Hernández et al. Ann.

Intensive Care (2018) 8:52

https://doi.org/10.1186/s13613-018-0398-2

RESEARCH Open Access

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

*Correspondence: [email protected]
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

© 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.
Hernández et al. Ann. Intensive Care (2018) 8:52 Page 2 of 10

Background perfusion-targeted resuscitation (PPTR) versus lactate-

Septic shock is a potentially lethal condition associated targeted resuscitation (LTR) in patients with septic shock,
with a mortality risk of up to 30–60% [1, 2]. Early recog- hypothesizing that resuscitation aimed at peripheral
nition of tissue hypoperfusion and its reversion are key perfusion will be associated with lower mortality rates.
factors for limiting progression to multiple organ dys- We also hypothesize that patients assigned to PPTR
function and death [1–6]. will require less volume of fluids with subsequent lower
Hyperlactatemia has been traditionally considered as a positive fluid balances. Accordingly, PPTR should be
hallmark of ongoing tissue hypoxia and anaerobic metab- associated with less organ dysfunctions, especially at res-
olism [7, 8]. A recent study targeting a decrease in lac- piratory, renal and gastrointestinal levels.
tate levels as a resuscitation goal in critically ill patients
showed a significant improvement in organ failure and Methods
outcomes associated with this endpoint [9]. Therefore, Primary objective
normalization of lactate levels has been recommended To determine if PPTR is associated with lower mortality
as a resuscitation target by current guidelines [10]. How- rates at 28 day than a LTR in patients with septic shock.
ever, other non-hypoperfusion-related causes of hyper-
lactatemia might predominate in an unknown number Secondary objectives
of patients [11, 12]. In that setting, sustained efforts to To determine if a PPTR is associated with less severe
increase cardiac output (CO) with fluids or vasoactive multiple organ dysfunction; more mechanical ventila-
drugs could lead to detrimental effects of over-resusci- tion (MV) free days; and less vasopressor load and renal
tation [13, 14]. In addition, lactate exhibits a biphasic replacement therapies (RRT) than a LTR strategy in
recovery rate even after a successful resuscitation [15], patients with septic shock.
introducing an important confounder for practitioners.
Monitoring peripheral perfusion is particularly attrac- Outcomes
tive because of its easy clinical accessibility and more Primary outcome will be all-cause mortality at 28-day.
importantly, because it could reflect the adequacy of Secondary outcomes:
intraabdominal visceral organ perfusion [16, 17]. The
skin territory lacks auto-regulatory flow control, and • Free days of MV, RRT and vasopressor support dur-
therefore, sympathetic activation impairs skin perfusion ing the first 28 days after randomization;
during circulatory dysfunction [17], a phenomenon that • Multiple organ dysfunction during the first 72 h after
could be evaluated by peripheral perfusion assessment. A randomization [26];
robust body of evidence confirms that abnormal periph- • Intensive care unit (ICU) and hospital lengths of stay;
eral perfusion after initial resuscitation is associated with • All-cause mortality at 90-day.
increased morbidity and mortality [18–23], whereby it
could be used as a potential resuscitation goal [24]. In Tertiary outcomes:
fact, the presence of a cold clammy skin, mottling or pro-
longed capillary refill time (CRT) has been suggested as • Amount of resuscitation fluids at 8 and 24-hours;
indicators to initiate fluid resuscitation in patients with • Total fluid balance at 8, 24, 48 and 72-h;
septic shock [17]. Interestingly, CRT was the first param- • Occurrence of intraabdominal hypertension (IAH)
eter to be normalized in patients surviving from septic during the first 72 h after randomization (%);
shock and predicted lactate normalization at 24  h [18]. • Use of RRT (%)
A recent pilot study suggests that targeting peripheral • In-hospital mortality
perfusion during septic shock resuscitation is safe and
associated with less fluid administration and organ dys- Study design
functions [25]. Therefore, the excellent prognosis associ- ANDROMEDA-SHOCK is a prospective, multicenter,
ated with CRT recovery, its rapid-response time to fluid parallel-group, randomized trial aimed to compare an
loading, its relative simplicity, its availability in resource- 8-h protocol of PPTR vs. LTR in patients with septic
limited settings and its capacity to change in parallel with shock [27].
perfusion of physiologically relevant territories such as
the hepatosplanchnic region [16] constitute strong rea- Patients
sons to evaluate the usefulness of CRT to guide resuscita- Consecutive adult patients (≥ 18 years) with septic shock
tion in septic shock patients. will be considered eligible. Septic shock is defined as
Consequently, we decided to conduct a rand- suspected or confirmed infection, plus hyperlactatemia
omized controlled trial (RCT) comparing peripheral (≥ 2.0 mmol per liter) and vasopressor requirements due
Hernández et al. Ann. Intensive Care (2018) 8:52 Page 3 of 10

to refractory hypotension [27]. This latter is character- Investigators at the sites will call a representative of the
ized as a systolic blood pressure (SBP) < 90  mmHg or a Study Coordinating Center (SCC) available 24 h/7 days
mean arterial pressure (MAP) < 65 mmHg after an intra- through a dedicated phone number. The group to which
venous fluid load of at least 20 ml/kg, administered over the patient is allocated will only be disclosed after the
the course of 60 min. information is recorded by the SCC. Such a measure
Patients will be excluded in case of: prevents the investigator and the medical team from
predicting to which treatment group the patient will be
• pregnancy; allocated.
• anticipated surgery or dialysis procedure during the
first 8 h after septic shock diagnosis; Interventions
• Do-Not-Attempt-Resuscitation status; General management protocol
• active bleeding; Both study groups will be treated with a common gen-
• acute hematological malignancy; eral management protocol. Sepsis source identification
• concomitant severe acute respiratory distress syn- and control, and antimicrobial therapy will be given at
drome (ARDS); the discretion of the treating physician. A central venous
• more than 4 h after the onset of septic shock criteria. catheter (CVC) and an arterial line will be inserted in all
cases, while the use of CO monitoring (pulmonary artery
An active daily screening for potentially eligible catheter or transpulmonary thermodilution techniques)
patients will be performed at all the participating ICUs. is recommended for patients with a past medical history
of heart failure or concomitant ARDS but leaving deci-
Randomization sion at discretion of the attending physician. Echocardi-
Eligible patients will be randomly allocated to PPTR or ography will be performed routinely as soon as possible
LTR groups. PPTR will be aimed to normalize CRT, while after admission to evaluate basal cardiac function, and
LTR will target lactate normalization or a decreasing to add in assessing fluid responsiveness (FR) [28]. Other
rate > 20% per 2  h of lactate levels during the 8 h of the dynamic predictors of response to fluids such as pulse
study period (Fig. 1). pressure variation (PPV), stroke volume variation (SVV)
A randomization sequence with an allocation of 1:1 or end-expiratory occlusion test (EEOT) will be used
will be generated by a computer program. Study-group whenever applicable (see below) [28, 29]. MV will be pro-
assignment will be performed by means of randomized vided (when needed) under light sedation (midazolam,
permuted blocks of eight. Allocation concealment will propofol or dexmedetomidine) and analgesia (fenta-
be maintained by means of central randomization. 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
Fig. 1 Pre-randomization phase assessments and interventions. CVC informed consent will be obtained. Basal measurements
central venous catheter including hemodynamics and blood sampling will be
Hernández et al. Ann. Intensive Care (2018) 8:52 Page 4 of 10

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

performed at Time 0 (T0) representing the starting point Lactate measurements

just after randomization. The intervention period will be A lactate value ≥ 2.0  mmol per liter will be considered
extended for 8 h. All other treatments, during the inter- as abnormal. Arterial lactate levels will be measured at
vention period and after, will be at the discretion of the each center, either at point of care or central laboratories
treating clinicians according to their local usual clinical (point of care: GEM 4000, Instrumentation Lab, IL, USA;
practices. central laboratories: Cobas b221, Roche Diagnostics
International; Basel, CH).
Tests and procedures during the study period
Capillary refill time assessment Fluid responsiveness (Fig. 3)
CRT will be measured by applying firm pressure to FR will be assessed using a structured approach out-
the ventral surface of the right index finger distal pha- lined in Fig.  2. Dynamic predictors of FR will be evalu-
lanx with a glass microscope slide. The pressure will be ated depending on the individual status, i.e., considering
increased until the skin is blank and then maintained for if under MV or spontaneous breathing, Vt, respiratory
10 s. The time for return of the normal skin color will be rate (RR), respiratory system compliance and the pres-
registered with a chronometer. A CRT > 3  s will be con- ence of arrhythmias. The protocol for patients under MV
sidered as abnormal [30]. is shown in Fig. 3 [28, 29].
Hernández et al. Ann. Intensive Care (2018) 8:52 Page 5 of 10

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

Fluid challenges the PPTR and 2 h after in the LTR. If after the vasopres-
In FR+ patients, the first resuscitation step will be to sor test, CRT improves, and lactate goals are achieved in
administer a fluid bolus (FB) of 500  ml of crystalloids PPTR and LTR, respectively, NE will be titrated to main-
every 30 min until normalizing CRT in the PPTR group. tain this new MAP goal throughout the study period. If
In the LTR group, FB will be stopped if at 2  h lactate is goals are not achieved despite increasing MAP, or NE
normalized or has decreased > 20%, or previously if after dose surpasses 0.8  mcg/kg/min or adverse effects are
any of the fluid boluses, central venous pressure (CVP) observed (heart rate (HR) > 140 ppm, arrhythmias or evi-
has increased ≥ 5  mmHg or the patients have become dent cardiac ischemia), NE dose will be reduced to the
fluid unresponsive (FR−). level before the vasopressor test, and the protocol will
move to the next step.
Safety measures during fluid challenges
CVP and FR will be reevaluated after any fluid chal- Inodilator test
lenge. If CVP increases < 5  mmHg and FR is still +, An open-label test of dobutamine at fixed 5  mcg/kg/
another FB will be administered and so on while the min or milrinone at fixed 0.25  mcg/kg/min doses (at
perfusion (CRT or lactate) goal are not attained. If CVP discretion of the attending physician) will be started in
increases ≥ 5  mmHg or FR is or become negative, fluids patients with persistent abnormal CRT or non-achieved
will be stopped and the patient will be moved to the next lactate goals, and negative FR status. CRT and lactate
step. goals will be rechecked such as in the vasopressor test.
If such resuscitation goals are not reached, drugs will be
Vasopressor test discontinued and no further action will be taken dur-
An open-label vasopressor test will be performed ing the study period, except for rechecking FR every
increasing MAP up to 80–85 mmHg by using progressive hour and restart fluid challenges if the patient gets again
incremental doses of NE in patients with previous history FR + . Dobutamine or milrinone doses will be maintained
of chronic hypertension and persistently abnormal CRT throughout the study period in those favorably respond-
or unfulfilled lactate goals accompanied by a fluid unre- ing to the open-label inodilators test. As a safety measure,
sponsive state. Parameters will be reassessed 1 h after in
Hernández et al. Ann. Intensive Care (2018) 8:52 Page 6 of 10

inodilators will be stopped if HR increases > 15%, or Baseline

arrhythmias, ischemia or hypotension develop. Demographics, comorbidities, acute physiology and
chronic health evaluation (APACHE) II [31], sepsis
Management of peripheral perfusion-targeted source and treatment
resuscitation
pre-ICU resuscitation and fluid balance
As a safety measure, if signs of inadequate macrohemo-
dynamics persist such as HR > 120 BPM or unstable MAP
Sequential Organ Failure Assessment (SOFA) [26] + and
with increases in vasopressors during the last hour, resus-
Acute Kidney Injury Network (AKI) criteria [32]
citation will be continued even if CRT is normal.
After CRT normalization at any step, it will be reas-
Hemodynamics: HR, SBP, diastolic blood pressure (DBP),
sessed hourly during the study period. If at any point it
MAP, CVP, FR status, intraabdominal pressure (IAP), NE
turns abnormal again, the resuscitation sequence will be
levels, diuresis.
restarted (Fig. 2)
Perfusion: lactate, central venous O2 saturation (ScvO2),
Management of lactate-targeted resuscitation central venous arterial pCO2 gradient (P(cv-a)CO2), Hb,
Lactate will be assessed every 2  h during the 8-h study central venous and arterial blood gases, CRT, mottling
period. If after achieving lactate goals, it becomes again score.
abnormal or the decrease rate slow down under 20%/2
h at any of the following controls, the resuscitation Evolution
sequence will be restarted (Fig. 2). SOFA and AKI criteria at 8, 24, 48 and 72 h
Hemodynamics hourly up to 8 h
Safety measures Fluid administration and balance at 8, 24, 48 and 72 h
The protocol can be stopped at any moment for safety Complete perfusion assessment when the targeted
considerations during the 8-h study period if the attend- parameter is normalized and then at 8, 24, 48 and 72 h
ing intensivist considers that the patient has developed Register of vasoactive drugs and dobutamine/milrinone
unexpected and severe complications or evolves into use
refractory shock, conditions that under his judgment Register of MV and RRT
require liberalization of management. This action has Source control re-analysis at 4 h
to be reported on the case report form (CRF), and the Rescue therapies: HVHF, vasopressin, epinephrine, ster-
patient will be followed up with major outcomes, and oids, others.
included in the intention-to-treat (ITT) analysis. Specific Echocardiography at least once during the study period
safety measures for fluid administration, vasopressor test Follow-up till 28 days for use of MV, RRT and vasopres-
and inodilator use are specified above. sors
All-cause mortality at hospital discharge, 28 and 90 days
Suspected unexpected serious adverse reactions (SUSAR) Cause of death.
Any adverse event that occurs in a clinical trial subject,
which is assessed by the study investigator as being unex- Quality control
pected, serious and as having a reasonable possibility of Several procedures will assure data quality, including (1)
a causal relationship with the study procedure will be all investigators will attend a training session before the
reported. Reports of these reactions are subject to expe- start of the study to standardize procedures, including
dited submission to health authorities. SUSAR’s will be data collection (2) the investigators may contact the SCC
analyzed by both the SCC and the data safety monitoring to solve issues or problems that may arise; (3) CRFs pro-
committee (DSMC). vided by the centers will be subjected to various checks
by members of the SCC for missing data, plausible, pos-
Blinding sible or non-permitted value ranges, and logic checks on
Since the intervention will be administered to critically ill a weekly basis. (4) centers will be notified of the incon-
patients (mostly sedated), blinding of these patients is not sistencies or missing data as queries and asked to correct
necessary. Because this is a non-pharmacological inter- them; (5) the SCC will review detailed reports on screen-
vention, blinding of the medical team is not feasible. ing, enrollment, follow-up, inconsistencies and com-
pleteness of data. Immediate actions will follow to solve
Data collection and management problems that arise; (6) only after the CRFs are cleared by
Study follow-up and the variables that will be collected the SCC, data will be entered in the final electronic data-
are described below. base by the data digitizer.
Hernández et al. Ann. Intensive Care (2018) 8:52 Page 7 of 10

Sample size Continuous outcomes with normal distribution will be

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

a monthly study newsletter; developing supporting patients. A sample-size re-estimation design is a flexible,
material for the study; adaptive design with the primary purpose of allowing
3. Statistical analysis and research reporting complete sample size of a study to be reassessed in the mid-course
statistical analysis; helping to write the final manu- of the study to ensure adequate power.
script.
Discussion
Trial Steering Committee ANDROMEDA-SHOCK is a relevant study in septic
The Trial Steering Committee (TSC) is responsible for shock for several reasons: (1) it determines the value of
the overall study supervision, assisting in developing a simple, bedside, universally available parameter to be
the study protocol and preparing the final manuscript. used as a resuscitation goal in early septic shock; (2) it
All other study committees report to the TSC. The TSC proposes an early goal-directed resuscitation strategy
members are investigators trained in designing and con- based on a holistic physiological view of the reperfusion
ducting randomized clinical trials in critically ill patients. process; (3) it challenges the gold-standard parameter of
lactate since this latter is not universally available and has
Study centers many interpretation difficulties.
The study centers for ANDROMEDA-SHOCK were If our hypothesis proves to be correct, resuscitation
selected through a rigorous process. This started with a algorithms might be simplified, assessing almost in real-
survey of professional and technical resources as well as time the reperfusion process, and in pursuing more
processes of care. Centers were contacted trying to make physiologically sound objectives through a peripheral
this process representative across public, private and uni- perfusion-based strategy, it could prevent the risk of
versity hospitals, different countries and cultures, and over-resuscitation and lead to a better utilization of ICU
hospital size. resources.
At the end, 34 centers were selected and all applied for
IRB approval, leaving finally 26 active centers to start on Study status
March 1, 2017, in 5 countries. Brazil is still pending ANDROMEDA-SHOCK study started recruiting on
Details of the centers which accepted to participating March 1 in 26 centers from five countries. At the submis-
in the trial at the time of this manuscript submission are sion of this manuscript, already 388 patients have been
given in the Appendix. recruited.

Publication policy
Abbreviations
The ANDROMEDA-SHOCK study success depends on CO: cardiac output; CRT: capillary refill time; RCT: randomized controlled
all its collaborators. Therefore, the primary results of the trial; PPTR: peripheral perfusion-targeted resuscitation; LTR: lactate-targeted
trial will be published under the name of ANDROM- resuscitation; MV: mechanical ventilation; RRT: renal replacement therapy;
ICU: intensive care unit; IAH: intraabdominal hypertension; SBP: systolic blood
EDA-SHOCK Investigators. The contributions of all col- pressure; MAP: mean arterial pressure; SCC: Study Coordinating Center; CVC:
laborators, their names and respective institutions, will central venous catheter; FR: fluid responsiveness; PPV: pulse pressure variation;
be acknowledged in the manuscript. To safeguard the SVV: stroke volume variation; EEOT: end-expiratory occlusion test; Vt: tidal vol-
ume; PEEP: positive-end-expiratory-pressure; NE: norepinephrine; HVHF: high-
scientific integrity of the study, data from this study will volume hemofiltration; RR: respiratory rate; VTI: aortic velocity time integral;
be submitted to publication only after the final approval PLR: passive leg raising; HR: heart rate; CRF: case report form; ITT: intention-
from the TSC. 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:
Data Safety Monitoring Committee intraabdominal pressure; ScvO2: central venous oxygen saturation; P(cv‐a)
The DSMC is set up with independent epidemiologists CO2: central venous‐arterial PCO2 gradient; IRB: Institutional Review Board; TSC:
Trial Steering Committee.
and intensivists. The DSMC is in charge of providing
recommendations for the SCC of continuing the study Authors’ contributions
as planned or discontinuing the recruitment based on 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
evidence that the intervention causes increased mortal- interpretation and the final manuscript draft. All authors read and approved
ity in the experimental group (PPTR) as compared to the this final manuscript.
control group (LTR). Interim analyses will be conducted
Author details
after recruitment of the first 100 patients and at 75% of 1
Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Uni-
the sample. versidad Católica de Chile, Diagonal Paraguay 362, Santiago, Chile. 2 Research
In addition, the DSMC will discuss and potentially rec- Institute HCor, Hospital do Coração, R. Des. Eliseu Guilherme, 147 - Paraíso, São
Paulo, Brazil. 3 Department of Intensive Care Medicine, Fundación Valle del
ommend a re-estimation of the sample size according Lili, Universidad ICESI, Carrera 98 # 18-49, Cali, Colombia. 4 Servicio de Terapia
to the interim analysis after recruitment of 75% of the Intensiva, Sanatorio Otamendi y Miroli, Azcuénaga 894, Ciudad Autónoma de
Hernández et al. Ann. Intensive Care (2018) 8:52 Page 9 of 10

Buenos Aires, Argentina. 5 Centro de Tratamiento Intensivo, Hospital Español, Cristian Tana, José Calahorrano, Freddy Solis; Hospital IESS Ibarra, Ibarra: Pedro
Escuela de Medicina, Universidad de la República, Avda. Gral. Garibaldi, 1729 Torres, Luís Herrera, Antonio Ornes, Verónica Peréz, Glenda Delgado, Alexei
esq. Rocha, Montevideo, Uruguay. 6 Departamento de Medicina Interna, Carbonell, Eliana Espinosa, José Moreira; Hospital General Docente Calderón,
Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, R. Ramiro Quito: Diego Barahona, Blanca Salcedo, Ivonne Villacres, Jhonny Suing, Marco
Barcelos 2350 – Santa Cecilia, Porto Alegre, Brazil. 7 St George’s University Lopez, Luis Gomez, Guillermo Toctaquiza, Mario Cadena Zapata, Milton Alonso
Hospitals NHS Foundation Trust, Rd, London SW17 0QT, UK. 8 Service de Orazabal, Ruben Pardo Espejo, Jorge Jimenez, Alexander Calderón. Hospital
Réanimation médicale, Hôpitaux universitaires Paris-Sud, Assistance Publique- Enrique Garcés, Quito: Gustavo Paredes, José Luis Barberán, Tatiana Moya.
Hôpitaux de Paris, Paris, France. 9 Division of Pulmonary, Allergy and Critical Colombia: Hospital San Vicente de Paul, Medellín: Horacio Atehortua, Rodolfo
Care Medicine, Columbia University Medical Center, 630 W 168th St, New York, Sabogal; Hospital de Santa Clara, Bogotá: Guillermo Ortiz, Antonio Lara; Hos-
USA. 10 Department Intensive Care Adults, Erasmus MC University Medical pital Universitario de Ñarino E.S.E, Pasto: Fabio Sanchez, Alvaro Hernán Portilla,
Center, Rotterdam, CA, The Netherlands. 11 Division of Pulmonary, and Critical Humberto Dávila, Jorge Antonio Mora; Fundación Valle del Lili, Cali: Gustavo-
Care Medicine, New York University-Langone, New York, USA. Ospina Tascón, Luis Eduardo Calderón, Ingrid Alvarez, Elena Escobar, Alejandro
Bejarano, Luis Alfonso Bustamante.
Acknowledgements
We acknowledge the support from the Departamento de Medicina Intensiva,
Facultad de Medicina, Pontificia Universidad Católica de Chile. Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
Competing interests lished maps and institutional affiliations.
The authors declare that they have no competing interests.
Received: 19 January 2018 Accepted: 12 April 2018
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.
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