Literature Review: Blood Pressure Targets in Pediatric Septic Shock
Introduction and Rationale
Pediatric septic shock remains a leading cause of morbidity and mortality worldwide, with outcomes heavily dependent on timely recognition and aggressive hemodynamic resuscitation. The optimal mean arterial pressure (MAP) target during resuscitation remains one of the most fundamental yet unresolved questions in pediatric critical care. 1 Current guidelines acknowledge this evidence gap, with the 2020 Surviving Sepsis Campaign unable to issue a recommendation about whether to target MAP at the 5th or 50th percentile for age in children with septic shock. 1 This uncertainty creates substantial practice variation and represents a critical research priority, as hemodynamic targets directly influence fluid administration, vasoactive medication dosing, and ultimately patient outcomes including mortality, organ dysfunction, and quality of life.
Pathophysiology of Shock and Blood Pressure in Children
Developmental Considerations in Pediatric Hemodynamics
Children possess unique physiological mechanisms that distinguish their hemodynamic responses from adults. The pediatric cardiovascular system compensates for hypovolemia and decreased cardiac output through vasoconstriction and tachycardia, making hypotension a late and ominous finding that often precedes cardiovascular collapse. 1 This compensatory capacity means that blood pressure alone is an unreliable endpoint for assessing adequacy of resuscitation in children. 1
The American College of Critical Care Medicine emphasizes that shock should be clinically diagnosed before hypotension occurs, using clinical signs including altered mental status, hypothermia or hyperthermia, peripheral vasodilation (warm shock), or vasoconstriction with capillary refill >2 seconds (cold shock). 1 Threshold heart rates associated with increased mortality in critically ill infants are <90 beats per minute or >160 bpm, and in children <70 bpm or >150 bpm. 1
Hemodynamic Patterns and Their Prognostic Significance
Orr and colleagues demonstrated that specific hemodynamic abnormalities in the emergency department correlate with progressive mortality: eucardia (1%) < tachycardia/bradycardia (3%) < hypotension with capillary refill <3 seconds (5%) < normotension with capillary refill >3 seconds (7%) < hypotension with capillary refill >3 seconds (33%). 1 Reversal of these hemodynamic abnormalities using recommended therapy was associated with a 40% reduction in mortality. 1
A landmark prospective observational study by Deep et al. (2008) revealed distinct hemodynamic patterns in fluid-resistant septic shock depending on etiology. 2 Central venous catheter-associated infections typically presented as "warm shock" (94% of cases) with high cardiac index and low systemic vascular resistance, while community-acquired sepsis predominantly showed normal or low cardiac index (86% of cases). 2 This heterogeneity suggests that a single blood pressure target may not be appropriate for all patients, and that individualized hemodynamic assessment is crucial.
The Cardiac Output Paradox
Low cardiac output—not low systemic vascular resistance—is independently associated with mortality in pediatric septic shock. 3 Approximately 58% of children with septic shock present with low cardiac output and high systemic vascular resistance, requiring combined inotropes and vasodilators rather than additional vasopressors. 3 About 22% exhibit low cardiac output and low systemic vascular resistance, necessitating both inotropes and vasopressors. 3 Only a minority present with the classic "warm shock" pattern of high cardiac output and low systemic vascular resistance. 3
This distribution challenges the traditional approach of targeting blood pressure alone, as continuing vasopressors in a low-output state increases afterload and worsens tissue perfusion. 3 Progressive cardiac dysfunction develops over time in fluid-refractory shock, accounting for the majority of persistent shock cases. 3
Current Guideline Recommendations on Hemodynamic Targets
Blood Pressure Targets: The Evidence Gap
The 2020 Surviving Sepsis Campaign explicitly states: "We were unable to issue a recommendation about whether to target mean arterial blood pressure (MAP) at the 5th or 50th percentile for age in children with septic shock and other sepsis-associated organ dysfunction." 1 This represents a critical knowledge gap, as the choice between these targets has profound implications for clinical management.
The American College of Critical Care Medicine (2009) recommends that emergency department therapies should be directed toward restoring normal mental status, threshold heart rates, peripheral perfusion (capillary refill <3 seconds), palpable distal pulses, and normal blood pressure for age. 1 However, "normal blood pressure for age" is not precisely defined—it could refer to the 5th percentile (below which hypotension is diagnosed) or the 50th percentile (median normal).
Comprehensive Hemodynamic Goals
The Society of Critical Care Medicine recommends targeting multiple hemodynamic parameters simultaneously: capillary refill ≤2 seconds, normal blood pressure for age, central venous oxygen saturation (ScvO2) >70%, cardiac index 3.3-6.0 L/min/m², and urine output >1 mL/kg/hour. 4 This multi-parameter approach recognizes that blood pressure is only one component of adequate tissue perfusion.
The 2020 guidelines suggest using advanced hemodynamic variables (cardiac output/cardiac index, systemic vascular resistance, ScvO2) when available, in addition to bedside clinical variables, to guide resuscitation. 1 They also recommend using trends in blood lactate levels, in addition to clinical assessment, to guide resuscitation, as persistent elevation may indicate incomplete hemodynamic resuscitation. 1
Clinical Assessment Limitations
The 2020 Surviving Sepsis Campaign suggests not using bedside clinical signs in isolation to categorize septic shock as "warm" or "cold." 1 This recommendation acknowledges the difficulty of accurately assessing hemodynamic patterns without objective measurements, particularly early in the disease process when therapeutic decisions are most critical. 2
Fluid Resuscitation Strategies and Their Relationship to Blood Pressure Targets
Initial Fluid Bolus Recommendations
Current guidelines universally recommend aggressive initial fluid resuscitation. The American Academy of Pediatrics and Society of Critical Care Medicine recommend beginning immediate resuscitation with 20 mL/kg isotonic crystalloid boluses (10 mL/kg in neonates) up to and exceeding 60 mL/kg within the first hour. 4 The American College of Critical Care Medicine suggests repeating boluses until perfusion improves, but stopping if rales or hepatomegaly develop, indicating fluid overload. 4
The 2020 International Consensus on Cardiopulmonary Resuscitation recommends an initial bolus of 20 mL/kg for infants and children with severe sepsis, with subsequent patient reassessment. 1 In healthcare systems with no availability of intensive care, if hypotension is present, the Surviving Sepsis Campaign suggests administering up to 40 mL/kg in bolus fluid (10-20 mL/kg per bolus) over the first hour with titration to clinical markers of cardiac output, discontinued if signs of fluid overload develop. 1
Fluid Type Selection
The Surviving Sepsis Campaign suggests using crystalloids rather than albumin for initial resuscitation (weak recommendation, moderate quality evidence), primarily based on cost considerations as outcomes are equivalent. 1 They suggest using balanced/buffered crystalloids rather than 0.9% saline (weak recommendation, very low quality evidence), and recommend against using starches (strong recommendation, moderate quality evidence) or gelatin (weak recommendation, low quality evidence). 1
Fluid Overload Concerns
Large fluid deficits can exist in the absence of hepatomegaly or rales, and initial volume resuscitation can require 40-60 mL/kg or more; however, if these signs are present, fluid administration should be ceased and diuretics should be given. 1 The American College of Critical Care Medicine suggests using diuretics to reverse fluid overload once shock resolves, and initiating continuous renal replacement therapy to prevent >10% total body weight fluid overload. 4, 3
The relationship between fluid volume and blood pressure targets is critical: higher MAP targets may drive more aggressive fluid administration, potentially increasing the risk of fluid overload and its associated complications including pulmonary edema, prolonged mechanical ventilation, and increased mortality.
Vasoactive Medication Selection and Timing
First-Line Vasoactive Agents
The 2020 Surviving Sepsis Campaign suggests using epinephrine or norepinephrine rather than dopamine in children with septic shock (weak recommendation, low quality evidence). 1 However, they explicitly state: "We were unable to issue a recommendation for a specific first-line vasoactive infusion for children with septic shock." 1
This recommendation is based on two randomized controlled trials. The first included 60 children and found that epinephrine was more likely than dopamine to achieve resolution of shock in the first hour (OR 4.8,95% CI 1.3-17.2, p=0.019), with lower sequential organ failure assessment scores on day 3 (8 versus 12, p=0.05). 1 The second double-blind RCT of 120 children with refractory septic shock found that dopamine administration was linked with increased risk of death and healthcare-associated infection compared with epinephrine. 1
Timing of Vasoactive Initiation
A critical question is when to initiate vasoactive medications relative to fluid resuscitation. The Society of Critical Care Medicine recommends beginning vasoactive infusions peripherally or via intraosseous access if central venous access is not immediately available, transitioning to central access as soon as feasible. 4 Cohort studies demonstrate that delay in the use of inotropic therapies is associated with major increases in mortality risk. 1
A prospective observational study by Karanvir et al. (2021) compared practices of initiating vasoactive infusions after the first (20 mL/kg), second (40 mL/kg), or third (60 mL/kg) fluid bolus. 5 Early initiation after the first bolus resulted in significantly less total fluid volume (40±10 mL/kg versus 70±10-20 mL/kg, p=0.02), less time to achieve hemodynamic stability (115±45 minutes versus 196-212 minutes, p=0.02), less fluid in the first 24 hours, and fewer complications. 5 No statistical difference in mortality was observed, though the study was not powered for this outcome. 5
A randomized trial by Fernández et al. (2022) compared early versus delayed epinephrine administration in 63 children with septic shock and hypotension. 6 All patients received 40 mL/kg of fluids during the first hour. Group 1 then received epinephrine infusion and maintenance fluids, while Group 2 received an additional 20 mL/kg before starting epinephrine. 6 Significant differences favoring early epinephrine included mortality (10% versus 33%, p=0.026, RR 3.1), need for mechanical ventilation (10% versus 41%, p=0.006, RR 4.0), and altered vascular hypoperfusion after one hour (7% versus 59%, p<0.001, RR 8.2). 6
Phenotype-Specific Vasoactive Selection
The choice of vasoactive agent should match the hemodynamic phenotype. For cold shock (low cardiac output, high systemic vascular resistance), dobutamine up to 10 µg/kg/min or escalation of epinephrine to 0.05-0.3 µg/kg/min is recommended to raise cardiac output, with addition of vasodilator therapy (milrinone, nitroprusside, prostacyclin) when blood pressure is adequate but cardiac output remains low. 3 For warm shock (high cardiac output, low systemic vascular resistance), vasopressin 0.03 U/min is recommended as a second-line agent when escalating norepinephrine doses are required. 3
Hemodynamic Monitoring Technologies
Advanced Monitoring Modalities
Point-of-care echocardiography assesses cardiac index, ventricular function, filling pressures, and detects mechanical complications. 3 Noninvasive cardiac output monitoring devices have enabled earlier hemodynamic assessment in shock, potentially informing choices for vasoactive drugs in fluid-resistant cases. 2
Central venous oxygen saturation (ScvO2) <70% confirms inadequate oxygen delivery. 3 The Society of Critical Care Medicine suggests targeting ScvO2 >70% during resuscitation, with hemoglobin of 10 g/dL when ScvO2 is <70%, and 7 g/dL after stabilization. 4, 3
Lactate-Guided Resuscitation
Lactate-guided resuscitation has been consistently shown to be effective. 7 The Surviving Sepsis Campaign recommends using trends in blood lactate levels, in addition to clinical assessment, to guide resuscitation. 1 However, the 2020 guidelines were unable to issue a recommendation about using blood lactate values to stratify children into low- versus high-risk categories. 1
The American College of Critical Care Medicine continues to recommend early recognition of pediatric septic shock using clinical examination, not biochemical tests, though two committee members dissented and suggested using lactate as well. 1 This reflects ongoing debate about the role of lactate in initial assessment versus ongoing monitoring.
Limitations of Current Monitoring
Despite technological advances, the 2020 Surviving Sepsis Campaign identified the need for randomized controlled trials comparing specific hemodynamic targets (>5th versus >50th mean arterial pressure percentile) and lactate-guided resuscitation. 1 The lack of such trials represents a critical gap in the evidence base for pediatric septic shock management.
Refractory Shock Management
Definition and Epidemiology
Refractory shock is defined as persistent hypotension and tissue hypoperfusion despite goal-directed use of inotropes, vasopressors, vasodilators, and maintenance of metabolic and hormonal homeostasis. 3 In pediatric septic shock, refractory shock develops in roughly one-third of patients despite aggressive fluid resuscitation and catecholamine therapy. 3
Refractory shock persisting despite five vasopressor/inotropic agents indicates failure to maintain metabolic/hormonal homeostasis, inadequate correction of the underlying hemodynamic phenotype, or progression to irreversible organ dysfunction that may require mechanical circulatory support. 3
Metabolic and Hormonal Corrections
Hypoglycemia impairs cellular energy metabolism and diminishes catecholamine responsiveness. 3 Hypocalcemia reduces myocardial contractility and vascular smooth-muscle tone, blunting vasopressor effectiveness. 3 Severe metabolic acidosis (pH <7.2) produces catecholamine resistance and worsens myocardial function. 3
The American College of Critical Care Medicine recommends administering hydrocortisone within 60 minutes for fluid-refractory, catecholamine-resistant shock with suspected or proven absolute adrenal insufficiency. 3 Initial stress dose is 50 mg/m²/24 hours as continuous infusion, with approximately 25% of children with septic shock having absolute adrenal insufficiency. 3 Relative adrenal insufficiency in patients with cirrhosis is linked to higher risk of septic shock and need for high-dose vasopressors. 3
Mechanical Circulatory Support
The Extracorporeal Life Support Organization recommends considering ECMO for refractory pediatric septic shock or respiratory failure. 1, 3 Survival rates are 73% for newborns and 39% for older children, with venovenous ECMO having the highest survival rates. 1, 3 Venoarterial ECMO is useful in children with refractory septic shock, with one center reporting 74% survival to hospital discharge using central cannulation via sternotomy. 1
The American College of Critical Care Medicine recommends initiating ECMO support while simultaneously administering stress-dose hydrocortisone for suspected adrenal insufficiency, and considering vasodilator therapy if the hemodynamic profile shows low cardiac output with high systemic vascular resistance. 3
Special Populations
Neonatal Considerations
Standard practices in resuscitation of preterm infants use a more graded approach to volume resuscitation and vasopressor therapy compared with term neonates and children. 1 This cautious approach responds to concerns that preterm infants at risk for intraventricular hemorrhage (<30 weeks gestation) can develop hemorrhage after rapid shifts in blood pressure, though some now question whether long-term neurologic outcomes relate more to periventricular leukomalacia (from prolonged underperfusion) than to intraventricular hemorrhage. 1
The American Academy of Pediatrics recommends using smaller fluid boluses (10 mL/kg) and beginning prostaglandin infusion until ductal-dependent lesion is ruled out in neonates. 4 The Society of Critical Care Medicine suggests using dopamine 5-9 mcg/kg/min plus dobutamine up to 10 mcg/kg/min as first-line inotropes, escalating to epinephrine 0.05-0.3 mcg/kg/min if dopamine-resistant. 4
Relative initial deficiencies in thyroid and parathyroid hormone axes have been reported and can result in need for thyroid hormone and/or calcium replacement. 1 Randomized controlled trials showed that prophylactic hydrocortisone on day 1 of life reduced incidence of hypotension, and a 7-day course reduced need for inotropes in very low birth weight infants with septic shock. 1
Resource-Limited Settings
In healthcare systems without intensive care availability, the Surviving Sepsis Campaign provides modified recommendations, suggesting up to 40 mL/kg in bolus fluid over the first hour with titration to clinical markers of cardiac output, discontinued if signs of fluid overload develop. 1 This acknowledges that optimal management strategies may differ based on available resources and monitoring capabilities.
Quality Improvement and Systematic Management
Screening and Early Recognition
The 2020 Surviving Sepsis Campaign suggests implementing systematic screening for timely recognition of septic shock and other sepsis-associated organ dysfunction (weak recommendation, very low quality evidence). 1 Systematic screening needs to be tailored to the type of patients, resources, and procedures within each institution, with evaluation for effectiveness and sustainability incorporated as part of the process. 1
The Surviving Sepsis Campaign identifies shock by decreased mental status, capillary refill >2 seconds, weak pulses, cool extremities, tachycardia, and hypotension (though hypotension is a late finding). 4
Protocol-Driven Care
The Surviving Sepsis Campaign recommends implementing a protocol/guideline for management of children with septic shock or other sepsis-associated organ dysfunction (best practice statement). 1 However, recent evidence suggests a paradigm shift from "protocolized care" to "individualized physiology-based care," mirroring the general trend in critical care toward more conservative approaches in fluids, ventilation, transfusion, antibiotics, and insulin. 8
This shift reflects growing recognition that rigid protocols may not account for the heterogeneity of hemodynamic patterns and individual patient responses. The inability of early goal-directed therapy (EGDT) to demonstrate superiority over "usual care" in adult trials has influenced pediatric practice, though pediatric-specific trials are lacking. 9
Research Gaps and Future Directions
Identified Research Priorities
The 2020 Surviving Sepsis Campaign identified at least 29 pathophysiology questions and 23 randomized controlled trials needed to address evidence gaps. 1 Specific to hemodynamic targets, they identified the need for trials comparing specific hemodynamic targets (>5th versus >50th mean arterial pressure percentile) and lactate-guided resuscitation. 1
Other critical research questions include: defining optimal level of hyperlactatemia, identifying clinical markers of cardiac output to guide fluid resuscitation, determining the choice of first-line vasoactive infusion, establishing optimal threshold for continuous vasopressin infusion, and evaluating use and effects of inodilators. 1
Methodological Considerations for Non-Inferiority Trials
A non-inferiority trial comparing two blood pressure targets must carefully define the non-inferiority margin based on clinically meaningful differences in patient-centered outcomes. The primary outcome should focus on mortality, organ dysfunction, or quality of life rather than surrogate hemodynamic endpoints. 1
Sample size calculations must account for the relatively low mortality rate in pediatric septic shock in high-resource settings (though mortality remains high in resource-limited settings), requiring large sample sizes to demonstrate non-inferiority. Multi-center collaboration will be essential to achieve adequate enrollment. 1
The trial design must address the heterogeneity of hemodynamic patterns by either stratifying randomization by phenotype (warm versus cold shock, community-acquired versus catheter-associated) or including hemodynamic phenotype as a covariate in analysis. 2 Blinding of blood pressure targets is challenging but could be achieved through use of a hemodynamic management team separate from bedside clinicians.
Outcome Measures
Primary outcomes should prioritize mortality, organ dysfunction scores, and quality of life measures. 1 Secondary outcomes might include time to shock resolution, total fluid volume administered, incidence of fluid overload, duration of mechanical ventilation, length of intensive care unit stay, and healthcare-associated infections. 5, 6
Long-term follow-up is essential to assess neurodevelopmental outcomes, particularly in neonates where concerns about intraventricular hemorrhage versus periventricular leukomalacia remain unresolved. 1 Quality of life assessments should extend beyond hospital discharge to capture functional outcomes relevant to patients and families.
Theoretical Framework for Blood Pressure Target Selection
Arguments for Lower (5th Percentile) Targets
Targeting the 5th percentile MAP (the threshold for defining hypotension) may reduce unnecessary fluid administration and vasoactive medication exposure. Given that shock can be present with normal blood pressure, and that clinical signs of perfusion are more sensitive than blood pressure for detecting shock, a lower target might be sufficient if other perfusion parameters are optimized. 1
Lower targets may reduce the risk of fluid overload and its associated complications. The evidence that early initiation of vasoactive medications (after 20-40 mL/kg fluid) improves outcomes suggests that achieving higher blood pressure targets through excessive fluid administration may be harmful. 5, 6
Arguments for Higher (50th Percentile) Targets
Targeting the 50th percentile MAP (median normal for age) may ensure adequate perfusion pressure to vital organs, particularly in the setting of impaired autoregulation during septic shock. Higher perfusion pressure might prevent progression to refractory shock and reduce the risk of periventricular leukomalacia in neonates from prolonged underperfusion. 1
The observation that reversal of hemodynamic abnormalities using aggressive therapy was associated with 40% reduction in mortality suggests that achieving normal (not just minimally acceptable) hemodynamics may be beneficial. 1 However, this must be balanced against the risks of aggressive fluid resuscitation and high-dose vasoactive medications.
The Role of Individualized Targets
The heterogeneity of hemodynamic patterns in pediatric septic shock argues against a one-size-fits-all approach. 2 Patients with warm shock and high cardiac output may tolerate lower MAP targets, while those with cold shock and low cardiac output may require higher targets to maintain adequate perfusion pressure. 3
Advanced hemodynamic monitoring enabling assessment of cardiac output, systemic vascular resistance, and tissue oxygen delivery may allow for more precise titration of therapy to individual patient physiology rather than arbitrary blood pressure targets. 1, 9 However, such monitoring is not universally available, particularly in resource-limited settings where septic shock mortality is highest.
Clinical Implications and Practice Recommendations
Current Best Practice Pending Trial Results
In the absence of definitive evidence comparing MAP targets, current practice should focus on multi-parameter assessment of perfusion rather than blood pressure alone. 1, 4 Clinicians should target restoration of normal mental status, threshold heart rates, capillary refill <2 seconds, palpable distal pulses, ScvO2 >70%, cardiac index 3.3-6.0 L/min/m², urine output >1 mL/kg/hour, and normalization of lactate. 1, 4
Fluid resuscitation should begin with 20 mL/kg boluses (10 mL/kg in neonates) up to 40-60 mL/kg in the first hour, with vasoactive medications initiated early (after 20-40 mL/kg) rather than waiting for completion of large-volume resuscitation. 4, 5, 6 Epinephrine or norepinephrine are preferred over dopamine as first-line agents. 1
Frequent reassessment is essential, as hemodynamic phenotypes commonly evolve during the first 48 hours of shock. 3 Therapy must be adjusted based on ongoing assessment of cardiac output and systemic vascular resistance, adding vasodilators when blood pressure is adequate but cardiac output remains low, and escalating vasopressors when cardiac output is adequate but systemic vascular resistance is low. 3
Critical Pitfalls to Avoid
Do not continue escalating vasopressors beyond 60 minutes without reassessing the hemodynamic phenotype and correcting metabolic/hormonal abnormalities. 3 Avoid using vasopressors alone in low-output states, as this raises afterload and worsens perfusion. 3 Do not assume a single hemodynamic phenotype persists; frequent reassessment is essential because phenotypes may transition during shock evolution. 3
Do not rely solely on blood pressure normalization—complement with multiple perfusion markers and clinical assessment. 7 Do not delay vasoactive medication initiation while pursuing large-volume fluid resuscitation, as this increases fluid overload risk and time to shock resolution. 5, 6
Monitoring for Complications
Signs of fluid overload that should limit further fluid bolus therapy include clinical signs of pulmonary edema or new or worsening hepatomegaly. 1 The American College of Critical Care Medicine recommends using diuretics to reverse fluid overload once shock resolves, and initiating continuous renal replacement therapy to prevent >10% total body weight fluid overload. 4, 3
Drug toxicity monitoring should be intensified during severe sepsis, as drug metabolism is reduced, increasing risk of adverse events. 3 Particular attention should be paid to ionized calcium, glucose, and arterial blood gas to identify correctable metabolic derangements. 3
Conclusion Regarding Trial Design
A non-inferiority trial comparing MAP targets at the 5th versus 50th percentile for age in pediatric septic shock addresses a critical evidence gap explicitly identified by the 2020 Surviving Sepsis Campaign. 1 The trial should be designed as a multi-center randomized controlled trial with mortality, organ dysfunction, and quality of life as primary outcomes, powered to demonstrate non-inferiority with a clinically meaningful margin.
The trial must incorporate advanced hemodynamic monitoring to characterize phenotypes, stratify or adjust for hemodynamic patterns, and ensure that both arms achieve adequate tissue perfusion as assessed by multiple parameters beyond blood pressure alone. 1, 2, 9 Long-term follow-up is essential to capture neurodevelopmental outcomes and quality of life.
Given the evidence that early vasoactive medication initiation improves outcomes, both trial arms should follow current best practice of initiating vasoactive support after 20-40 mL/kg fluid resuscitation rather than pursuing large-volume resuscitation to achieve blood pressure targets. 5, 6 This will isolate the effect of the MAP target itself from the effect of timing of vasoactive medication initiation.
The results of such a trial have the potential to significantly impact clinical practice by either validating a more conservative approach (5th percentile target) that may reduce fluid overload and vasoactive medication exposure, or confirming the need for higher targets (50th percentile) to ensure adequate organ perfusion and prevent progression to refractory shock. 1 Either result would provide much-needed evidence to guide one of the most fundamental decisions in pediatric septic shock management.