Early Goal Directed Therapy Using a Physiological Holistic View. The ANDROMEDA-SHOCK Study
Condition: Septic Shock; Hyperlactatemia; Peripheral Perfusion
MeSH terms: Shock, Septic; Hyperlactatemia; Shock
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Peripheral Perfusion guided resuscitation; Lactate guided resuscitation
Intervention type(s): Other; Other
Intervention description(s): Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), vasopressors titration, and inodilators according to peripheral perfusion.; Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), vasopressors titration, and inodilators according to lactate decrease.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Septic Shock; Lactate; Capillary Refill Time; Fluid Responsiveness; Mortality