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TYPE Review
PUBLISHED 29 January 2025
DOI 10.3389/fped.2025.1530984

The Resuscitation, Equilibrium

and De-escalation (RED) strategy:
EDITED BY
Claudio Flauzino De Oliveira,
Latin American Sepsis Institute, Brazil
a phased, personalized
REVIEWED BY
Joris Lemson,
hemodynamic support in children
Radboud University, Netherlands
Daniela De Souza, with sepsis
University of São Paulo, Brazil

*CORRESPONDENCE Jaime Fernández-Sarmiento1*, Sushitra Ranjit2,

Jaime Fernández-Sarmiento
jaimefe@unisabana.edu.co
L. Nelson Sanchez-Pinto3, Vinay M. Nadkarni4,
RECEIVED 19 November 2024 Roberto Jabornisky5 and Niranjan Kissoon6
ACCEPTED 07 January 2025 1
Department of Critical Care Medicine and Pediatrics, Fundación Cardioinfantil-Instituto de Cardiología,
PUBLISHED 29 January 2025 Universidad de La Sabana, Bogotá, Colombia, 2Department of Pediatric Intensive Care Unit, Apollo
CITATION
Children’s Hospital, Chennai, India, 3Department of Pediatrics, Northwestern University Feinberg School
of Medicine, Stanley Manne Childreńs Research Institute, Ann & Robert H. Lurie Children’s Hospital,
Fernández-Sarmiento J, Ranjit S, Sanchez-
Chicago, IL, United States, 4Division of Critical Care Medicine, Department of Anesthesiology and
Pinto LN, Nadkarni VM, Jabornisky R and
Critical Care, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of
Kissoon N (2025) The Resuscitation, Medicine, Philadelphia, PA, United States, 5Department of Pediatrics, Facultad de Medicina, Universidad
Equilibrium and De-escalation (RED) strategy: Nacional del Nordeste, Corrientes, Argentina, 6Department of Pediatrics, Children’s Hospital Research
a phased, personalized hemodynamic support Institute, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
in children with sepsis.
Front. Pediatr. 13:1530984.
doi: 10.3389/fped.2025.1530984
Hemodynamic support in critically ill children with septic shock is a pervasive
COPYRIGHT challenge in the intensive care settings. Cardiovascular involvement in sepsis
© 2025 Fernández-Sarmiento, Ranjit,
Sanchez-Pinto, Nadkarni, Jabornisky and
entails both macro- and microcirculation abnormalities, with the main
Kissoon. This is an open-access article treatment objectives seeking to increase cardiac output and improve tissue
distributed under the terms of the Creative perfusion, respectively. Fluid therapy and vasoactive drugs are cornerstone
Commons Attribution License (CC BY). The
use, distribution or reproduction in other
therapies for circulatory problems in sepsis. Fluid boluses are a common first-
forums is permitted, provided the original line treatment for actual and relative hypovolemia. However, their use has
author(s) and the copyright owner(s) are been linked to adverse events due to factors such as their composition, high
credited and that the original publication in
this journal is cited, in accordance with
volumes and rapid infusion rates, and the variable response of individual
accepted academic practice. No use, patients. Furthermore, they often have transient efficacy or lack of response in
distribution or reproduction is permitted many patients. Vasoactive drugs are also often used late, which favors
which does not comply with these terms.
repetitive fluid boluses, leading to hypervolemia, tissue edema and worse
outcomes. After the resuscitation phase, active fluid removal through diuresis
or dialysis is increasingly being used in patients who receive fluid therapy, but
it has not yet been standardized, and the safest and most effective strategies
in children are still not known. We believe that these interventions for
hemodynamic problems in sepsis offer an opportunity to personalize
treatment and apply precision medicine strategies. Using a phased approach
adapted to each patient’s context and clinical condition can potentially
improve outcomes. The proposed Resuscitation, Equilibrium and De-
escalation (RED) strategy is a simplified phased hemodynamic management
approach for patients with sepsis and septic shock. Our goal with the
introduction of this concept is to organize and underscore the fact that the
cardiovascular support of sepsis is dynamic and should be adapted to each
individual and context.

KEYWORDS

septic shock, children, guidelines, fluid bolus, adrenaline, mortality

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Introduction must be dynamic rather than static. What may initially be

helpful may be harmful in advanced stages of the disease. It also
Sepsis continues to be a public health problem with high highlights the idea that the interventions should be structured
morbidity and mortality, especially in countries with limited and adapted to the patient’s clinical condition and both macro-
resources (1). Up to half of all sepsis-related deaths occur within and micro-circulatory changes.
the first 48 h, mainly due to refractory shock (2). The most
recent pediatric sepsis management guidelines recommend
considering the context and presence of hypotension when using The RED strategy
fluid boluses as the first line of management for children with
septic shock (3, 4). Today, the main research and development The Resuscitation, Equilibrium and De-escalation (RED)
lines in children with sepsis-related hemodynamic abnormalities strategy involves a holistic, dynamic and updated approach to all
are aimed at evaluating fluid responsiveness indicators, the hemodynamic intervention phases in pediatric sepsis and
hypervolemia associated with non-resuscitation fluids, early septic shock. In addition to conventional management strategies
initiation of vasoactive agents, and fluid redistribution in children that includes early recognition and initiation of antibiotics, a
with sepsis (5–7). structured, phased approach allows the hemodynamic
We believe that the use of a structured, phased hemodynamic resuscitation phases or phenotypes in sepsis to be streamlined
management approach could help improve outcomes in children and personalized (Table 1).
with septic shock (8, 9). The approach to shock in adults was For this review and viewpoint, a systematic search of the PubMed,
initially proposed in four phases, seeking to adapt the Embase and Cochrane Library databases was conducted up to July
monitoring and treatment goal to each phase (Salvage, 2024. The search terms included “pediatric sepsis,” “fluid therapy,”
Optimization, Stabilization and De-escalation, known as SOSD) “vasopressors”, “shock management,”, “diuretics”, “hypervolemia”,
(10). This approach was later termed the resuscitation, “tolerance fluids”, “albumin”, and “fluid creep,” combined using
optimization, stabilization and evacuation (ROSE) strategy, Boolean operators. Studies in English and Spanish that evaluated
highlighting that hemodynamic resuscitation in shock is a fluid and vasopressor management strategies in pediatric patients
dynamic concept (11). Streamlining and identifying each of these with sepsis were included. We included clinical trials, observational
hemodynamic intervention stages in septic shock can provide studies, systematic reviews, and opinion articles, while editorials,
clinicians with a more holistic approach and can help personalize letters to the editor and case reports were excluded.
treatments according to the clinical condition and timing of This RED strategy could help personalize interventions
septic shock diagnosis (11). according to the patients’ characteristics and clinical condition in
However, while the optimization phase seeks to adjust all phases of circulatory failure in children with sepsis. Below, we
hemodynamic support to improve perfusion, excessive reliance present each of the proposed phases with an initial clinical case
on macrocirculation parameters may not accurately reflect tissue that illustrates the challenges and difficulties faced by clinicians
perfusion. In addition, some macrocirculatory changes tend to in real-world practice.
occur late in pediatrics, as is the case of hypotension which, The RED strategy phases include (Figure 1).
when present, indicates greater disease severity (12). The
stabilization phase involves a continuous administration of fluids
and vasopressors which may result in hypervolemia and 1 Resuscitation
pulmonary edema. Additional fluid boluses must be well justified
and based on much more precise and specific monitoring. We James, a previously healthy six-year-old boy, presents to the
believe that these two stages (optimization and stabilization) have emergency room with signs of septic shock, including hypotension,
common objectives aimed at seeking hemodynamic equilibrium tachycardia, and cold extremities. Antibiotics are started within
in children with sepsis and could be simplified to a single phase. the first hour of care, and his blood pressure improves slightly after
In pediatrics, the inclusion of both phases under the concept of the initial fluid bolus; however, hypotension persists, raising the
“equilibrium” can facilitate continuous and adaptable clinical dilemma of whether to continue fluid resuscitation or start
management, especially in critical care settings. Furthermore, it vasopressors to avoid fluid overload. The team decides to administer a
provides a simplified framework which may be useful for clinical second fluid bolus and, given the suboptimal response, initiates
practice, in which adherence and speed are essential. This epinephrine while considering a transfer to the pediatric intensive care
approach is especially relevant for institutions with limited unit (PICU) to continue treatment. The PICU informs the team that
resources or less specialized staff, where simplified terminology there are no immediately available beds.
can promote better outcomes. The main goal of this phase is fluid resuscitation, seeking to
Therefore, in this review, we propose a new pediatric strategy of optimize both macrocirculatory parameters (cardiac output
Resuscitation, Equilibrium and De-escalation (RED) as an and/or arterial blood pressure) and microcirculatory parameters
approach to circulatory shock which, adapted from ROSE, aims (tissue perfusion and oxygenation). Streamlined fluid
to be more personalized and updated with the most recent resuscitation and early initiation of vasoactive drugs are
pathophysiological advances. The RED strategy seeks to make becoming more common in the initial management of pediatric
healthcare staff aware that the hemodynamic approach in sepsis sepsis and septic shock (13, 14). Although the use of crystalloid

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TABLE 1 Objectives of the R.E.D. phases and monitoring strategies in septic shock.

Phase of R.E.D Targets Interventions Monitoring strategies

concept
1. Resuscitation Macrocirculation - Fluids bolus 10–20 ml/kg in patients with hypotension - Clinical examination
- Optimize AP - Hypoperfusion with PICU: fluids bolus - Respiratory mechanics
- Optimize CO - Noninvasive or invasive arterial pressure/PP
Microcirculation - Hypoperfusion without PICU: no fluids bolus - Heart rate
- Optimize tissue perfusion - Inotropes - CRT
- Vasopressors - Urine output
- Lactate
- Echocardiography
- POCUS
2. Equilibrium Macrocirculation - Fluids according to fluid responsiveness and tolerance. - Clinical examination
- Provide organ support - Vasopressors - Respiratory mechanics
- Inotropes - Arterial pressure/PP
Microcirculation - Avoid fluid creep - Heart rate
- Normalize tissue perfusion indices - Monitor fluid balance - Diastolic blood pressure (low in
vasodilatory shock)
- CRT
- Lactate
- Urine output
- Advanced hemodynamic monitoring
(minimally invasive CO)
- ScvO2 and ΔP(v-a)CO2
3. De-escalation Macrocirculation - Monitor fluid balance - Maintain existing monitoring
- Decreased organ support. - Fluid restriction in patients with fluid overload. - Clinical examination
Microcirculation - Decrease dose of vasopressors/inotropes or suspend - Respiratory mechanics
- Limit exposure to high doses of fluids - Fluid removal in case of tisular edema with positive fluid - Normal CRT prior to fluid removal.
- Limit impact of accumulated fluids balance: diuretics, albumin, CRRT. - Urine output
and tisular edema - Lactate

AP, arterial pressure; CO, cardiac output; PICU, pediartric intensive care units; PP, pulse pressure; CRT, capillary refill time; POCUS, point-of-care ultrasonography; CRRT, continuos
replacement renal therapy. ScvO2 central venous oxygen saturation. ΔP(v-a) CO2 central venous-to-arterial CO2 difference.

FIGURE 1
The resuscitation, equilibrium and De-escalation (RED) strategy in hemodynamic interventions in pediatric sepsis. Hemodynamic interventions in
pediatric sepsis depend on the clinical presentation, time elapsed since identification and context. The RED strategy underscores the idea that
these interventions are dynamic, not static, and are tailored to the course of the disease (precision medicine) and the available resources. CRRT,
continuous renal replacement therapy.

boluses in sepsis resuscitation has historically been considered a 1.1 Fluid therapy
cornerstone treatment, this strategy is not free of adverse effects.
However, despite these limitations, timely fluid resuscitation in Fluid resuscitation is used to correct the actual and relative
children with sepsis is a universally accepted strategy used in hypovolemia caused by decreased fluid intake prior to
almost all possible care settings. presentation, increased insensible losses, vasodilation, and

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increased capillary leak. The most recent pediatric sepsis (22). This low tolerance to fluid boluses could be explained by
management guidelines recommend applying fluid boluses macrocirculatory dysfunction (heart failure) or worsening
according to the care context and the patient’s clinical condition endothelial activation related to fluid loads, which some authors
(3, 4). All hypotensive children, regardless of the availability have termed resuscitation-associated endotheliopathy (RAsE). The
of resources, should receive balanced crystalloid boluses at RAsE concept suggests that endothelial activation and
10–20 ml/kg/dose within the first hour of care (3). A rapid macrocirculatory dysfunction contribute to low fluid tolerance,
administration of crystalloid loads has been associated with which limits the effectiveness of crystalloids in some patients.
greater endothelial injury, shock, and respiratory distress, while Therefore, not all patients are simply “fluid responders” or
slower administration has been associated with little or transient “nonresponders,” but rather may have a more complex combination
cardiac output recovery (15–17). Studies are needed in children of factors that affect their response to fluid treatment (17, 23). One
to help clarify the most effective fluid bolus administration rate of these factors is sympathoadrenal hyperactivation related to
according to the context, phenotype and severity of presentation. endothelial activation, glycocalyx injury and altered perfusion, a
For normotensive patients with hypoperfusion (prolonged phenomenon known as shock-induced endotheliopathy (SHINE) (24).
capillary refill, altered consciousness), a crystalloid bolus is only
recommended when critical care services are available. The Pathophysiological aspects
Surviving Sepsis Campaign (SSC) guidelines recommend only a. Macrocirculation
using maintenance fluids, without crystalloid boluses, if critical The hemodynamic response to fluid boluses in children with sepsis
care services or support are not available (3, 4). However, this is associated with both macro- and microcirculatory changes
recommendation should be integrated into the context and (Figure 2). The first change is expanded intravascular volume.
capacity of the care setting. A patient may be severely According to Guyton et al. (25), intravascular volume can be
dehydrated, hypoperfused and require a fluid bolus despite the divided into stressed and unstressed volume. Stressed volume is
lack of available critical care support. This is an example of how that which distends the blood vessel walls with a simultaneous
each sepsis intervention should be aimed at personalization. increase in pressure, while unstressed volume fills the blood
Recently, the Fluid Resuscitation for Suspected Septic shock in vessels but does not generate any pressure. A 10–20 ml/kg fluid
Paediatric Emergency Departments (FRESSPED) study evaluated bolus temporarily increases the stressed volume, thereby
the adherence to SSC guidelines in the pediatric emergency increasing the mean systemic filling pressure (Pmsf), which is the
rooms of various hospitals (18). The results showed high pressure in the vessels without blood flow or during circulatory
adherence at the beginning of fluid resuscitation but moderate arrest (Figure 2A) (26). However, the hemodynamic response to
adherence to the volume and type of crystalloids used. The main fluid boluses varies in pediatric septic shock, with evidence of no
barriers reported by physicians were difficult venous access, lack increase in ejection volume with a fluid challenge (despite an
of team training and missing or outdated protocols. increased Pmsf) and even a decrease in blood pressure in some
An important aspect to keep in mind is that improvements in cases (26).
cardiac output after fluid boluses in children tend to be transient. Similarly, animal models of septic shock have shown that
Long et al. (19) found an increased cardiac index in 63% of recovery of the macrocirculatory variables with fluid boluses is
patients five minutes after infusing crystalloid boluses, which not necessarily associated with improved microvascular flow and
decreased to 14% after 60 min. Suchitra et al. (20) found that the oxygen delivery to the tissues (27). This loss of hemodynamic
hemodynamic response to a fluid bolus was unpredictable in coherence has been associated with worse outcomes and greater
children with sepsis. Patients tended to have an improvement in mortality (28). In observational studies in adults, improved
mean arterial pressure (MAP) but not necessarily increased microvascular blood flow after a fluid bolus has been found to
cardiac output after a fluid bolus. In fact, in some patients, fluid occur only in the first 48 h after identifying sepsis (29). Persistent
boluses were associated with a vasodilating effect, and those who microcirculatory dysfunction, especially low 4–6-micron capillary
did not experience MAP recovery after a crystalloid bolus had density (known as functional capillary density), in children with
greater mortality (20). Rapid fluid redistribution and excretion in sepsis after fluid boluses was found to be associated with greater
children explains why up to 50% of the infused crystalloid mortality (17% vs. 6%) and worse outcomes, despite normalized
volume may leave the intravascular space within the first 30 min, macrocirculatory variables, when compared to children with
with significantly higher urinary excretion than in adults (21). sepsis and a normal functional capillary density (30).
This physiological characteristic underscores the importance of
dynamic management in pediatrics, adjusting fluid resuscitation b. Microcirculation
to maintain perfusion without causing hypervolemia. It has been generally accepted that normalization of tissue
In patients with sepsis, the fluid redistribution mechanism is perfusion and oxygen delivery are the ultimate endpoints for
influenced by several pathophysiological factors like the degree of fluid resuscitation in septic shock. Microcirculation changes after
endothelial dysfunction, cardiac output status, and inflammatory fluid boluses are largely determined by the timing of the
activation. Some patients may develop respiratory distress, greater interventions and the extent macrocirculatory abnormalities.
oxygen requirements, intra-abdominal hypertension and/or acute Oxygen is transported in the microcirculation through
kidney injury (AKI) after a fluid load, due to increased capillary leak convection and diffusion (Figure 2B). Convection depends on the
and tissue edema. These patients have been called “fluid intolerant” microcirculatory blood flow (determined by the arteriolar tone)

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FIGURE 2
Hemodynamic changes after fluid boluses in sepsis. (A) Macrocirculation. After fluid boluses, mean systemic filling pressure (Pmsf) increases due to
increased stressed volume, with the unstressed volume remaining constant. (B) Microcirculation. In hypovolemia (point A), there is an abnormal driving
pressure (DP) that determines the convective flow. The DP results from subtracting the venule blood pressure from the precapillary blood pressure.
Point B corresponds to euvolemia without microvascular abnormalities with a lower risk of worse outcomes. In fluid overload with tissue edema,
diffusive flow is altered (point C). The gas exchange distance increases and, due to microvascular heterogeneity, the functional capillary density
(number of perfused capillaries/tissue area) decreases in sepsis.

and the oxygen content (which depends on the capillary interventions have theoretical benefits, they do not have enough
hematocrit). Diffusion depends on the exchange distance (greater evidence yet to support their widespread use. Genomic,
in tissue edema), the capillary/mitochondrial partial oxygen metabolomic and pharmacogenomic development is expected to
pressure (PO2) gradient and, finally, the gas exchange area. identify the specific groups of patients who would benefit from
Under normal conditions, only 25%–30% of the capillaries are the recovery of mitochondrial function with these
perfused, and the cardiovascular system is extremely efficient in pharmacological measures.
adjusting blood flow to the metabolic demands of the tissues and After crystalloid boluses, there are changes in the capillary
recruiting additional capillaries when necessary (31). This driving pressure (the difference between precapillary and venule
ensures tissue perfusion without a high metabolic cost. pressure) with improved convection, and changes in diffusion
Microcirculatory changes during sepsis entail heterogeneity with more recruitment of capillaries and better functional
in capillary perfusion, with slow-flow areas (approximately capillary density. However, these responses to fluid boluses have
100 µm/s) and others with normal flow (400–500 µm/s) (32). been seen in adults only in the 48 h after sepsis diagnosis (29).
Additionally, there is a lower density of vessels smaller than Pranskunas et al. reported that patients who had improved
10 µm, reducing the functional capacity of the microcirculation microcirculation perfusion after fluid boluses had an associated
(29). The red blood cell velocity in the perfused vessels does not improvement in organ function (35). Furthermore, in children,
change according to the width of the vessel but is influenced by unbalanced fluid boluses have been associated with negative
the velocity of the larger capillaries, which suggests that small microcirculatory changes, including glycocalyx degradation and
capillaries (4–6 µm) do not respond appropriately to local increased endothelial permeability (36). In this regard, the
changes in oxygen demand, which translates into clinical volume of intravenous fluids administered during sepsis
perfusion alterations (30). In patients with septic shock, the resuscitation in adults has been found to be independently
disassociation between tissue oxygen demand and vascular associated with the degree of glycocalyx degradation (37). This
perfusion is thought to be responsible for the progression to layer, that covers the endothelial cells, is essential for
multiple organ dysfunction (MODS) (28, 31). microvascular homeostasis, mediates the vasorelaxation induced
Mitochondrial dysfunction is one of the most important by shear stress and prevents leukocyte adhesion to the
consequences of this oxygen delivery imbalance in the cells. endothelial cells. In sepsis, tumor necrosis factor-α and
Under normal conditions, mitochondria use approximately 98% angiopoietin-2, among others, induce heparanase expression and
of the available cellular oxygen for energy production through activation, which causes endothelial dysfunction and organ insult
the Krebs cycle. Mitochondrial dysfunction in sepsis is associated mediated by damage to heparan sulfate, a component of the
with the onset and severity of MODS (33). Interventions aimed endothelial glycocalyx (38). Heparanase and the inflammatory
at improving mitochondrial activity with medications (thiamine) response in sepsis also cause degradation of syndecan-1, another
or micronutrients (ascorbic acid, tocopherol, selenium and zinc) structural component of the glycocalyx. These phenomena lead
have been termed “metabolic resuscitation” (34). Although these to the loss of integrity of the protective layer of the endothelial

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cell, increase microvascular permeability and foster the onset of peripherally administered noradrenaline is necessary to maintain
capillary leak syndrome. the target blood pressure. He is admitted to intensive care and the
team begins invasive monitoring and places a central venous
catheter, but prolonged capillary refill persists despite achieving the
1.2 Vasoactive medications macrocirculation goals. In light of the persistent signs of
hypoperfusion despite fluid resuscitation and vasoactive drugs, the
In this initial resuscitation phase of the dynamic strategy it may team decides to begin an inodilator.
be necessary to begin vasoactive support. Pediatric sepsis guidelines The goal of this phase is to maintain a hemodynamic balance
(3, 4) recommend initiating vasoactive support when signs of in both the macro and microcirculation after the initial fluid bolus
hypoperfusion persist after fluid resuscitation or signs of fluid and vasoactive support interventions. It often occurs within a few
overload appear. The SSC recommends considering beginning hours of sepsis diagnosis. In this phase of hemodynamic
vasoactive drugs after 40–60 ml/kg of crystalloid boluses. management, it is important to adjust the vasoactive drugs
However, a recent multicenter randomized pilot trial comparing and titrate fluid input to avoid unnecessary additional
early initiation of adrenaline (after a 20 ml/kg crystalloid bolus) crystalloid boluses, which can lead to fluid overload and worse
vs. the treatment recommended by SSC found that there was a outcomes (43, 44).
lower total 24-hour fluid input in the intervention group, with
no differences in the frequency of organ dysfunction, pediatric
intensive care unit (PICU) admission or length of PICU stay 2.1 Objectifying the need for additional
(13). Another open-label trial in children with sepsis found that fluid boluses
early initiation of adrenaline (after 40 ml/kg of crystalloids)
reduced the need for mechanical ventilation, as well as persistent Identifying children in septic shock who could benefit from
shock and mortality (39). In adults, observational studies have additional crystalloid boluses tends to be a significant clinical
shown that early administration of noradrenaline (less than one challenge. According to the availability of resources, clinical
hour after identifying shock) has been associated with a assessments and minimally invasive monitoring tools have been
reduction in the total volume of fluids administered and lower used to determine the fluid response status in critically ill
28-day mortality (40, 41). patients (Table 1). A systematic review and meta-analysis of 62
There are no studies in children specifically comparing pediatric studies that sought to evaluate the performance of
adrenaline (or epinephrine) with noradrenaline (or norepinephrine) different tools in predicting response to fluids in critically ill
as a first-line vasoactive drug in septic shock. Banothu KK et al. children found that the variables with a good capacity for
(42) conducted an open-label randomized controlled study at a predicting the response to fluids were passive leg raising stroke
single center in India, comparing the effectiveness of two treatment volume (PLR-SV), respiratory variation in aortic peak flow
regimens in children with fluid-refractory septic shock. Two (RVAF), and left ventricular velocity time integral (LVVTI)
approaches were studied: norepinephrine plus dobutamine vs. measured using an ultrasound device (45). However, these tools
epinephrine as a first-line vasoactive agent. The primary objective are often not available at the bedside. Furthermore, the
was to determine which of these treatments offered better association between preload recovery as defined by ultrasound
outcomes in terms of hemodynamic stabilization and reduced techniques and actual clinical improvement is unclear and
mortality. The results showed that both approaches were effective requires further study. When these tools are not available, tissue
for managing shock. However, there were differences in their side perfusion monitoring (i.e., capillary refill time) can guide the
effect profiles and the time required to recover cardiovascular clinician on the risks or benefits of administering additional fluid
function, with the norepinephrine plus dobutamine group resolving boluses. A post-hoc analysis of the ANDROMEDA-SHOCK trial
shock more rapidly (HR 1.84; 95% CI 1.11–3.08). (which included a systematic evaluation of the baseline response
When there is evidence of low cardiac output, clinicians prefer to fluids prior to beginning the protocol) found that, in a
adrenaline or dobutamine, and when there is evidence of significant percentage of patients the fluid resuscitation could be
vasodilation, noradrenaline is preferred. Both drugs stimulate the guided by clinical variables like capillary refill time (46). In
beta 1 adrenergic receptors, with increased chronotropy and patients who did not respond to fluid resuscitation, fluid boluses
inotropy, and the alpha-adrenergic receptors, with increased could be stopped with no negative impact on the relevant
peripheral vascular resistance (PVR) (10). By increasing the PVR, clinical outcomes.
some vasopressors also increase venous tone, increasing Pmsf and
adding to the effect of the crystalloid boluses (40).
2.2 Monitoring fluid creep

2 Equilibrium Another important aspect in all the hemodynamic intervention

phases, especially in this equilibrium phase, is to consider the
James develops respiratory failure, is intubated in the emergency volume administered that is not related to fluid boluses. The
room, and an x-ray shows signs of pneumonia. The addition of amount of maintenance fluids, continuous infusions, nutrition,

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blood products, medication dilution fluids, and flushes to maintain interleukin-6) and matrix proteases result in a loss of binding
the patency of intravascular lines can contribute to hypervolemia in between the B1 integrins and collagen fibers (52). Furthermore, the
the post-resuscitation phase. The contribution of these non- endothelial activation, glycocalyx damage, loss of intercellular
resuscitation fluids to fluid overload has been termed “fluid binding and lymphatic system saturation that occur in patients with
creep” (47, 48). Some studies have found that fluid creep sepsis lead to increased filtration pressure (capillary pressure –
accounts for a third of the total daily administered fluid, with its interstitial pressure) with subsequent fluid accumulation in the
proportion gradually increasing throughout the PICU stay, interstitial space (51, 52). Under inflammatory conditions, the
becoming the main source of fluids by the fourth or fifth day of interstitial pressure has been found to reach up to −100 mmHg,
PICU stay (41). Barhight et al. (6) evaluated 14,483 PICU which progressively increases the amount of fluid accumulated in
patients in two hospitals and found that more than half of these the interstitium, a phenomenon that has been called interstitial
children received non-resuscitation fluid beyond hydration suction (53). The clinical expression of this condition is tissue edema
requirements, which was associated with greater mortality (a 1% with hypoperfusion and associated organ failure, often found in
increase in mortality for every 10 ml/kg of excess fluid) children with capillary leak and septic shock.
regardless of age, Pediatric Risk of Mortality III score, study site,
acute kidney injury, resuscitation volume and volume output.
Excess maintenance fluids are a modifiable factor that can 3.1 Active fluid removal
contribute to hypervolemia and should be actively titrated,
particularly in the post-resuscitation phase. Performing proper One way to reduce hypervolemia, sustain euvolemia and
daily fluid balance monitoring, tracking inputs and outputs along optimize tissue perfusion is through active fluid removal. Very
with the patient’s weight, can help the clinician prevent often, the treatment measures used to decrease hypervolemia are
overhydration and adverse outcomes which have been related to not planned and can lead to relative hypovolemia and new,
hypervolemia (AKI, abdominal hypertension or greater mortality). unnecessary fluid boluses. A survey by Aramburo et al. (5) in 48
countries showed that 93% of physicians employed active fluid
removal or fluid limiting practices for children in critical care.
3 De-escalation The most common interventions were the use of loop diuretics
(93.3%), restriction or avoidance of maintenance fluids (86.6%),
James is stabilized, but after 48 h of care, he has a positive minimizing drug diluents (72.4%) and the use of renal
balance of 22% of his body weight, with significant generalized replacement therapy to prevent or treat fluid accumulation
edema, and he develops oliguria and mild azotemia. The team (55%), especially in children with poor response to diuretics or
decides to begin loop diuretics after confirming that James is on evidence of severe AKI. In adults, active fluid removal has been
low doses of vasoactives and is hemodynamically stable. associated with a reduction in the duration of mechanical
After the initial stabilization and reaching equilibrium, the ventilation, shorter ICU length of stay and lower mortality (54).
clinician should concentrate on gradually decreasing the Another active fluid removal strategy employed commonly is
hemodynamic support, limiting exposure to unnecessary fluids and the use of hyperoncotic albumin (20 or 25% albumin fluid) in
facilitating the removal of excess fluids. During the resuscitation and conjunction with the diuretics. In adults being ventilated due to
equilibrium phases there is often hypervolemia, positive balances lung injury, the use of hyperoncotic albumin with furosemide,
and soft tissue edema due to fluid administration often complicated coupled with adjusted positive end-expiratory pressure, has been
by AKI and increased endothelial permeability with fluid transfer associated with a negative cumulative fluid balance and decreased
from the intravascular to the interstitial space. lung water (55). Following initial resuscitation in adults with
sepsis, hyperoncotic albumin has been associated with improved
tissue hypoperfusion compared to 0.9% saline solution (55). In
Pathophysiological aspects patients with sepsis, plasma and albumin have also been found
to have a potential protective effect on the endothelium through
Under normal conditions, there is a close interaction between antioxidant and anti-inflammatory effects (56, 57). Likewise, in
microcirculation and the interstitial extracellular matrix. The children with sepsis, the correction of hypoalbuminemia has
integrity of the endothelial barrier, the glycocalyx layer and been associated with improved functional capillary density,
interstitial pressure help regulate transcapillary flow between the endothelial glycocalyx damage recovery and lower levels of
intravascular and interstitial spaces (6). Interstitial space pressure is angiopoietin-2 (58, 59). In addition, a multicenter observational
kept within a narrow range (between −2 and −3 mmHg) by the study of children with a sepsis phenotype characterized by
constant tension exerted by the fibroblasts on the collagen bundles persistent hypoxemia, encephalopathy and shock -which is
through the B-1 integrin transmembrane protein (49, 50). This associated with increased systemic inflammation and endothelial
tension, coupled with appropriate functioning of the lymphatic activation- found that those who received 0.5 g/kg or more of
system, is essential for keeping the interstitial space free of excess intravenous albumin within the first 24 h of care were associated
fluid (51). Under inflammatory conditions, increased cytokines with a higher survival rate (75% vs. 66%) than those who did
(mainly tumor necrosis factor alpha, interleukin-1B, and not after adjusting for confounders (60).

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Fernández-Sarmiento et al. 10.3389/fped.2025.1530984

3.2 Renal replacement therapy as an explicit component, RED addresses the growing evidence
of the importance of minimizing hypervolemia and
Another strategy used to remove fluids is renal replacement withdrawing hemodynamic support in a controlled fashion,
therapy (RRT). Acute kidney injury is common in children with which is associated with better clinical outcomes (44, 54, 63).
sepsis and may require extracorporeal renal support therapies when This simpler, action-oriented framework facilitates
there is no response to diuretics (2, 4). In adults with sepsis, there implementation in pediatric scenarios, especially in settings
have been conflicting study results regarding the use of these with limited resources.
therapies to remove excess fluids (61). No differences have been
found in mortality, length of ICU stay or duration of AKI with early
vs. late RRT (62). In a recent multinational survey, 55% of the Conclusion
physicians reported using RRT to prevent or treat hypervolemia
in critically ill children (6). In this phase of the RED strategy, one Sepsis is one of the main causes of morbidity, mortality and
of the most important aspects is AKI prevention, avoiding new functional disorders in children worldwide. The
overhydration or high doses of vasopressors. A recent systematic cardiovascular system is one of the most frequently affected, with
review and meta-analysis in children found that a fluid overload both macro- and microcirculation abnormalities. Fluid
greater than 10% at any time during the PICU stay was associated resuscitation and vasoactive drugs modify the clinical course of
with a greater need for mechanical ventilation and mortality (44). the disease but are not free of adverse effects. The structured and
personalized use of these interventions during resuscitation, the
rational administration of non-resuscitation fluids, and the timely
removal of accumulated fluid have the potential to improve
3.3 Tissue perfusion monitoring
outcomes in such a complex and dynamic syndrome. The
proposed RED strategy provides a holistic, phased approach to
Active fluid removal must be closely monitored and
the hemodynamic management of children with circulatory
individually adjusted to each case. The prerequisite for active
involvement, anticipates potential complications associated with
fluid removal is an achievement of hemodynamic stability with
these interventions, and aims at faster cardiovascular stabilization
resolved hypoperfusion and requirement for low (or no) doses of
and improved clinical outcomes.
vasoactive drugs. Furthermore, close tracking of fluid balance (as
well as daily weights when possible) is needed estimate the
amount of accumulated fluid. Close monitoring of serum lactate
and capillary refill time is useful for guiding this fluid
Author contributions
redistribution phase and can help determine the microcirculation
JF-S: Conceptualization, Data curation, Formal Analysis,
status of children with sepsis (46, 63). Pediatric randomized trials
Funding acquisition, Investigation, Methodology, Project
are needed to evaluate the best strategy for performing active
administration, Resources, Software, Supervision, Validation,
fluid removal and the most appropriate monitoring tools (64).
Visualization, Writing – original draft, Writing – review &
editing. SR: Conceptualization, Data curation, Investigation,
Methodology, Writing – original draft, Writing – review &
Limitations editing. LNS-P: Conceptualization, Data curation, Formal
Analysis, Funding acquisition, Investigation, Methodology,
The RED strategy proposal has not yet been standardized or Project administration, Resources, Software, Supervision,
validated in clinical studies. It clusters a series of updated Validation, Visualization, Writing – original draft, Writing –
interventions for hemodynamic management in sepsis which review & editing. VN: Conceptualization, Data curation, Formal
should be evaluated in prospective studies. We do not know if Analysis, Investigation, Resources, Writing – original draft,
reaching hemodynamic goals will translate into better Writing – review & editing. RJ: Conceptualization, Data curation,
neurological and functional outcomes. In addition, the varied Writing – original draft, Writing – review & editing. NK:
hemodynamic response in the different pediatric sepsis Conceptualization, Data curation, Formal Analysis, Funding
phenotypes and the challenges to clinical implementation in acquisition, Investigation, Methodology, Project administration,
different care settings are aspects that must be evaluated in the Resources, Software, Supervision, Validation, Visualization,
RED strategy. However, the RED strategy brings a more Writing – original draft, Writing – review & editing.
dynamic and practical perspective to the circulatory
management of pediatric shock, by unifying the optimization
and stabilization phases (from the ROSE strategy for adults) Funding
under the concept of “equilibrium.” This better reflects the
clinical reality, where transitions between these phases are often The author(s) declare financial support was received for the
blurred, and continuous and adaptable management is needed research, authorship, and/or publication of this article. JF-S was
to achieve homeostasis without affecting perfusion or tissue supported by the Medical School at Universidad de La Sabana,
oxygenation. Moreover, by including the “de-escalation” phase (Project MED 256-2019) and the Research Department at

Frontiers in Pediatrics 08 frontiersin.org

Fernández-Sarmiento et al. 10.3389/fped.2025.1530984

Fundacion Cardioinfantil-Instituto de Cardiologia, Bogotá, Colombia Generative AI statement

to conduct this review and pay the journal publication costs.
The author(s) declare that no Generative AI was used in the
creation of this manuscript.
Acknowledgments
We want to thank the PICU medical and nursing staff as well
as the research department at Fundación Cardioinfantil-IC for
their constant support. Publisher’s note
All claims expressed in this article are solely those of the
Conflict of interest authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
The authors declare that the research was conducted in the reviewers. Any product that may be evaluated in this article, or
absence of any commercial or financial relationships that could claim that may be made by its manufacturer, is not guaranteed
be construed as a potential conflict of interest. or endorsed by the publisher.

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