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Updates on pediatric sepsis

Abstract Sepsis, defined as an infection with dysregulated host response leading to life‐threatening organ dysfunction, continues to carry a high potential for morbidity and mortality in children. The recognition of sepsis in children in the emergency department (ED) can be challenging, related to the high prevalence of common febrile infections, poor specificity of discriminating features, and the capacity of children to compensate until advanced stages of shock. Sepsis outcomes are strongly dependent on the timeliness of recognition and treatment, which has led to the successful implementation of quality improvement programs, increasing the reliability of sepsis treatment in many US institutions. We review clinical, laboratory, and technical modalities that can be incorporated into ED practice to facilitate the recognition, treatment, and reassessment of children with suspected sepsis. The 2020 updated pediatric sepsis guidelines are reviewed and framed in the context of ED interventions, including guidelines for antibiotic administration, fluid resuscitation, and the use of vasoactive agents. Despite a large body of literature on pediatric sepsis epidemiology in recent years, the evidence base for treatment and management components remains limited, implying an urgent need for large trials in this field. In conclusion, although the burden and impact of pediatric sepsis remains substantial, progress in our understanding of the disease and its management have led to revised guidelines and the available data emphasizes the importance of local quality improvement programs.

the disease and its management have led to revised guidelines and the available data emphasizes the importance of local quality improvement programs.

K E Y W O R D S
antibiotic management, fluid resuscitation, pediatric, sepsis, sepsis risk factors, septic shock, severe sepsis

INTRODUCTION AND EPIDEMIOLOGY
Sepsis contributes to 19% of all deaths globally, with the highest agespecific incidence in children younger than 5 years of age. 1,2 Pediatric sepsis resulted in 0.7% of all hospital encounters, with an incidence of 2.8% in inpatients in the United States. 3 Epidemiologic studies using clinical data have found an incidence of pediatric sepsis in up to 8% of all pediatric intensive care unit (PICU) admissions, 4 contributing to 1 in 4 deaths in PICUs. 5 Accurate estimates of pediatric sepsis are hampered by inaccuracies of diagnostic coding, resulting in gross underreporting; at the same time, increasing sepsis awareness may lead to identification earlier in the disease process, with resultant increases in apparent survival rates. 6 To address this, novel sepsis surveillance criteria derived from electronic health record data have been proposed. 7,8 Risk factors for sepsis and the most common sites and pathogens associated with sepsis are described in Tables 1 9-11 and 2, 3,10,11 respectively. In 1 US multicenter study, the most common pathogens affecting previously healthy children were Staphylococcus aureus (9.4%), streptococcal species (7.9%), and Escherichia coli (7.1%), whereas the most common pathogens in children with chronic diseases were S. aureus (11%), Candida (9.8%), and Pseudomonas (8.1%). 12 Similar patterns have been observed in recent population-based studies in other countries and contrast with the predominance of meningococcal infections observed in previous decades. 5,13 More than one-third of children with sepsis do not have an identifiable pathogen. This may be attributed to sepsis being caused by viral etiologies or because of the limits in detection of bacterial pathogens, particularly if the volume inoculated into blood cultures is low or if the pathogens are fastidious or have specific growth requirements. Table 3 summarizes the most common pathogens by site of infection in non-resource-limited settings. 12

DEFINITIONS
Historically, the term sepsis (from Greek "sepsin," meaning "rot, make putrid") has been used to characterize life-threatening infections usually caused by bacterial pathogens if untreated progress to shock and death. 14 (Table 4). [15][16][17] Although SIRS criteria have been used in many EDs to assist in the

SEPSIS BUNDLES AND QUALITY IMPROVEMENT INITIATIVES
Failure to recognize sepsis increases the risk of morbidity and mortality, as illustrated by the case of Rory Staunton, a 12-year-old boy who died of initially unrecognized streptococcal sepsis. 20 A year after Rory's death, "Rory's Regulations" were passed, 21 requiring all New York hospitals to implement evidence-based protocols to facilitate early recognition of sepsis through screening tools, identify individuals who qualified for sepsis care, and implement guidelines for sepsis management through bundled care, consisting of protocols to assist in sepsis recognition and subsequently prompt initiation of fluid resuscitation, parenteral antibiotics, and obtaining blood cultures. Multiple studies demonstrated an improvement in in-hospital mortality rates after bundled sepsis care in both children 22 and adults. 23 In addition to legislative efforts, US children's hospitals have collaborated to enhance multicenter quality improvement activities in pediatric sepsis.
The largest of these efforts is the ongoing Improving Pediatric Sepsis Outcomes Collaborative through the Children's Hospital Association and involves >50 hospitals across the United States. 24 The benefits of early recognition, treatment, and reversal of shock using bundled sepsis care extend beyond reductions in mortality. 22,23,25 Multiple pediatric studies have demonstrated decreased hospital length of stay after implementation of bundled care 26,27 and reductions in the rates of acute kidney injury. 28 Delays in receipt of antimicrobial therapy are associated with increased mortality, with children who experienced antibiotic delays of more than 3 hours having an almost 4-fold risk of mortality in the PICU. 29 Other studies have found that each additional hour of persistent shock is associated with a >2-fold increased odds of mortality. 30 Ultimately, many pediatric studies have evaluated the relationship between the timing of antibiotic administration and fluid resuscitation through protocol-driven care and patient-level outcomes, 22,[25][26][27][28] driving ongoing revisions to institutional, national, and international guidelines.

DIAGNOSIS
Early diagnosis is critical to reversing shock. Barriers to recognition include age-related variation in vital signs (resulting in failure to recognize abnormal vital signs), hypotension being a late manifestation, a relatively low prevalence of pediatric sepsis in EDs in high-income countries, and alternative explanations for abnormal vital signs (fever or crying contributing to tachycardia or tachypnea). There are also associated challenges in identifying which children meeting SIRS criteria may be at risk for sepsis. As such, we review triage-based and laboratory-based tools that may optimize sepsis recognition.

Triage-based recognition
Rapid, systematic identification of children with sepsis is paramount to initiating timely interventions. Without this critical step, delays in care may impact morbidity and mortality. In 2017, the American College of Critical Care Medicine (ACCCM) on Pediatric and Neonatal Septic Shock emphasized the importance of triggers or screening tools to rapidly identify patients with septic shock. 31 In 2020, the first Pediatric Surviving Sepsis Campaign (SSC) international guidelines extended the goal of identification to non-cardiovascular dysfunction. 17 The clinical signs of those at risk for pediatric sepsis are largely based on the presence of suspected infection and abnormal physical examination findings such as perfusion abnormalities, altered mental status, hypotension, temperature abnormality (fever or hypothermia), and tachycardia. 31,32 A pragmatic screen/alert should be based on these readily identifiable and available parameters. Incorporating a sepsis screen into the triage process is efficient and identifies most patients with sepsis. 25 In 1 ED study, moving from a paper-based to an electronic health record process significantly decreased time to recognition. 33 The significant mortality and morbidity associated with pediatric sepsis drives the inherent balance of sensitivity versus specificity of all screening models to favor sensitivity at the cost of specificity. However, this results in a low positive predictive value, and balancing measures related to false positive alerts and the potential for alert fatigue need to be considered. Design should consider institution-specific characteristics (ie, tertiary/quaternary vs rural or community setting, acuity, healthcare workers awareness/sensitivity to sepsis) 17,34 and can include temperature-corrected heart and/or respiratory rate, 35,36 agebased vital sign adjustments, 33,[36][37][38][39] and the inclusion of high-risk conditions. 25,33,37 Some of the earliest adopters of sepsis screening in pediatric EDs primarily leveraged vital sign abnormalities to identify patients with possible sepsis (Table 5). [35][36][37][38][39][40] An ideal pediatric sepsis screening process should be efficient, initiated at first contact with the patient, incorporate reassessment/identification throughout the visit, and harness the strength of the electronic health record. The screen should incorporate pertinent vital sign and clinical parameters, recognize children with high-risk conditions, involve a care team huddle/bedside assessment, and be monitored by a dedicated quality improvement team.
Because clinician assessment can significantly improve screening performance, a 2-step process consisting of a screening tool prompting timely medical evaluation has the potential to combine the advantages in terms of the sensitivity and specificity of both steps. 37,41 Performing a 2-step screening process is well aligned with other care processes in the ED setting and is effective. 25

Laboratory-based diagnostics
A WBC count ≥15,000 cells/µL was historically used to identify febrile young children at higher risk of occult bacteremia. 42 However, studies conducted in the post-pneumococcal conjugate vaccine era have demonstrated that WBC count has poor test characteristics for bacterial infections across age groups and that no single cut-off value has a sufficient sensitivity or specificity for clinical utility. [43][44][45][46] Although elevated absolute band count >1500 cells/µL has high specificity (>90%) for bacterial infections, the sensitivity is very low (<30%). 45,47 Similarly, an absolute neutrophil count >10,000 cells/µL has moderate to high specificity (78%-88%) but poor sensitivity (<50%) for bacterial infection when used in isolation. [44][45][46] The absolute neutrophil count is part of the step-by-step approach and Pediatric Emergency Care Applied Research Network (PECARN) prediction rule to identify febrile infants ≤60 days of age at low risk of bacterial infections (Table 6). 48,49 C-reactive protein is often integrated into identification of febrile infants with bacterial infections. A C-reactive protein cut-off of 2 mg/dL has moderate sensitivity (88%) and specificity (60%) for identification of febrile children with bacterial infections, with higher levels (eg, >8 mg/dL) having higher specificity. 50 Other studies have found lower diagnostic utility for C-reactive protein used in isolation to identify septic children. 51,52 Yet all of these laboratory parameters have low positive predictive value for predicting sepsis.
Procalcitonin (PCT) has the most favorable test characteristics for the identification of children with bacterial infections, particularly for invasive bacterial infection (IBI) (bacteremia and/or bacterial meningitis). 45,53 Among febrile infants ≤60 days of age, a PCT level of <0.5 ng/mL should be used in combination with other clinical and laboratory parameters to identify infants at low risk of IBI (Table 6). 48,49 For febrile older children, a PCT level of >0.5 ng/mL has low sensitivity (55%) and moderate specificity (85%) for bacterial infections, although its sensitivity is higher for IBI (82%). 53 A PCT level of >2 ng/mL has low sensitivity (61%) for IBI but high specificity (94%) and can be used to identify febrile children at higher risk of sepsis. 53 PCT use in adults with suspected sepsis has demonstrated

TA B L E 6
Step-by-step approach and PECARN prediction rule for identification of well-appearing febrile infants with bacterial infections Step-by-step approach PECARN prediction rule

Novel biomarkers and sepsis phenotypes
The complexity of pediatric sepsis makes it unlikely that any single biomarker in isolation will have sufficient diagnostic or prog-  Table 7). 17 For most of the guidelines, there were inadequate data to make strong recommendations in support of or against various interventions, reflecting the paucity of randomized trials in the field of pediatric sepsis. The guidelines are based on systematic literature review followed by rigorous evaluation of the evidence and discussion in the expert panel to provide guidance for most scenarios relevant to ED management.

General management
The

Antibiotic management
Empiric antibiotic therapy should be initiated as quickly as possible for children with sepsis. Empiric broad spectrum parenteral agents should be administered based on the child's age, presenting features/focus of infection, comorbidities such as immunocompromise, and local epidemiology in relation to disease prevalence and antimicrobial resistance patterns. One approach for empiric antibiotics based on the presumed site of infection and a child's comorbid medical conditions is described in Table 8. 17,[67][68][69] Antibiotics should be administered as soon as possible, ideally within an hour of the recognition of septic shock. 17 This recommendation is based on the observational data demonstrating improved survival associated with early antibiotics in cohorts of children with a predominance of septic shock. 22,29,70,71 Antibiotic administration should follow blood culture sampling, but not be delayed while awaiting the collection or results of diagnostic testing, including lumbar puncture, in children with shock. In practice, however, many children presenting to EDs being evaluated for sepsis are not in shock, and sepsis may represent one of several diagnostic options. In children without shock, the SSC panel considered the benefits of rapid antibiotic administration with balancing measures related to the exposure of non-septic children to potentially unnecessary antibiotics. 72 In children with sepsis without shock, the 2020 SSC recommends starting antimicrobial therapy after appropriate evaluation and within 3 hours of recognition. Endocrine and metabolic Do not use IV hydrocortisone in children with septic shock responding to fluids and/or vasopressor therapy. No recommendation regarding the use of IV hydrocortisone in refractory shock Do not use insulin to target lower blood glucose levels Consider early enteral nutrition Note. Adapted from Weiss et al. 17 Abbreviations: ARDS, acute respiratory distress syndrome; BPS, best practice statements; iNO, inhaled nitric oxide; IV, intravenous; PEEP, positive endexpiratory pressure. a Weak recommendation, very low-quality evidence. b In most US settings, intensive care support therapies such as inotropes or ventilation can, at least temporarily, be administered in the emergency department and ward environments even in facilities with no on-site ICU; this recommendation is indicated for settings where no such support can be provided. Normal saline, lactated Ringer's, and to a lesser extent PlasmaLyte are the most commonly used isotonic fluids in pediatric sepsis. The administration of normal saline results in a hyperchloremic metabolic acidosis that can exacerbate the acidosis already common in sepsis and has been associated with decreased renal perfusion and increases in morbidity. [74][75][76] Balanced fluids have been demonstrated to reduce acute and persistent kidney injury and mortality in adults with sepsis. 77 For these reasons, the new pediatric SSC recommendations suggest using balanced fluids for initial resuscitation, acknowledging that TA B L E 8 Empiric antimicrobial coverage in children with sepsis a

Group Regimen Notes
Previously healthy Third-generation cephalosporin + vancomycin Can use cephalosporin monotherapy in regions with minimal MRSA or resistant pneumococci; consider adding an aminoglycoside in regions with substantial ceftriaxone resistance among Gram-negative organisms Immunocompromise Vancomycin + anti-pseudomonal cephalosporin (eg, cefepime) or extended-range PCN/Beta-lactamase combination (eg, piperacillin-tazobactam) or a broad-spectrum carbapenem (eg, meropenem) Vancomycin and cefepime has been associated with less AKI in adults than vancomycin combined with an extended-range PCN/Beta-lactamase combination

Central venous catheter
Vancomycin + anti-pseudomonal cephalosporin (eg, cefepime) or extended-range PCN/Beta-lactamase combination (eg, piperacillin-tazobactam) or a broad-spectrum carbapenem (eg, meropenem) further pediatric data are needed to ascertain the optimal fluid for resuscitation of children with sepsis. 78 The group recommended against the administration of blood products for non-bleeding children who were not anemic (hemoglobin ≥7 g/dL), as data do not support empiric administration of packed RBCs, platelets, or plasma in improving outcomes in this group.
Epinephrine or norepinephrine are recommended as first-line vaso-

Near-infrared spectroscopy
The microcirculatory changes of sepsis precede diversion of blood  88 However, the utility of StO2 in pediatric sepsis has not been well studied. The potential for StO2 as a resuscitation target in sepsis and incorporation into a risk score along with other predictor variables are possible avenues for future investigation.

Respiratory support
Many children will respond to initial sepsis therapy. and optimize oxygenation, and best practices for pediatric acute respiratory distress syndrome including prone positioning and consideration for ECMO in cases of refractory respiratory failure should be followed. 79

OUTCOMES
Recent studies from high-income countries indicate that ≈3%-7% of children with sepsis presenting to EDs die, with mortality rates increasing to up to 20% for those with septic shock treated in PICUs. 1,9,90 In resource-limited settings, mortality rates as high as 50% remain a daily reality. 4 The majority of pediatric sepsis deaths occur within 48 hours of presentation, and specific risk factors for mortality have been identified (Table 9). 10,11,[91][92][93] Early deaths are usually attributed to refractory shock, whereas late deaths are more often associated with multiorgan system dysfunction. 94 In recent years, the relevance of long-term outcomes beyond the hospitalization of children with sepsis received increasing attention. Of concern, more than one-third of pediatric survivors had not regained their baseline health-related quality of life one year after an episode of community-acquired sepsis. 95 Lower quality-of-life scores were associated with multiorgan dysfunction, renal replacement therapy, ECMO or cardiopulmonary resuscitation, and duration of mechanical ventilation and inotropes. 96 Similar findings were observed internationally. 11 Given that most children with sepsis are younger than 10 years of age, the long-term impact of sepsis sequelae on children, their families, and society cannot be emphasized enough.

CONCLUSIONS
Sepsis remains a leading cause of death in children in the United States and globally, and its toll on short-term and long-term outcomes for this vulnerable patient group is substantial. Yet the relative rarity of sepsis in comparison to common febrile infections, combined with often nonspecific early manifestations, can make prompt recognition in EDs challenging. The use of clinical decision support and sepsis protocols have been shown to reduce morbidity and mortality in children with sepsis and should be implemented and audited as best practice to save lives and improve outcomes for children with sepsis.