Can We RED-efine Hemodynamic Support in Pediatric Septic Shock? A Precision Medicine Approach

Abstract

Hemodynamic support in critically ill children with septic shock is one of the most common challenges faced by PICU practitioners. Cardiovascular involvement in sepsis includes both macro- and microcirculatory disturbances and the goals for both of these are enhancements in cardiac output and correction of tissue perfusion, respectively. Fluid resuscitation and vasopressors form the mainstay of management of circulatory disturbances in sepsis. Fluid boluses are commonly used as first-line treatments for both actual and relative hypovolemia. However, their use has resulted in numerous adverse events because of the composition, high volumes and rapid infusion rates, and individual patient variability in response. In many cases, they also only have transient efficacy or not at all. Vasoactive drugs are also commonly used late, which favors the use of repetitive fluid boluses with a risk of hypervolemia and tissue edema leading to worse outcomes. Active removal of fluids through diuresis or dialysis after the resuscitation phase is increasingly being used in children who get fluid therapy, but this is not standardized yet, and the safest strategies as well as their effectiveness have still not been reported in children. We believe these interventions for hemodynamic problems in sepsis offer an opportunity to tailor treatment and precision medicine strategies. Application through a phased approach adapted to each patient's context and clinical condition should improve outcomes. The proposed RED strategy is a simplified phased approach to managing patients with sepsis and septic shock: Resuscitation, Equilibrium, and De-escalation. The purpose of the introduction of this concept is to organize and underscore the fact that support for the cardiovascular system in sepsis is dynamic and should be adapted to each individual and context.  

Introduction

The complexity of the clinical presentation and the potential for catastrophic deterioration in septic shock, characterized by circulatory dysfunction, cellular metabolic abnormalities, and organ dysfunction, pose a great challenge in pediatric intensive care. Children, with their unique physiology, developing organ systems, and limited physiological reserves, are particularly vulnerable to the cardiovascular derangements associated with sepsis. Effective and timely hemodynamic support should be directed to restore adequate tissue perfusion, oxygen delivery, and cellular function to improve survival in these critically ill children and limit long-term morbidity. This article explores the intricacies of hemodynamic management in pediatric septic shock, as a way of examining limitations in current approaches and proposing a novel, phased strategy-Resuscitation, Equilibrium, and De-escalation (RED)-designed to personalize treatment with optimized outcomes, paving the way for precision medicine in this critical area of pediatric care.

The Cardiovascular Challenge in Pediatric Septic Shock: A Complex Interplay

Sepsis profoundly affects the cardiovascular system, affecting both the macrocirculation-involving large blood vessels and cardiac output and the microcirculation, which is the intricate network of small vessels responsible for tissue perfusion. Once this initial insult, typically an infection, occurs, it begins a cascade of inflammatory responses, involving the release of pro-inflammatory cytokines among other mediators. This inflammatory storm leads to a complex interplay of pathophysiological changes, including widespread vasodilation, increased capillary permeability with fluid leakage into tissues, and myocardial dysfunction or impairment of heart muscle contractility. These changes lead to a complex interplay of hypovolemia, reduced systemic vascular resistance, and impaired cardiac contractility, which ultimately compromise tissue perfusion, oxygen delivery, and cellular metabolism. The challenge lies in effectively addressing these interconnected abnormalities while minimizing the potential adverse effects of the interventions themselves.

Fluid Therapy: Balancing Benefits and Risks

Fluid therapy forms the backbone of initial resuscitation in pediatric septic shock. Rapid boluses of fluids are often used to correct real or apparent hypovolemia, with an intent to enhance preload and subsequently improve cardiac output. Fluid therapy in sepsis, however, is not without its own challenges and side effects. The outcome will depend on various factors, such as the type of fluid (crystalloids like normal saline or lactated Ringer's solution vs. colloids like albumin), volume and rate of infusion, and response in the individual patient. Additionally, fluid boluses often have only transient benefits, and most patients have limited or variable responses, especially at later stages of septic shock. It results in hypervolemia (fluid overload) and tissue edema, but it can get worse with increased morbidity and mortality through distress of the respiratory system, abdominal compartment syndrome, and so forth. The approach of "one size fits all" in fluid therapy is found to be quite inadequate, as there is an increasing need for more personalized and dynamic fluid management strategies.

Vasoactive Drugs: Timing, Choice, and Personalized Dosing

Vasoactive drugs, including vasopressors (e.g., norepinephrine, vasopressin) and inotropes (e.g., epinephrine, dobutamine), are critical for supporting circulation in septic shock, especially when fluid resuscitation alone is inadequate. Vasopressors increase systemic vascular resistance and improve blood pressure, whereas inotropes enhance cardiac contractility and increase cardiac output. The optimal timing of administration, the choice of specific agents, and the appropriate dosing strategies for these drugs are areas of active investigation and controversy. These drugs are often given relatively late in the course of resuscitation after multiple fluid boluses have been administered. This delay may contribute to repetitive fluid administration, which perpetuates hypervolemia and can lead to undesirable consequences. Earlier and wiser use of vasoactive drugs, along with hemodynamic assessment and judgment, may indeed reduce the extent of fluid overloading, mitigate fluid overload itself, and contribute to better outcomes. In this regard, particular vasoactive agents should ideally be chosen and tailored to specific patients' individual hemodynamic profiles and clinical backgrounds.

Fluid Removal: Navigating the De-escalation Phase and Managing Fluid Overload

In the subsequent refractory shock phase of septic shock, most patients undergo large volumes of fluid resuscitation. Fluid overload occurs as manifested clinically by signs like edema, ascites, or pleural effusions as well as objectified measures including increasing body weight and depressed oxygenation. Severe fluid overload requires active removal through diuresis (with diuretics) or dialysis for patients with deteriorating renal function. However, optimal strategies for fluid removal in pediatric septic shock are not standardized, and there is a lack of high-quality evidence to guide clinical practice. There is an urgent need for further research into the safest and most effective methods of fluid removal in children, taking into account the timing of intervention; the type and dose of diuretic or modality of dialysis, the patient's overall clinical condition; and the potential impact on electrolyte balance and renal function.

The RED Strategy: A Phased Approach to Hemodynamic Support in Pediatric Septic Shock

We propose the Resuscitation, Equilibrium, and De-escalation (RED) strategy as a simplified, phased approach to hemodynamic management in pediatric septic shock. This framework emphasizes the dynamic nature of cardiovascular support in sepsis and the need for individualized, context-adapted treatment, moving away from a "one-size-fits-all" approach.

• Resuscitation Phase: This initial phase focuses on rapid assessment and stabilization of the patient's hemodynamic status. Fluid therapy is administered judiciously to address hypovolemia, while vasoactive drugs are initiated early, as needed, to support blood pressure and cardiac output. The goals of this phase are to restore adequate tissue perfusion and oxygen delivery to vital organs, reverse shock, and prevent further deterioration. Monitoring of vital signs (heart rate, blood pressure, respiratory rate), urine output, capillary refill, and lactate levels (a marker of tissue hypoperfusion) helps guide the resuscitation process. The use of point-of-care ultrasound (POCUS) can be invaluable in assessing fluid responsiveness and guiding fluid therapy.

• Equilibrium Phase: Once the patient's hemodynamic status has stabilized and the shock has been reversed, the focus shifts to achieving a state of fluid and electrolyte equilibrium. Further fluid administration is carefully titrated based on ongoing assessment of the patient's fluid status, response to therapy, and evolving clinical picture. Vasoactive drug doses are adjusted to optimize cardiac output, systemic vascular resistance, and microcirculatory perfusion. This phase emphasizes careful monitoring and individualized fluid management to prevent both hypovolemia and hypervolemia, minimizing the risks of fluid overload and its associated complications.

• De-escalation Phase: As the patient's condition improves, the inflammatory response subsides, and organ function recovers, the need for hemodynamic support gradually decreases. Vasoactive drugs are carefully weaned, and fluid therapy is de-escalated. If fluid overload develops, active fluid removal through diuresis or dialysis is considered, guided by clinical assessment and objective measures of fluid status. This phase requires close monitoring to ensure that the patient remains hemodynamically stable during the de-escalation process, avoiding any rebound hypotension or worsening of perfusion.

Personalized Medicine and Precision Hemodynamic Support: Tailoring Therapy to the Individual Child

This approach allows for flexibility in personalizing hemodynamic support with the RED strategy in pediatric septic shock. By using clinical assessment and advanced monitoring techniques such as cardiac output monitoring, microcirculatory assessment, pulse contour analysis, and laboratory data (lactate, base deficit, mixed venous oxygen saturation), the clinician will tailor fluid and vasoactive drug therapy according to the patient's specific needs and evolving clinical context. Therefore, this hemodynamic status optimization via precision medicine will reduce side effects and then enhance outcomes. Much further research should be required to find the specific biomarkers or clinical parameters that, eventually, may predict a particular patient's response to a particular hemodynamic intervention, thereby allowing more precise and proactive adjustments in therapy.

Future Directions: Advancing the Field of Pediatric Hemodynamic Support

The field of hemodynamic support in pediatric septic shock is constantly evolving, driven by ongoing research and technological advancements. Several promising areas of research hold the potential to significantly improve outcomes for these critically ill children:

• Advanced Hemodynamic Monitoring: Developing and implementing more sophisticated and less invasive methods for assessing cardiac output, microcirculatory blood flow, and tissue oxygenation is crucial for guiding individualized therapy. Techniques such as pulse contour analysis, transpulmonary thermodilution, and near-infrared spectroscopy offer valuable insights into hemodynamic status and can help optimize fluid and vasoactive drug administration. Further research is needed to validate the use of these advanced monitoring tools in pediatric septic shock and to develop standardized protocols for their interpretation and application.

• Biomarkers of Sepsis and Hemodynamic Status: Identifying reliable and readily available biomarkers that can accurately predict the severity of sepsis, the patient's response to hemodynamic interventions, and the risk of complications is a critical area of investigation. Biomarkers such as lactate, procalcitonin, C-reactive protein, and various cytokines may provide valuable information about the inflammatory state and the adequacy of tissue perfusion. Integrating these biomarkers into clinical decision-making algorithms may allow for earlier and more targeted therapy.

• Personalized Fluid Management Strategies: Developing algorithms or protocols that integrate clinical data (e.g., vital signs, urine output, capillary refill), advanced hemodynamic monitoring data, and biomarker levels to guide individualized fluid therapy is essential for optimizing fluid resuscitation and preventing both under-resuscitation and over-resuscitation. These personalized fluid management strategies should take into account the patient's age, underlying medical conditions, and the specific phase of septic shock.

• Novel Vasoactive Drugs and Inotropes: Research into new vasoactive drugs and inotropes with improved efficacy, fewer side effects, and more targeted mechanisms of action is ongoing. The development of drugs that specifically target microcirculation and improve tissue perfusion is a particularly promising area of investigation.

• Clinical Trials of Fluid Removal Strategies: Conducting well-designed clinical trials to evaluate the safety and efficacy of different fluid removal strategies (e.g., diuretics, continuous renal replacement therapy) in pediatric septic shock is crucial. These trials should compare different fluid removal techniques, assess their impact on clinical outcomes, and identify the optimal timing and patient selection criteria for fluid removal.

• Artificial Intelligence and Machine Learning: The application of artificial intelligence and machine learning to hemodynamic management in pediatric septic shock holds great promise. These technologies can analyze vast amounts of data from various sources (e.g., electronic health records, vital signs monitors, laboratory data) to identify patterns, predict patient responses to therapy, and provide real-time decision support to clinicians.

Conclusion

Pediatric septic shock continues to be an important clinical challenge in hemodynamic support. However, the RED strategy, combined with personalized medicine, may introduce a promising framework that can enhance outcomes. The integration of clinical assessment, advanced techniques of monitoring, and ongoing research should strive for effective and more individualized care for these critically ill children that eventually ends with survival. The future of hemodynamic support in pediatric sepsis will be geared toward the pursuit of more knowledge, innovation, and tenacious dedication to the best possible care for our youngest and most fragile patients. With strong research underpinning the approach, along with technological advancement, precision medicine strategies will come into place and guide the path toward even more targeted and effective therapy, thus transforming the pediatric critical care landscape and holding hopes for better outcomes in this complex and life-threatening condition. The journey towards optimizing hemodynamic support in pediatric septic shock is an ongoing one, demanding continued collaboration between clinicians, researchers, and technology developers to translate scientific discoveries into tangible improvements in patient care.