Advancing Microcirculatory Therapies in Pediatric Sepsis: Current Opportunities and Future Directions

Abstract

Microcirculatory dysfunction in pediatric sepsis is a key factor in the development of tissue hypoperfusion and multiple organ failure. Endothelial glycocalyx alteration, increased capillary permeability, and blood flow heterogeneity are common findings in these patients, suggesting that a microcirculation-targeted approach could improve clinical outcomes. In this context, strategies such as resuscitation with balanced solutions have been shown to minimize hyperchloremia and metabolic acidosis, reducing endothelial dysfunction and inflammatory activation. Likewise, correcting hypoalbuminemia has been associated with reduced glycocalyx degradation and improved vascular stability. The use of inotropes and inodilators has shown favorable effects on capillary perfusion and modulation of the inflammatory response, suggesting their potential to optimize tissue oxygenation in septic shock patients. Additionally, fresh frozen plasma may play a role in glycocalyx restoration and endothelial homeostasis regulation, although its impact on pediatric sepsis still requires further clinical evidence. Despite these advances, questions remain regarding the best strategy to evaluate and treat microcirculatory dysfunction in children with sepsis. Identifying specific biomarkers and developing tools for real-time perfusion assessment could allow for more personalized therapies. Further clinical studies are needed to validate the impact of these interventions on pediatric mortality and morbidity. Integrating a microcirculation-targeted approach into pediatric septic shock management protocols represents an opportunity to improve care and outcomes in this vulnerable population.

Introduction

Circulatory shock is the leading cause of death in children with sepsis within the first 48 h of diagnosis.¹ It is characterized by inadequate tissue perfusion and oxygenation due to varying degrees of macro- and microcirculatory compromise. At the microvascular level in sepsis, there is a loss of local compensatory mechanisms that normally enhance oxygen delivery. Increased microcirculatory flow heterogeneity, decreased functional capillary density, and poor capillary recruitment capacity have been observed.^2-4 These alterations may be caused or exacerbated by the inflammatory response, interstitial edema, hemodilution, or microvascular obstruction.^5,6

Under normal conditions, only 25% of blood capillaries are recruited.⁷ Depending on basal metabolic demands, nutrient availability, and waste product accumulation, additional capillaries can be recruited. This local regulation of perfusion occurs mainly at the precapillary sphincter.⁸ Sympathetic innervation is present in the arterial and venous trees but is absent in capillaries. The lack of innervation and muscle layer in true capillaries means that flow in each capillary bed is regulated by hemodynamic pressure generated between the precapillary sphincter and the postcapillary venules. A single capillary bed can receive flow from multiple arterioles, allowing capillary flow to increase by 200–500% without significant changes in arteriolar pressure.^4,8 In critically ill children, when tissues increase their metabolic activity, they generate byproducts such as carbon dioxide, lactate, and reduced oxygen levels, which trigger dilation of arterioles and precapillary sphincters, increasing capillary blood flow.⁹ Similarly, the capillary endothelium plays a key role by releasing nitric oxide and prostaglandins, which induce vasodilation in response to local signals.

In sepsis, these compensatory mechanisms are frequently impaired, leading to microcirculatory dysfunction and multiple organ failure. Related mechanisms include uncontrolled activation of the inflammatory response, resulting in the massive release of proinflammatory cytokines (such as TNF-α, IL-1, and IL-6) and vasoactive mediators, leading to excessive vasodilation or vasoconstriction, capillary plugging, microvascular shunting, increased vascular permeability, and endothelial damage.¹⁰ In many cases, this damage is exacerbated by medical interventions aimed at achieving macrocirculatory goals without considering microcirculatory changes, such as the administration of large volumes of unbalanced crystalloids, excessive vasopressor use, or aggressive fluid resuscitation without dynamic assessment of fluid responsiveness.¹¹

In recent years, the critical importance of perfusion-guided resuscitation in the management of septic shock has gained increasing recognition, supported by clinical evidence favoring this approach.^12-14 Recognizing that hemodynamic compromise in sepsis presents opportunities for microcirculatory interventions that may improve tissue oxygenation is a challenge for physicians caring for critically ill children (Table 1). This review aims to explore potential therapies that could promote microvascular stabilization and prevent further endothelial damage in children with sepsis.

Table 1.

Main Investigations on Targeted Interventions to Stabilize the Microcirculation in Sepsis.

Authors and Year	Study Design	Population	Number of Participants per Group	Microcirculatory Function Indicators	Main Results
Prevention and Treatment of Hypoalbuminemia
Fernández-Sarmiento J, et al13	Prospective cohort study	Patients aged 1 month to 18 years with sepsis or septic shock	125 patients divided into: 48 with hypoalbuminemia (<3 g/dL) 77 with normal albumin levels	Sublingual videomicroscopy: PBR, Capillary density (4-6 μm), and Capillary blood volume percentage Plasma biomarkers: Syndecan-1, Angiopoietin-2, Endocan, and Annexin A5	In children with hypoalbuminemia, the following was observed: • Greater glycocalyx degradation with increased PBR (2.16 μm [IQR 2.03-2.47] vs 1.92 [1.76-2.28], p = 0.01). • Higher recruitment of 4–6 μm capillaries (60% vs 40%; p = 0.04). • Higher levels of Angiopoietin-2 (p = 0.04) and Annexin A5 (p =0.03).
Hariri G, et al45	Prospective cohort study	Adult patients with septic shock	30 patients: 15 resuscitated with human serum albumin (HSA) infusion 15 resuscitated with 0.9% saline solution	Transdermal acetylcholine iontophoresis	• Endothelial reactivity improved after infusion with HSA (p = 0.04).
Fluid Resuscitation with Plasma
Straat M, et al14	Secondary analysis of a prospective cohort study	Critically ill non-hemorrhagic coagulopathic adult patients receiving prophylactic FFP transfusion (12 ml/kg)	33 patients	Endothelial function markers: von Willebrand factor antigen (vWF:Ag), ADAMTS13, Syndecan-1, Factor VIII	• Lower levels of Syndecan-1 (675 pg/ml vs 565 pg/ml, p = 0.01) and vWF with higher ADAMTS 13 (23.9% vs 31.7%, p<0.01).
Use of Inotropes and/or Inodilators
Sarta-Mantilla M, et al77	Prospective cohort study	Patients aged 1 month to 18 years with septic shock	140 patients: 81 receiving Milrinone infusion 59 receiving only crystalloid fluid resuscitation	Sublingual videomicroscopy: PBR, Capillary density (4-6 μm), CBV-RC, Microvascular Health Score (MVHS™)	• Milrinone group maintained functional capillary density and capillary recruitment capacity (80.1% vs 57.6%; p = 0.04).
De Backer D, et al78	Prospective study	Adult patients with septic shock	22 patients evaluated before and after Dobutamine (5 μg/kg/min)	Sublingual videomicroscopy: Total vascular density, Perfused venules, Perfused capillaries, Perfused capillary density, Non-perfused capillaries, Intermittently perfused capillaries, Coefficient of variation of perfused vessels	• Significant improvement in perfused capillaries (48% vs 67%, p = 0.001), but no full restoration in patients receiving dobutamine.
Enrico C, et al79	Prospective study	Adult patients with septic shock	23 patients evaluated before and after Dobutamine administration	Sublingual videomicroscopy: Total vascular density, Perfused capillaries, MFI, RBC velocity	• Recovery of total microvascular density.
Morelli A, et al83	Prospective, randomized, double-blind clinical trial	Adult patients with septic shock	40 patients: 20 receiving Levosimendan 0.2 μg/kg/min 20 receiving 5 μg/kg/min	Sublingual videomicroscopy: Total vascular density, MFI of small vessels (MFIs), MFI of medium vessels (MFIm), Heterogeneity index (HI)	• Levosimendan group showed an increase in MFI of small and medium microvessels (MFIm 3.0 vs 2.9, p = 0.02; MFIs 2.9 vs 2.7, p < 0.001). • Greater increase in total vascular density compared to baseline (dMFIm 10% vs 0%, p = 0.007; dMFIs 47% vs 10%, p < 0.001).

**Abbreviations:**

IQR: Interquartile range, MFI: Microvascular Flow Index, PBR: Perfused Boundary Region, FFP: Fresh Frozen Plasma.

Fluid Resuscitation with Balanced Crystalloids

Physiological Aspects

While balanced solutions are currently the preferred choice for fluid resuscitation due to their favorable profile on acid–base balance and endothelial protection, the most effective therapeutic strategy remains the prevention of microcirculation injury. This is best achieved by avoiding fluid overload and limiting unnecessary or excessive crystalloid boluses. Fluid stewardship guided by restrictive strategies and dynamic assessment of fluid responsiveness is essential to preserve microvascular integrity and improve outcomes in pediatric sepsis. Accordingly, an individualized and closely monitored approach to fluid administration—based on continuous evaluation of perfusion and strict justification for additional boluses—should be prioritized to minimize iatrogenic microvascular injury and promote physiologically coherent resuscitation.

Recently, a debate has emerged regarding the most appropriate type of intravenous solution for fluid resuscitation in various clinical contexts. Balanced solutions, such as Ringer’s Lactate and Plasma-Lyte^®, have a salt composition similar to blood plasma. This property results in fewer side effects compared to non-balanced solutions such as 0.9% Saline Solution.¹⁵ Hyperchloremia, along with metabolic acidosis and acute kidney injury (AKI), have been described as the main side effects related to the use of large volumes of 0.9% saline solution administered over short periods.¹⁶

In this context, excess chloride ions lead to the consumption of available bicarbonate, which is essential for the body’s acid-base balance, facilitating the development of metabolic acidosis.¹⁷ Both hyperchloremia and pH reduction contribute to processes associated with microcirculatory dysfunction, endothelial damage, and glycocalyx degradation (Figure 1).^18,19 Immunologically, these conditions have a pro-inflammatory effect due to the stimulation of Nuclear Factor-κB (NF-κB), Tumor Necrosis Factor-alpha (TNF-α) synthesis, and the expression of endothelial adhesion molecules such as ICAM-1.^20-24 The sum of these effects promotes leukocyte adhesion and rolling within the intravascular space, leading to direct glycocalyx destruction mediated by neutrophil elastase and amplifying the pro-inflammatory processes of sepsis through leukocyte-endothelial interactions.^22,23

Figure 1.

Impact of Fluid Therapy on Endothelial Integrity and Glycocalyx. The choice of resuscitation fluid in patients with sepsis has a direct impact on endothelial integrity and microcirculation. Balanced solutions and plasma appear to exert a protective effect on the glycocalyx, whereas unbalanced solutions induce glycocalyx disruption, promote endothelial activation, systemic release of glycocalyx-derived damage-associated molecular patterns (DAMPs), intercellular separation, and increased microvascular permeability.

Additionally, a decrease in pH promotes the generation of reactive oxygen species (ROS), which, together with an increased number of leukocytes adhering to the endothelium, induce an increase in endothelial permeability.^24,25 As a result of increased vascular permeability, tight and adherens junctions between endothelial cells are disrupted, causing the extravasation of fluids, proteins, and inflammatory cells into the interstitial space, activating signaling pathways that lead to endothelial cell apoptosis or necrosis.²⁶

Large sodium and chloride loads over short periods have been implicated in glycocalyx degradation with the use of 0.9% saline boluses. In an experimental model using umbilical arteries, increasing serum sodium from 135 mEq/L to 150 mEq/L over five days resulted in a 50% reduction in glycocalyx thickness and a 130% increase in its stiffness.^27,28 This glycocalyx alteration was associated with a 68% reduction in heparan sulfate, the primary glycosaminoglycan of the endothelial glycocalyx. Furthermore, in preclinical models of hemorrhagic shock, acute hyperchloremia related to large boluses of unbalanced solutions has been associated with microcirculatory dysfunction due to vasoconstriction mediated by alterations in nitric oxide release.²⁹ Similarly, the osmotic gradient created by increased serum chloride levels can disrupt endothelial intercellular junction integrity, promoting capillary leakage and an increase in pro-inflammatory cytokines such as IL-6 and TNF-α, exacerbating endothelial damage and perpetuating the inflammatory cycle in sepsis.^28,29

Clinical and Experimental Evidence

Recently, Resuscitation-associated endotheliopathy (RAsE) has been described as a clinical entity characterized by worsening endothelial dysfunction resulting from acute resuscitative therapies administered in shock states. The use of non-balanced solutions in fluid resuscitation has been associated with acute hyperchloremia, renal artery vasoconstriction, and an increased frequency of acute kidney injury (AKI) in children.^18,30 A recent clinical trial comparing different fluid resuscitation strategies in 708 children with septic shock found a lower risk of new and/or progressive AKI in patients who received balanced solutions compared to 0.9% saline (21% vs 33%; RR 0.62, 95% CI: 0.49-0.80; p < 0.001).³¹

In preclinical models, aggressive volume expansion in endotoxemic shock has been associated with progression and exacerbation of endothelial and microcirculatory dysfunction.³² In children with sepsis, fluid resuscitation with non-balanced solutions has been linked to greater endothelial activation and glycocalyx degradation. The possible pathophysiological explanation is that the acidic pH of 0.9% saline, combined with its composition (40% more chloride than plasma), alters the endothelial microenvironment and promotes the progression of endothelial dysfunction in sepsis.¹⁹

Prevention and Treatment of Hypoalbuminemia

Physiological Aspects

Endothelial cells are covered by the endothelial glycocalyx (EGC), a dynamic structure composed of proteoglycans, glycosaminoglycans (GAGs), and glycoproteins.³³ The glycocalyx generally covers almost all cellular surfaces, where it plays a role in mediating cell-surface interactions with the extracellular matrix as well as with intracellular signaling molecules, proteins, and inflammatory cells. Under normal conditions, proteins such as albumin (ALB) interact with the glycocalyx and are essential for maintaining its structural integrity.³⁴

Structurally, albumin carries a negative charge at physiological pH, due to its high content of acidic amino acids (aspartic acid, glutamic acid). This characteristic causes albumin to be electrostatically repelled by the GAGs of the glycocalyx, which also carry a negative charge due to sulfhydryl radicals on their surface. In diseases such as sepsis, glycocalyx damage occurs due to the release of proinflammatory cytokines, the overproduction of reactive oxygen species (ROS), and inflammatory cell-induced damage. Activated monocytes/macrophages, neutrophils, and mast cells produce heparanases, hyaluronidases, and matrix metalloproteinases (MMPs) after contact with endothelial matrix proteins.³⁵ Heparanase cleaves heparan sulfate, and hyaluronidases degrade hyaluronan from proteoglycans, contributing to EGC damage and facilitating the adhesion of activated lymphocytes to the surface of endothelial cells, consequently allowing their migration into the interstitial space.^35,36

Albumin, the most abundant protein in plasma, plays key roles in maintaining colloid osmotic pressure, transporting substances, and regulating pH.³⁷ In the microcirculation, albumin helps regulate vascular permeability, modulate the inflammatory response, and has antioxidant functions. On average, the human intravascular space contains 4.0 g/dL of albumin, while the interstitial space contains 1.8 g/dL.³⁸ Under normal conditions, albumin crosses the endothelial cell from the intravascular to the interstitial space at a rate of approximately 5% of its plasma value per hour, a process known as the transcapillary escape rate (TER).³⁹ Subsequently, albumin returns to the intravascular space via the lymphatic system.

During inflammatory states, glycocalyx degradation and endothelial damage increase TER, causing leakage of fluids, proteins, cytokines, and cells from the intravascular to the interstitial space. This overwhelms the lymphatic system’s ability to return fluid and proteins, promoting edema formation and increasing interstitial negative pressure (from −1 mm Hg to −100 mm Hg), a phenomenon known as interstitial suction.⁴⁰ Clinically, this condition is referred to as capillary leak syndrome, which is characterized by tissue edema, relative hypovolemia, and multiple organ dysfunction syndrome (MODS).⁴¹

Relative hypoalbuminemia, caused by transcapillary albumin escape, may be exacerbated by sepsis treatments, such as dilutional effects from crystalloid bolus administration.¹⁸ Additionally, low serum albumin levels increase the free fraction of protein-bound drugs, reducing their efficacy, as seen with antibiotics and diuretics.⁴² Some studies have found that the effects of albumin administration may also depend on the simultaneous use of diuretics, which can prevent an albumin-induced increase in hydrostatic pressure. The simultaneous use of diuretics and hypoalbuminemia correction has been shown to increase diuresis induced by furosemide, improve oxygenation, and optimize fluid balance in patients with acute lung injury.^43-46

Experimental and Clinical Evidence

Hypoalbuminemia (serum albumin ≤ 3.0 g/dL) exacerbates endothelial damage in sepsis and is associated with worse outcomes and increased mortality.¹³ In this regard, Geng et al, in a recent systematic review and meta-analysis, found that albumin infusions at different concentrations were associated with improved survival in patients with septic shock compared to crystalloids.⁴⁷

There is frequent confusion regarding the indications for isooncotic albumin (5%) versus hyper-oncotic albumin (20%). The former is recommended for fluid boluses, while the latter is used for hypoalbuminemia correction. The Surviving Sepsis Campaign (SSC) in adults recommends fluid resuscitation with 5% albumin when high crystalloid volumes have been used and signs of hypoperfusion persist.⁴⁸

In the ALBIUS trial, hyper-oncotic albumin was used to maintain serum albumin levels above 3.0 g/dL throughout the ICU stay.⁴⁹ This strategy was associated with a lower odd of 28-day mortality in the sepsis subgroup. Additionally, in patients with acute kidney injury (AKI), hypoalbuminemia correction has been linked to a lower incidence of AKI,⁵⁰ and some researchers consider it a cost-effective intervention.⁵¹

In pediatric patients with sepsis, our group recently found that hypoalbuminemia was associated with increased levels of endothelial permeability biomarkers (angiopoietin-2), a heightened inflammatory response, and worse outcomes.¹³ Children who received hypoalbuminemia correction with 20% albumin infusions had shorter ICU stays and lower mortality.

In pediatric patients with a sepsis phenotype characterized by encephalopathy, persistent hypoxemia, and shock (PHES), the subgroup that received albumin supplementation (0.5 g/kg every 6 h to maintain levels above 2.5 g/dL) had improved survival compared to those who did not receive supplementation (75% vs 66%; p < 0.01).⁵² Patients with the PHES phenotype had higher inflammatory responses (ferritin >1000 ng/mL), coagulopathy, and hypoperfusion. It is possible that they experienced more severe endothelial dysfunction and loss of the anti-adhesive endothelial phenotype, which might explain why the subgroup receiving hypoalbuminemia correction had better outcomes. One hypothesis explaining this effect is that maintaining physiological albumin levels facilitates the transport of sphingosine-1-phosphate (S1P). This sphingolipid plays a crucial role in sepsis, as it inhibits MMP activity on the endothelial glycocalyx, modulates the inflammatory response, and reduces endothelial activation and glycocalyx degradation.⁵³

It is possible that in patients with PHES, hypoalbuminemia correction was associated with higher sphingosine-1-phosphate levels, leading to better clinical outcomes. However, prospective studies are needed to confirm this hypothesis, specifically evaluating endothelial response and sphingosine-1-phosphate levels in sepsis patients with the PHES phenotype.

Role of Fresh Plasma on the Endothelium and Its Glycocalyx

Physiological Aspects

Plasma consists of all the non-cellular components of blood, including albumin. Its use in fluid resuscitation in patients with sepsis is mainly based on preclinical studies in animal models and clinical data extrapolated from fluid resuscitation in sterile inflammatory conditions, such as children with polytrauma.^54-56 Plasma components, particularly albumin, have been associated not only with the restoration and maintenance of the glycocalyx and endothelium but also with modulating inflammation and oxidative stress.¹⁴

Some plasma components, such as high-density lipoproteins (HDL), facilitate the release of sphingosine-1-phosphate (S1P) from red blood cells and platelets, which suppresses the activity of matrix metalloproteinases (MMPs) on the endothelial glycocalyx and modulates the inflammatory response.^53-57 Additionally, S1P reduces oxidative stress and strengthens endothelial cell tight junctions.⁵⁴

Another plasma component that may help stabilize the microcirculation and endothelial activation in sepsis is the plasma protease “A Disintegrin and Metalloprotease with Thrombospondin Type 1 Motif, Member 13” (ADAMTS-13). In sepsis, endothelial activation occurs, leading to the release of von Willebrand factor (VWF), which can form large multimers (ULVWF) with a high protein-binding potential. Additionally, excessive thrombin generation results in a procoagulant state characteristic of sepsis.⁵⁸ By regulating the size of VWF multimers, ADAMTS-13 prevents excessive platelet aggregation and thrombus formation.⁵⁹

Some phenotypes in children with sepsis have been described, where ADAMTS-13 deficiency contributes to macrophage activation syndrome and MODS, with higher mortality and worse outcomes. Replacing this deficiency with ADAMTS-13 is another microcirculatory benefit of fresh plasma that has been demonstrated in preclinical models.⁶⁰ Additionally, plasma contains antithrombin and adiponectin, which have the potential to protect and restore the endothelial glycocalyx while also reducing inflammation, endothelial cell permeability, and leukocyte adhesion.^61,62 Specifically, adiponectin, a cytokine produced in adipose tissue, has notable antiinflammatory and vasoprotective effects, reducing endothelial permeability induced by TNF-α.^14,63

Experimental and Clinical Evidence

Considering the role of various plasma components in microvascular homeostasis, its use has been proposed in trauma and sepsis patients.^54,55 Current pediatric trauma guidelines recommend early and rapid transfusion of blood, plasma, and platelets to ensure adequate oxygen delivery, correct coagulopathy, and stabilize the microcirculation and endothelial damage. Several clinical trials are currently evaluating the impact of early plasma transfusion compared to standard care in terms of mortality and other key outcomes.⁶⁴

A secondary analysis of the PAMPer clinical trial in 405 adults with trauma found that fluid resuscitation with plasma may reduce inflammation and glycocalyx degradation in critically ill patients.⁶⁴ In preclinical models, fresh frozen plasma (FFP) administration has been shown to attenuate glycocalyx shedding, reduce vascular permeability, and decrease leukocyte adhesion.⁶⁵ Specifically, in shock resuscitation animal models, plasma use demonstrated better volume expansion, reduced pulmonary edema, and decreased inflammatory markers, endothelial injury, and catecholamine use compared to crystalloids.⁶⁶ A clinical trial in adults with trauma found that pre-hospital resuscitation with plasma was not associated with mortality differences if the time from injury to hospital admission was less than 20 min.⁶⁷ However, in settings where transport time after trauma was expected to exceed 20 min, a post hoc analysis of the PAMPer and COMBAT trials in adults found that using fresh plasma as the initial resuscitation fluid was associated with a 35% lower mortality risk.⁶⁸

Currently, limited clinical data exist evaluating the role of plasma in sepsis as a therapy to restore the microcirculation, endothelium, and glycocalyx. However, like in trauma, sepsis involves dysregulated inflammation, excessive sympathetic-adrenal activation, endothelial activation, and glycocalyx degradation, which have been recognized in critical illness as Shock-Induced Endotheliopathy (SHINE).⁶⁹

Thus, plasma has been proposed as a potential therapy in sepsis to stabilize the microcirculation and endothelial damage.⁷⁰ In a substudy of 33 critically ill, coagulopathic, nonbleeding patients, Straat et al¹⁴ analyzed inflammatory and endothelial biomarkers after FFP transfusion. Half of the patients had sepsis (n = 15) and organ failure. FFP administration reduced TNF-ɑ (11.3 vs 2.3 pg/mL) and syndecan-1 (675 vs 565 pg/mL) (p < 0.01), suggesting anti-inflammatory and protective effects on the endothelium and glycocalyx.

In both pediatric and adult patients who received plasma exchange for refractory septic shock, studies found organ failure recovery and lower mortality compared to historical controls.^71,72 However, its clinical impact in sepsis remains uncertain. Further studies are needed to clarify the role of plasma in microcirculatory stabilization and endothelial damage in sepsis.

Use of Inotropes and/or Vasodilators

Septic shock is characterized by abnormal vasodilation, hypovolemia, myocardial dysfunction, and impaired tissue perfusion. Resuscitation protocols include fluids, vasopressors, and inotropes to restore perfusion. Current guidelines recommend inotropes in cases of myocardial dysfunction, identified by low cardiac output, elevated filling pressures, or persistent hypoperfusion despite adequate fluids and vasopressors.⁷³ Evidence for their use is based on physiological studies suggesting macrocirculatory improvements, especially in patients with myocardial dysfunction. However, their effect on splanchnic circulation has been variable. Some studies suggest potential benefits on microvascular perfusion, independent of cardiac output.^74-79

Inotropes and vasodilators are therapeutic interventions used to restore tissue perfusion. Inotropes improve cardiac output and oxygen delivery, thus restoring aerobic metabolism.^73,77 On the other hand, inodilators are used in patients with myocardial dysfunction to enhance cardiac contractility and stroke volume. In vivo studies have shown their ability to improve blood flow perfusion.^74,75 Capillary recruitment has been described as the main mechanism linked to microcirculatory improvement, ultimately enhancing tissue perfusion in patients with microcirculatory impairment.¹⁰

Among inodilators, milrinone acts as a phosphodiesterase III (PDE-III) inhibitor, exerting positive inotropic and vasodilatory effects through increased cAMP concentrations.^74,75 Additionally, milrinone has been found to have immunomodulatory effects on cardiac myocyte signaling, reducing remodeling and oxygen consumption, which may also benefit the vascular endothelium.⁷⁴ In a preclinical study by De Miranda et al,⁷⁴ milrinone administration (0.5 to 1 μg/kg/min) reduced arteriolar vasoconstriction induced by lipopolysaccharides, improved capillary perfusion, and modulated the inflammatory response. In pediatric sepsis patients, milrinone has been associated with improved microcirculation parameters, better microvascular flow, increased capillary recruitment, and restoration of capillary density.⁷⁶ Sublingual videomicroscopy measurements also revealed reduced endothelial glycocalyx degradation.⁷⁶

On the other hand, dobutamine exerts mainly positive inotropic effects through β1-adrenergic stimulation in the heart, with milder vasodilatory effects mediated by β2 and α1-adrenergic receptors.⁷⁷ Its effects on microcirculation have been proposed based on preclinical septic shock models, where increased capillary recruitment and reduced arteriolar vasoconstriction have been observed.⁷⁷ In clinical practice, dobutamine at doses of 5 μg/kg/min has been shown to improve but not fully restore capillary perfusion in septic shock patients,^78,79 particularly in those with severe baseline microcirculatory alterations.

On the other hand, this local response has been explored to identify different phenotypes and microcirculatory reserve in states of hemodynamic compromise. Bertachi M et al⁸⁰ found that in 54 adult patients with circulatory shock, sublingual functional capillary density (FCD) was lower after initial resuscitation, despite having a similar cardiac index and mean arterial pressure compared to non-shock patients. However, their response to nitroglycerin was preserved, reaching FCD levels comparable to non-shock patients, suggesting dysfunction in intrinsic microcirculatory regulation mechanisms that could explain this inadequate response. These findings highlight the importance of assessing microcirculatory reserve beyond traditional hemodynamic parameters and suggest it could be a tool to identify patient phenotypes with greater microcirculatory impairment. Further studies are needed to clarify these findings.

Finally, Levosimendan acts by increasing Troponin-C sensitivity to intracellular calcium, enhancing myocardial contractility and, to a lesser extent, inducing vasodilation.⁸¹ Experimental studies indicate that this drug directly improves microcirculation and modulates the inflammatory response through negative regulation of NF-κB-dependent transcription.^82,83 Its effects on microcirculation have been confirmed in clinical studies conducted in septic shock patients at doses of 0.2 μg/kg/min.³³ Figure 2 summarizes the main strategies for managing microcirculatory dysfunction in sepsis.

Figure 2.

Strategies for the Stabilization of Microcirculation and Endothelial Glycocalyx in Sepsis. This figure represents the effects of different hemodynamic resuscitation strategies in patients with sepsis, highlighting their impact on microcirculation, vascular permeability, inflammatory state, and endothelial glycocalyx integrity.

Other Therapies

The pathophysiology of microcirculatory damage in sepsis is complex and multifactorial. Various strategies have been proposed to prevent and mitigate endothelial injury. Cui N et al investigated the mechanisms of sepsis-induced vascular hyperpermeability and the protective effect of glucocorticoids on the endothelium.⁸⁴ In an animal model, lipopolysaccharide (LPS) administration significantly increased MMP-2 and MMP-9 activity, reducing the levels of ZO-1 proteins and syndecan-1. Both dexamethasone and doxycycline inhibited MMP activity and restored ZO-1 and syndecan-1 expression, though dexamethasone had a stronger effect on syndecan-1 recovery. The authors concluded that MMP activation plays a key role in sepsis-induced endothelial disruption, and inhibiting these enzymes with dexamethasone and doxycycline may contribute to endothelial protection. De Oliveira et al⁸⁵ found that doxycycline may protect the EGC in an LPS-induced sepsis model, showing that its administration preserved EGC structure and reduced serum syndecan-1 levels. Additionally, doxycycline decreased vascular hyperpermeability, neutrophil transmigration, and improved microvascular parameters, suggesting potential therapeutic applications in sepsis patients.

Conclusion

Microcirculatory dysfunction in pediatric sepsis compromises tissue perfusion and cellular oxygenation, influencing clinical outcomes. Strategies such as resuscitation with balanced solutions, correction of hypoalbuminemia, and inotropic use have demonstrated benefits in stabilizing the microcirculation and preserving the endothelial glycocalyx. Additionally, fresh plasma use in sepsis has been shown to modulate inflammation and improve capillary perfusion. However, further clinical studies are needed to validate its impact on mortality and morbidity, as well as to develop real-time tools for assessing tissue perfusion, which could optimize pediatric septic shock treatment.