Early Goal Directed Therapy Using a Physiological Holistic View. The ANDROMEDA-SHOCK Study
Early Goal Directed Therapy Using a Physiological Holistic View. The ANDROMEDA-SHOCK Study
Septic shock is a highly lethal condition associated with a mortality risk of 30 to 60%.
 Optimizing tissue perfusion and oxygenation is the aim to decrease mortality and morbidity in
 septic shock patients.

 Persistent hyperlactatemia after initial resuscitation is particularly difficult to
 interpret, although optimizing systemic blood flow might reverse ongoing hypoperfusion.
 Nevertheless, if persistent hyperlactatemia is caused by non-hypoperfusion-related
 mechanisms, then sustained efforts aimed at increasing cardiac output (CO) could lead to
 detrimental effects of excessive fluids or inotropes. Another potential alternative
 resuscitation target is peripheral perfusion as assessed by capillary refill time (CRT),
 mottling score or central-to-toe temperature differences. Reversal of abnormal peripheral
 perfusion might represent improvement in tissue hypoperfusion with the advantage of a faster
 recovery than lactate.

 Hypothesis: Peripheral perfusion guided resuscitation in septic shock is associated with
 lower mortality, less organ dysfunctions, less mechanical ventilation (MV), less vasopressor
 load, and less renal replacement therapies than a lactate-targeted resuscitation strategy.

 Main Objective To test if peripheral perfusion targeted resuscitation in septic shock is
 associated with lower 28-day mortality than a lactate targeted resuscitation.

 Design: Multicenter, Parallel Assignment randomized controlled study, conducted under
 supervision of an independent Data Safety Monitoring Board (DSMB).

 Interventions:

 1. Active Comparator- Peripheral Perfusion guided resuscitation

 2. Active Comparator- Lactate guided resuscitation

 Randomization: 1:1 the randomization using a block size of eight will be stratified according
 to participating centers.

 Trial size: 400 randomized patients in 30 ICUs.
Early Goal Directed Therapy using a Physiological Holistic View. A multicenter study in Latin
 America: The ANDROMEDA-SHOCK Study

 Hypothesis Peripheral perfusion guided resuscitation in septic shock is associated with lower
 mortality, less organ dysfunctions, less mechanical ventilation (MV), less vasopressor load,
 and less renal replacement therapies than a lactate-targeted resuscitation strategy.

 Using a holistic view of optimizing tissue perfusion and oxygenation the investigators aim to
 decrease mortality and morbidity in septic shock patients.

 A. Background Septic shock is a highly lethal condition associated with a mortality risk of
 30 to 60%. It is currently the most frequent cause of death in the intensive care unit (ICU)
 as the investigators demonstrated in a recent Chilean prevalence study. Several pathogenic
 factors such as hypovolemia, myocardial depression, vasoplegia, and microcirculatory
 abnormalities can induce progressive tissue hypoperfusion in severe cases. In this context,
 persistent hyperlactatemia has been traditionally considered as the hallmark of ongoing
 tissue hypoxia during septic shock, and therefore lactate normalization is recommended as a
 resuscitation target by the Surviving Sepsis Campaign (SSC).

 Pathophysiologic determinants of persistent hyperlactatemia

 The physiologic basis of lactate generation or clearance during septic shock has been matter
 of active research. Hypovolemia-induced hypoperfusion is probably the predominant pathogenic
 mechanism during the early phase. Some patients resolve acute circulatory dysfunction and
 clear lactate after initial fluid resuscitation, while others evolve into a persistent
 circulatory dysfunction with hyperlactatemia. Several mechanisms have been associated to
 persistent hyperlactatemia besides hypoperfusion, but recent literature has highlighted the
 role of sustained hyperadrenergia with increased muscle aerobic glycolysis, a condition
 denominated stress hyperlactatemia, and also of impaired hepatic lactate clearance.

 The investigators have explored the significance and potential determinants of
 hyperlactatemia in a series of clinical physiological studies performed over the last 15
 years. These studies have addressed the three most relevant pathogenic factors involved in
 persistent hyperlactatemia: overt or occult hypoperfusion, hyperadrenergic state and impaired
 hepatic clearance. The complexity of this subject is also highlighted by a more recent study
 where the investigators demonstrated that lactate decrease during successful septic shock
 resuscitation exhibits a biphasic pattern, an early rapid decrease in parallel to
 normalization of more flow-sensitive variables (see below), followed by a slower recovery
 thereafter. The latter eventually related to non-flow dependent mechanisms such as
 hyperadrenergic state and/or delayed hepatic clearance.

 Persistent hyperlactatemia after initial resuscitation is particularly difficult to interpret
 as suggested by the extensive research summarized above. Optimizing systemic blood flow might
 reverse ongoing hypoperfusion, a potential source of anaerobic lactate generation. Under this
 perspective, some of the pathogenic factors involved in hyperlactatemia are potentially
 flow-sensitive, and others are not. Distinction between the two scenarios could strongly
 impact further resuscitation. If persistent hyperlactatemia is caused by
 non-hypoperfusion-related mechanisms, then sustained efforts aimed at increasing CO could
 lead to detrimental effects of excessive fluids or inotropes, a fact now well demonstrated in
 the literature. The decision of when to consider that a patient has been fully resuscitated
 and as a consequence stop further interventions is a milestone, and appears as highly
 relevant since the results of a number of recent studies have increased awareness about the
 risk of fluid overload and/or of vasopressors and inodilators such as pulmonary edema,
 increased intraabdominal hypertension, acute kidney injury, delayed weaning, arrhythmias,
 hepatosplanchnic or myocardial ischemia, among other problems. By these means,
 over-resuscitation could eventually increase morbidity and/or mortality.

 Is hyperlactatemia a valid resuscitation target in septic shock?

 Not surprisingly, lactate clearance or normalization is used worldwide as resuscitation
 targets. Indeed, SSC the most ambitious and global collaboration in critical care has
 proposed to focus septic shock resuscitation on normalizing macrohemodynamic parameters and
 lactate. SSC guidelines are followed in many countries and adherence to recommended
 management bundles have been reported to be associated to improved survival, although the
 role of each individual component is not clear. Lactate clearance, defined by a change of
 lactate levels between two time-points, and expressed as a 10-20% hourly lactate reduction,
 or a decrease of at least 10% in 6h during early resuscitation has been related to survival,
 and tested as a goal in two important studies with conflicting results.

 However, there are several unresolved aspects and concerns about the role of lactate as an
 appropriate resuscitation target. First, it is not clear if selecting lactate clearance
 versus lactate normalization as resuscitation goals is equivalent, but more importantly, if
 this decision leads to similar timely resolution of tissue hypoperfusion or hypoxia. Second,
 since non-hypoperfusion related causes of hyperlactatemia might predominate in an unknown
 number of patients, this could lead to over-resuscitation in at least some of them as stated
 above. Third, the dynamics of recovery of lactate might exhibit a biphasic pattern and
 therefore, the real-time response of lactate to fluid challenges could be not straightforward
 depending on the hypoperfusion context. Some survivors might even normalize lactate only
 after 24h of evolution. Therefore, to explore other potential resuscitation targets appears
 as mandatory.

 Potential alternative resuscitation targets in septic shock

 A foremost priority is to rule out ongoing hypoperfusion in septic septic shock patients
 under active resuscitation. The investigators recently proposed that a simultaneous analysis
 of central venous O2 saturation (ScvO2), central venous-arterial pCO2 gradient (P(cv-a)CO2),
 and peripheral perfusion as assessed by capillary refill time (CRT), mottling score or
 central-to-toe temperature differences, might be helpful in suggesting a hypoperfusion
 context for patients with or without hyperlactatemia. From a theoretical point of view, these
 three easily assessable perfusion-related variables offer an important advantage over lactate
 as potential resuscitation targets in septic shock patients: they are clearly flow-sensitive
 and exhibit a much faster dynamics of recovery after systemic blood flow optimization. In
 other words, these parameters might clear in minutes in fluid-responsive patients as compared
 to lactate, which sometimes takes hours to recover. The investigators demonstrated this by
 analyzing the dynamics of recovery of these parameters in a cohort of ultimately surviving
 septic shock patients. ScvO2, P(cv-a)CO2 and CRT where already normal in almost 70% of the
 patients after 2h of fluid resuscitation, as compared with only 15% in the case of lactate.

 However, there are also a couple of drawbacks for some of these perfusion-related
 flow-sensitive parameters. ScvO2 is a complex physiological variable. It was widely used
 until recently as the resuscitation goal in critically ill patients, although several
 limitations may preclude a straightforward interpretation of its changes. For instance,
 normal or even supranormal ScvO2 values do not rule-out global or regional tissue hypoxia for
 several reasons that have been highlighted elsewhere, but that include severe
 microcirculatory derangements impairing tissue O2 extraction capabilities. Vallee et al found
 persistent abnormal P(cv-a)CO2 values in 50% of septic shock patients who had already
 achieved normal ScvO2 values after initial resuscitation. Nevertheless, in some hyperdynamic
 states a high efferent venous blood flow could be sufficient to wash out the global carbon
 dioxide (CO2) generation from hypoperfused tissues and thus, P(cv-a)CO2 could be normal
 despite the presence of tissue hypoxia. Another problem for these two variables is that they
 necessarily require a central venous catheterization to be assessed, a task that might be
 complex to perform in limited-resource settings or emergency departments (ED). Therefore,
 peripheral perfusion appears as the most promising alternative resuscitation target in septic
 shock patients.

 Peripheral perfusion as a potential resuscitation target in septic shock patients

 The skin territory lacks auto-regulatory flow control, and therefore sympathetic activation
 impairs skin perfusion during circulatory dysfunction, a process that could be evaluated by
 peripheral perfusion assessment. Indeed, peripheral perfusion can be easily evaluated in many
 ways at bedside, and therefore, it could be a valuable monitoring tool in any setting. The
 presence of a cold clammy skin, mottling or CRT are frequently described as indications to
 initiate fluid resuscitation in patients with sepsis-related acute circulatory dysfunction.

 The concept of CRT, the most relevant parameter, is based on this assumption. It was proposed
 initially in trauma patients but some negative studies that found no correlation with
 systemic hemodynamics precluded further research on this variable. More recently however,
 Lima et al found that abnormal peripheral perfusion is associated with hyperlactatemia and
 organ dysfunctions in critically ill patients. Other authors confirmed this finding and built
 up a robust body of evidence supporting the strong prognostic value of abnormal peripheral
 perfusion in the intensive care unit (ICU) context.

 The investigators observed that CRT was the first parameter to be normalized in a cohort of
 septic shock patients and this predicted lactate normalization at 24h and survival. Moreover,
 some recent clinical data suggest that targeting peripheral perfusion during septic shock
 resuscitation might improve outcome. van Genderen et al performed a randomized controlled
 trial comparing two resuscitation protocols; one targeted at normal peripheral perfusion and
 the other to standard management in 30 ICU patients. The study demonstrated that targeting
 peripheral perfusion is safe, and associated with less fluid administration and organ
 dysfunctions. Therefore, a parameter like CRT with a rapid-response time could be very useful
 to test the response to treatments with strong physiologic impact such as fluid loading,
 especially at the ED or in limited-resource settings. In a prospective non published study
 performed in a cohort of 100 patients just admitted to the ED, the investigators found that
 patients exhibiting a normal CRT after initial fluid loading had a hospital mortality of less
 than 10% as compared to 55% in patients with abnormal values.

 How can fluid loading and resuscitation improve peripheral perfusion? There is an intricate
 relationship between macrohemodynamics and peripheral perfusion. Both are affected by
 hypovolemia and tend to improve in parallel in fluid-responsive patients. Their relative
 changes, though, are not well correlated. The beneficial effects of fluids and vasoactive
 drugs may be explained by an increase in CO or perfusion pressure, a decrease in the
 neurohumoral response to hypovolemia, and eventually by direct effects at the
 microcirculatory level. Whatever the mechanism, normalization of peripheral perfusion
 parameters appears to indicate a successful reversal of initial circulatory dysfunction.

 There are some data that suggest that vasopressor adjustment and/or inodilators could induce
 favorable effects on peripheral perfusion or microcirculation under certain circumstances.
 Jhanji et al demonstrated that increasing mean arterial pressure (MAP) to 90 mmHg with
 norepinephrine (NE) doses up to 0.41 mcg/kg/min improved cutaneous tissue oxygen pressure
 (PtO2) and cutaneous microvascular red blood cell flux in a cohort of septic shock patients.
 The same group obtained similar results in another cohort of postoperative patients after
 major abdominal surgery but with an intervention consisting in stroke volume optimization
 with fluid challenges and an inodilator (dopexamine) in fixed dose. Dubin et al demonstrated
 that rising MAP to 85 mmHg with incremental doses of norepinephrine (NE) up to 0.74
 mcg/kg/min improved sublingual microcirculatory flow in septic shock patients with the worst
 microcirculation at baseline. Dobutamine in fixed doses of 5 mcg/kg/min improved sublingual
 microcirculatory flow in another cohort of septic shock patients. On the other hand active
 vasodilation with nitroglycerine induced a clear improvement of peripheral perfusion
 parameters in a group of shock patients, despite a mean fall in MAP of 14 mmHg. Based on
 these findings and other data, it was proposed that permisive hypotension could eventually
 improve microcirculatory driving-pressure in patients with acute circulatory failure. In
 summary, it appears that pharmacological therapies aimed at improving peripheral perfusion
 might be individually tailored but could imply increasing or lowering vasopressors and MAP,
 inodilators or pure vasodilators according to the clinical context.

 More recently Bakker et al, added another important piece of information after performing a
 pilot study in 30 septic shock patients subjected to early resuscitation. In this study, CRT
 and skin mottling were correlated with the pulsatility index, a sonographic surrogate of
 vascular tone, of visceral organs. This means that improvement in peripheral perfusion might
 move in parallel with improvement in hepatosplanchnic perfusion, eventually explaining the
 good prognosis associated with recovery of CRT and other related parameters.

 Using peripheral perfusion to target resuscitation in septic shock has also several potential
 drawbacks. First, there is some degree of subjectivity and inter-observer variability in some
 of the parameters used to assess it such as CRT and mottling. Second, it cannot be evaluated
 in some settings such as dark skin patients. Third, and more importantly, the corpus of
 evidence that supports that improvement of peripheral perfusion is associated with resolution
 of profound tissue or microcirculatory hypoperfusion, or hypoxia is still scanty.

 However, the excellent prognosis associated with CRT recovery, the rapid-response time to
 fluid loading, the simplicity of its assessment, its availability in limited resource
 settings, and recent data suggesting that it might change in parallel to perfusion of
 physiologically more relevant territories such as the hepatosplanchnic region, constitute a
 strong background to promote studies evaluating its usefulness to guide resuscitation in
 septic shock patients.

 Why to compare peripheral perfusion with lactate as targets for septic shock resuscitation?

 Summarizing the theoretical background stated above, it is plausible that normalization of
 peripheral perfusion as compared to normalization or a rapid decrease (>20%/2h) of lactate
 might be associated with less fluid resuscitation and secondarily less positive 24h fluid
 balances. Eventually, less positive fluid balances might be associated with less organ
 dysfunctions, especially respiratory (oxygenation, mechanical ventilation days), renal (less
 increase in creatinine and renal replacement therapy), and gastrointestinal (less increase in
 intra-abdominal pressure). In addition, peripheral perfusion targeted-resuscitation might be
 also associated with less vasopressor load and inodilator use thus preventing other set of
 potential complications such as hepatosplanchnic hypoperfusion, arrhythmias or myocardial
 ischemia. At the end, this could result in less mortality for a combination of the previous
 reasons.

 Hypothesis Peripheral perfusion guided resuscitation in septic shock is associated with lower
 mortality, less organ dysfunctions, less mechanical ventilation (MV), less vasopressor load,
 and less renal replacement therapies than a lactate-targeted resuscitation strategy.

 Design Multicenter, open-label randomized controlled study, conducted under supervision of an
 independent Data Safety Monitoring Board (DSMB).

 Main Objective To test if peripheral perfusion targeted resuscitation in septic shock is
 associated with lower 28-day mortality than a lactate targeted resuscitation.

 Primary Outcome All-cause 28-day mortality

 Secondary outcomes Need of mechanical ventilation Need of renal replacement therapies (RRT)
 Days free of MV, vasopressors and RRT in 28-days Sequential Organ failure Assessment (SOFA)
 at 8, 24, 48 and 72h Acute kidney injury (AKI) Intra-abdominal hypertension Fluid balances at
 8, 24, 48 and 72h All-cause hospital and 90-day mortality Intensive care unit (ICU) and
 hospital length of stay

 I. Patients Inclusion Criteria

 Adult patients (≥18 years) will be screened for the following inclusion criteria:

 Septic shock diagnosed at ICU admission according to the Sepsis-3 Consensus Conference,
 (basically septic patients with hypotension requiring norepinephrine (NE) to maintain a mean
 arterial pressure (MAP) of ≥ 65 mmHg, and serum lactate levels > 2 mmol/l after initial fluid
 resuscitation with at least 20/ml kg in one hour.

 Exclusion Criteria

 1. Pregnancy

 2. Anticipated surgery or dialysis procedure during the first 8h after septic shock
 diagnosis

 3. Do-not-resuscitate status

 4. Child B or C liver cirrhosis

 5. Active bleeding

 6. Acute hematological malignancy

 7. Severe concomitant acute respiratory distress syndrome (ARDS)

 8. More than 4h after officially meeting septic shock criteria

 II. Randomization Recruited patients will be randomized to a peripheral perfusion-targeted
 resuscitation (group A) with a goal of normalizing capillary refill time (CRT), or a
 lactate-targeted resuscitation (group B) with a goal of either normalizing lactate or
 achieving a >20% decrease per hour during the 8h study period.

 The randomization sequence will be generated by an external statistician of the DSMB with the
 use of a computer program and an allocation of 1:1. The randomization using a block size of
 eight will be stratified according to participating centers.

 Allocation concealment will be maintained by means of a web-based central, automated
 randomization system, available 24 hours a day (RedCap Cloud). The group to which the patient
 is allocated will only be disclosed after the information is recorded in the electronic
 system. Such measure prevents the investigator and the medical team from predicting to which
 treatment group the patient will be allocated. To include a patient in the study,
 investigators must simply access the study website and fill in a short medical record form.

 Statisticians and the researcher responsible for event assignment will be blinded to the
 group allocation.

 Treatment assignment will not be recorded in the medical chart or electronic patient data
 monitoring system and clinicians on general wards, who care for the patients after ICU
 discharge, will not be aware of the treatment assignment.

 III. Assessments Baseline Demographics, comorbidities, acute physiology and chronic health
 evaluation (APACHE) II, sepsis source and treatment

 pre-ICU resuscitation and fluid balance

 Biomarkers: procalcitonin (PCT) or c-reactive protein (CRP), and adrenomedullin (MR-ProADM)
 sampling

 SOFA + AKI criteria

 Hemodynamics: heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP),
 MAP, central venous pressure (CVP), dynamic predictors (DP) of fluid responsiveness (FR),
 intraabdominal pressure (IAP), NE levels, diuresis

 Perfusion: lactate, ScvO2, P(cv-a)CO2, hemoglobin (Hb), central venous and arterial blood
 gases, CRT, mottling score, perfusion index (where available)

 Evolution SOFA and AKI criteria at 8, 24, 48 and 72h Hemodynamics hourly up to 8h Fluid
 administration and balance at 8, 24, 48 y 72h Complete perfusion assessment when the targeted
 parameter is normalized and then at 8, 24, 48 and 72h Register of vasoactive drugs and
 dobutamine/milrinone use Register of MV and RRT Source control re-analysis at 4h Rescue
 therapies: high-volume hemofiltration (HVHF), vasopressin, epinephrine, steroids, others
 Echocardiography at least once during the study period Follow-up till 28 days for use of MV,
 RRT and vasopressors All cause mortality at hospital discharge, 28 and 90 days Cause of death

 IV. Principles of general management Sepsis source identification and treatment should be
 pursued as a priority of first line treatment. A central venous catheter and an arterial line
 are inserted in all, and the use of a pulmonary artery catheter or a PiCCO device is
 recommended for patients with a past medical history of heart failure or with concomitant
 ARDS.

 Echocardiography will be performed routinely as soon as possible after admission to evaluate
 basal cardiac function, and repeated as necessary to aid in assessing preload status through
 inferior vena cava distensibility when necessary.

 NE will be the vasopressor of choice and adjusted to a MAP ≥ 65 mmHg in all patients.

 Hemoglobin concentrations will be maintained at 8 g/dl or higher to optimize arterial O2
 content. Mechanical ventilation settings are adjusted according to current recommendation.
 Rescue therapies such as epinephrine, vasopressin analogues, steroids or different blood
 purification techniques like high-volume hemofiltration will be decided following usual
 practice of the involved centers in patients evolving with refractory septic shock.

 C. Study protocol

 A sequential approach to resuscitation will be followed in both groups. Time 0 is the
 starting point when after randomization, a central venous catheter (CVC) and an arterial line
 are in place, and the basal measurements are performed including hemodynamics and blood
 sampling.

 The study period will be of 8 hours and after this, attending intensivists can continue
 treatment according to their usual practice or department protocol.

 I. 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
 phalanx with a glass microscope slide. The pressure will be increased until the skin is blank
 and then maintained for 10 seconds. The time for return of the normal skin color will be
 registered with a chronometer, and > 3 seconds is defined as abnormal.

 Lactate measurements A normal lactate value is defined as less then 2 mmol/l. Lactate will be
 assessed with the technique more easily available for each center, including arterial serum
 levels (with common gas analyzers at the central lab), or capillary levels with lactate scout
 strips.

 Fluid responsiveness (FR) This is the first step. FR will be assessed with a structured
 approach. Basically, dynamic predictors (DP) will be evaluated depending on the patient
 background status.

 In sedated adapted mechanically ventilated patients without arrhythmias, pulse pressure
 variation (PPV) or stroke volume variation (SVV) will be used as first choice. A FR+ status
 is established with values ≥ 13% and 10%, respectively. If negative, PPV and SVV will be
 reassessed after transiently increasing tidal volume (VT) to 8 ml/kg (one minute). An
 increase >3.5% and 2.5% in PPV or SVV, respectively will be considered as FR+.

 In patients with arrhythmia, the preferred tests will be the end expiratory occlusion test
 with a 15 sec pause (> pulse pressure >5% considered as positive), or echocardiography
 assessing inferior vena cava (IVC) distensibility index (>15% considered as +).

 In spontaneous breathing patients or non-sedated patients under MV, a passive leg rising
 (PLR) maneuver will performed with an early (<1min) increase in pulse pressure > 10%
 considered as FR+. If this is not obtained and to rule out a false negative response, the
 maneuver will be repeated assessing aortic velocity time integral (VTI) with echocardiography
 before and after PLR with a >15% increase in VTI accepted as FR+.

 Fluid Challenge In FR+ patients, the first resuscitation step is to administer a fluid bolus
 (FB) of 500 ml of crystalloids every 30 min until CRT is normalized in group A, or DP becomes
 negative in group B. DP and CVP will be measured before and after each bolus in both groups.

 Safety measures during fluid challenges Central venous pressure (CVP) and FR will be
 reevaluated after any fluid challenge. If CVP increases <5 mmHg and FR is still +, another FB
 is administered and so on while the goal is not reached.

 If CVP increases ≥ 5 mmHg or FR is -, fluids will be stopped and the patient will be moved to
 the next step.

 Vasopressor test In FR- patients with persistent abnormal CRT or with a still abnormal
 lactate that decreased <20%/2h, a vasopressor test will be performed.

 In previously hypertensive patients, MAP will be increased to the range of 80-85 mmHg by
 transiently rising NE doses. CRT and lactate rechecked (CRT at one h and lactate at 2h). If
 CRT is normal in the group A, or lactate normalizes or decreases >20% in group B,
 resuscitation will be stopped and NE dose maintained. If not, NE will be reduced to the
 pre-test doses, and the protocol moves to the next step.

 In all the other patients, MAP will be reduced to the range of 60-65 mmHg by transient
 decreases in NE doses, with the same objectives and principles as stated above.

 Use of inodilators Dobutamine 5 mcg/kg/min or Milrinone 0.25 mcg/kg/min in fixed doses will
 be started, and CRT or lactate rechecked (CRT at one h and lactate at 2h). If, the goals are
 not reached, drugs will be discontinued and no further action will be taken during the study
 period, except recheck FR every hour and restart fluid challenges if patients get FR+ again.

 In responders (same criteria as with vasopressor test), the inodilator will be continued
 along the study period.

 As a safety measure, inodilators will be stopped if HR increases >15%, or arrhythmias,
 ischemia or hypotension develop.

 Group A. Management of peripheral perfusion-targeted resuscitation.

 In this group, the goal is to normalize CRT by following the next steps in the given order:

 1. Assessment of FR

 2. Fluid challenges until CRT is normal, the patient is fluid unresponsive or a safety
 measure is met

 3. Vasopressor test

 4. Inodilator test

 As a safety measure, resuscitation will be stopped even with normal CRT only in the presence
 of a stable macrohemodynamics as demonstrated by heart rate (HR) <120 beats per minute, and
 stable MAP with no increase in vasopressors during the last hour.

 After CRT normalization at any step, CRT will be reassessed hourly during the study period.
 If at any point, it turns abnormal again the resuscitation sequence will be restarted.

 Group B. Management of lactate-targeted resuscitation.

 In this group the goal is to normalize lactate levels or get a decrease rate of at least
 20%/2h, by following the next steps in the given order, always reevaluating lactate at 2h
 intervals.

 1. Assessment of FR

 2. Fluid challenges until FR- or safety CVP limit is reached during the bi-hourly intervals
 between lactate assessments

 3. Vasopressor test

 4. Inodilators

 Lactate will be assessed every two hours during the 8h study period. If after obtaining the
 lactate goal, lactate gets abnormal again or the decrease rate turns <20%/2h at any of the
 following bi-hourly controls during the study period, the resuscitation sequence will be
 restarted.

 D. Sample size Mortality in patients with increased lactate levels in circulatory dysfunction
 has been shown to exceed 40%. In addition, several studies have shown that abnormal
 peripheral perfusion is associated with a mortality exceeding 40%.

 The investigators should enroll 420 patients. With these sample size the study will have 90%
 power to detect a reduction in 28-day mortality from 45% to 30%, at a significance level of
 5%, considering time-to-event analysis. The investigators consider a decrease of 15% in
 mortality to have direct clinical implementation effect. Similar effects on mortality have
 been shown in early resuscitation studies. In addition 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.

 When aiming for a smaller decrease in mortality (like 10%), this sample size would only have
 57% power to detect benefit. Therefore the investigators will use an adaptive approach that
 will allow for a sample-size re-estimation at the interim analysis when 75% of the sample has
 been recruited. The sample-size re-estimation will be conducted by the DSMB if the effect
 size observed in the interim analysis is between 10% and <15% absolute reduction in
 mortality. A smaller effect size would turn achieving adequate sample size unfeasible,
 whereas a larger effect size will provide the study with more than 90% power to detect the
 effect.

 E. Statistical analysis plan

 A detailed statistical analysis plan will be prepared before proceeding to patient enrolment.
 The essential characteristics of this statistical analysis plan are described below.

 All analyses will be based on the intention-to-treat principle. The investigators will assess
 the effect of peripheral perfusion-targeted resuscitation (group A) compared to
 lactate-targeted resuscitation (group B) on the primary outcome through hazard ratio with 95%
 of confidence interval (CI) and Kaplan-Meier curve comparison (using log-rank test). Binary
 secondary outcomes will be compared through relative risks, 95%CIs, and chi-square tests.
 Results for continuous outcomes with normal distribution will be expressed as mean
 difference, 95%CI, and P-value calculated by the t-test. Continuous outcomes with
 asymmetrical distribution will be assessed by the Wilcoxon test.

 The investigators will analyze the effects of the study fluids on the primary outcome in the
 following subgroups:

 1. Patients with lactate > 4.0 mmol/l as set by SSC

 2. Patients without a confirmed source of infection (as this could increase the translation
 of the study to other critically ill).

 3. Patients with low APACHE II / SOFA scores

 4. Patients with a more than 10% difference in lactate level between the very first one
 measured and the baseline when starting the study.
Inclusion Criteria:

 -  Septic shock diagnosed at ICU admission according to the Sepsis-3 Consensus
 Conference, (basically septic patients with hypotension requiring norepinephrine (NE)
 to maintain a mean arterial pressure (MAP) of ≥ 65 mmHg, and serum lactate levels > 2
 mmol/l after initial fluid resuscitation with at least 20/ml kg in one hour.

 Exclusion Criteria:

 -  Pregnancy

 -  Anticipated surgery or dialysis procedure during the first 8h after septic shock
 diagnosis

 -  Do-not-resuscitate status

 -  Child B or C liver cirrhosis

 -  Active bleeding

 -  Acute hematological malignancy

 -  Severe concomitant acute respiratory distress syndrome (ARDS)

 -  More than 4h after officially meeting septic shock criteria