ivonne Villacres, Jhonny Suing, Marco 
Lopez, Luis Gomez, Guillermo Toctaquiza, Mario Cadena Zapata, Milton Alonso 
Orazabal, Ruben Pardo Espejo, Jorge Jimenez, Alexander Calderón. Hospital 
Enrique Garcés, Quito: Gustavo Paredes, José Luis Barberán, Tatiana Moya. 
Colombia: Hospital San Vicente de Paul, Medellín: Horacio Atehortua, Rodolfo 
Sabogal; Hospital de Santa Clara, Bogotá: Guillermo Ortiz, Antonio Lara; Hos-
pital Universitario de Ñarino E.S.E, Pasto: Fabio Sanchez, Alvaro Hernán Portilla, 
Humberto Dávila, Jorge Antonio Mora; Fundación Valle del Lili, Cali: Gustavo-
Ospina Tascón, Luis Eduardo Calderón, Ingrid Alvarez, Elena Escobar, Alejandro 
Bejarano, Luis Alfonso Bustamante.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional aﬃliations.
Received: 19 January 2018   Accepted: 12 April 2018
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