Pediatric Annals

Special Issue Article 

Pediatric Sepsis: A Primer for the Pediatrician

Edward E. Conway Jr., MD, MS, FAAP, FCCM

Abstract

Sepsis is the body's systemic response to infection and is a serious health care concern that affects neonatal, pediatric, and adult populations worldwide. Severe sepsis (sepsis that has progressed to cellular dysfunction and organ damage or evidence of hypoperfusion) and septic shock (sepsis with persistent hypotension despite adequate fluid resuscitation) are still associated with high mortality rates despite improvements in the management of infectious processes. The cellular processes that occur as a result of the inflammatory response in sepsis, including impaired perfusion and microcirculatory coagulation, can lead to organ system dysfunction. Early recognition of sepsis can help prompt treatment to improve patient care. Current pediatric guidelines emphasize early recognition, aggressive fluid resuscitation, and administration of antibiotics within the first hour for a better outcome. The practitioner needs to always be mindful of the possibility of sepsis when examining a patient with potential symptoms. [Pediatr Ann. 2018;47(7):e292–e299.]

Abstract

Sepsis is the body's systemic response to infection and is a serious health care concern that affects neonatal, pediatric, and adult populations worldwide. Severe sepsis (sepsis that has progressed to cellular dysfunction and organ damage or evidence of hypoperfusion) and septic shock (sepsis with persistent hypotension despite adequate fluid resuscitation) are still associated with high mortality rates despite improvements in the management of infectious processes. The cellular processes that occur as a result of the inflammatory response in sepsis, including impaired perfusion and microcirculatory coagulation, can lead to organ system dysfunction. Early recognition of sepsis can help prompt treatment to improve patient care. Current pediatric guidelines emphasize early recognition, aggressive fluid resuscitation, and administration of antibiotics within the first hour for a better outcome. The practitioner needs to always be mindful of the possibility of sepsis when examining a patient with potential symptoms. [Pediatr Ann. 2018;47(7):e292–e299.]

Pediatric sepsis is a leading cause of morbidity, mortality, and health care costs in infants and children in the United States. Pediatric sepsis-associated mortality decreased from 97% among infants in 1966 to approximately 9% by the early 1990s.1 Severe sepsis is a major health problem in children, with more than 42,000 cases and 4,400 associated deaths per year in th United States.2 Although we have made major strides in reducing pediatric sepsis-related morbidity and mortality over the past decades, it continues to be a major health care concern as more patients may now be at risk due to better neonatal outcomes, increasing use of high-risk interventions (eg, transplantation, chemotherapy and immunosuppressive therapies), use of implantable devices, better surgical techniques for complex disease processes, development of drug resistance, and more virulent infections. The estimated financial impact of pediatric sepsis is $4.8 billion dollars or approximately 16% of US health care costs for hospitalized children.1 Children with chronic comorbid conditions have a particularly high risk of death from sepsis, and the majority of children who die do so within the first 24 hours of referral to a pediatric intensive care unit (PICU); one-half of these children die even before reaching the PICU.3

Sepsis is a systemic inflammatory response to a variety of infectious processes. This phenomenon was described more than 2 millennia ago by Hippocrates as the process through “which flesh rots, swamps generate foul airs and wounds fester.”4 Despite our awareness of sepsis, it remains a current challenge to properly diagnose and treat it in a timely fashion despite protocolized care. One of the first sepsis protocols was implemented by Ignaz Semmelweis in the 19th century when he insisted on hand washing with chlorinated lime solution prior to examinations of pregnant women, which helped reduce mortality from puerperal fever.5 It is amazing that the importance of something as simple as handwashing was seemingly lost and recently rediscovered and has become a major quality issue for hospitals all over the world. The oft quoted “To Err is Human”6 published by the Institute of Medicine in 2000 generated the current patient safety and quality movement that has challenged us to examine how we do things and to develop best practices. In response to these challenges, the American College of Critical Care Medicine published clinical practice parameters for hemodynamic support of pediatric and neonatal shock in 2002,7 2009,8 and most recently in 2017.9 The purpose of the most recent guideline was to update and grade new studies that were performed, to test the utility and efficacy of the 2009 recommendations, to examine and identify any new treatment and outcome studies, and to determine if the 2009 guidelines should be modified.9 Pediatricians, family practitioners, pediatric and adult emergency physicians, pediatric residents, school nurses, triage nurses in practitioner's office, and many other practitioners who care for pediatric patients are faced daily with children presenting with fever, tachycardia, and tachypnea. One needs to determine if this is a simple pediatric process or if it is a symptom of sepsis? How does one differentiate between these? Are there triggers that practitioners should be aware of? Are there any biomarkers with good sensitivity and specificity to help differentiate between the two? What are the most recent treatment recommendations? These issues are addressed in this brief overview of pediatric sepsis.

Definitions

In 2005, an international consensus conference published specific pediatric definitions to define the spectrum of the pediatric systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock, (Table 1) which are summarized in the following text.10

Basic Pediatric Definitions Involving Sepsis

Table 1:

Basic Pediatric Definitions Involving Sepsis

In addition to defining SIRS, sepsis, and septic shock, the pediatric group defined organ dysfunction to include the following: (1) Cardiovascular dysfunction: intravenous isotonic fluid bolus >40 mL/kg in 1 hour, hypotension, need for vasoactive drug to maintain blood pressure in normal range, unexplained metabolic acidosis, increased arterial lactate >2 times upper limit normal, oliguria (urine output <0.5 mL/kg per hour), prolonged capillary refill (>5 seconds); (2) Respiratory dysfunction: need for >50% FiO2 to maintain saturation at >92%, PaCO2 >65 torr or 20 mm Hg above baseline, PaO2/FiO2 ≤300 in absence of cyanotic heart disease or preexisting lung disease; (3) Neurologic: Glasgow Coma Scale ≤11; (4) Hematologic: platelet count <80,000/mm3, International Normalized Ratio ≥2; (5) Renal: serum creatinine ≥2 times upper limit of normal for age or 2-fold increase in baseline creatinine; and (6) Hepatic: total bilirubin ≥4 mg/dL or alanine aminotransferase 2 times upper limit for age.10

Guidelines became available through the American College of Critical Care Medicine (ACCM), American Heart Association, and Pediatric Advance Life Support (PALS) with algorithms for rapid recognition and treatment of sepsis in pediatric patients.7–9

The definitions cited above were used for the most recent ACCM pediatric sepsis guidelines.8,9 There has been much discussion in the adult literature about updating/modifying current definitions of sepsis and organ failure scores. Recent adult guidelines,11 based on a consensus process using results for a systematic review, surveys, and cohort studies, have modified their definitions in 2016; however, this has not occurred in pediatrics.11 The most current adult definition of sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) uses the Sequential Organ Failure Assessment (SOFA) score to grade organ dysfunction in adult patients with suspected infection.11 Sepsis is now defined as evidence of infection plus life-threatening organ dysfunction, clinically characterized by an acute change of 2 or more points in the SOFA score. The SOFA score is not adjusted for age and, therefore, is currently felt to be not suitable for children.12

Recognition

One of the most challenging dilemmas is to identify the septic child early in the course of the disease process and to implement time-sensitive resuscitation. The Institute of Healthcare Improvement developed the concept of “bundles” to help health care providers improve the reliability of delivery of essential health care processes.6 A bundle is defined as a selected set of elements of care that, when implemented as a group, have an effect on the outcomes beyond the individual elements alone. Bundles incorporate evidence-based science into practice. The concept of bundles emerged from the acknowledgment that health care was too dependent on individual clinicians' knowledge, motivation, and skills, with the result being that only approximately 50% of patients received the recommended care.13 Ideally, bundles should consist of 3 to 6 elements that are well-established practices that are delivered consistently. They should be delivered by one health care team at one point in time to every patient meeting the bundle criteria. An example of an early bundle was one designed to lower the incidence of hospital-acquired blood stream infections due to central lines. Adult and pediatric sepsis bundles have been developed and analyzed and used for the past decade. Evidence-based pediatric sepsis guidelines recommend early and aggressive fluid administration to reverse shock and restore tissue perfusion.7–9

Successful pediatric sepsis bundles published to date include a recognition bundle (patient is screened for sepsis), a resuscitation bundle (where intravenous/intraosseous access is obtained within 5 minutes, appropriate fluid resuscitation is administered rapidly, blood cultures are obtained, and antibiotics administered within the first hour) and finally a stabilization and performance bundle.8,9Figure 1 is an example of a Septic Shock Trigger/Identification Tool developed by the Pediatric Septic Shock Collaborative of the American Academy of Pediatrics (AAP) to help the practitioner identify at-risk patients.

Septic shock/trigger identification tool. CP, cerebral palsy; ED, emergency department; MR, mental retardation; PALS, Pediatric Advance Life Support; SCD, sickle cell disease. Reprinted with permission of the Pediatric Septic Shock Collaborative of the American Academy of Pediatrics.31

Figure 1.

Septic shock/trigger identification tool. CP, cerebral palsy; ED, emergency department; MR, mental retardation; PALS, Pediatric Advance Life Support; SCD, sickle cell disease. Reprinted with permission of the Pediatric Septic Shock Collaborative of the American Academy of Pediatrics.31

The goal of the recognition bundle is to rapidly identify any of the following within the first 5 minutes:

  1. Altered mental status (irritability or decreased level of consciousness, lethargy, drowsiness, poor interaction with parents)

  2. Altered temperature

  3. Hypotension (late finding)

  4. Tachypnea

  5. Altered heart rate,

  6. Altered perfusion (prolonged >3 seconds or flash capillary refill (<2 seconds for warm shock)

  7. Pulse abnormality (decreased or bounding)

  8. Cool or warm extremities, mottled, ecchymosis or purpura, decreased urine output

If a previously healthy patient presents with 3 or more of the 8 triggers listed above, it suggests the patient may be at risk for sepsis. In high-risk patients, the presence of 2 or more of the 8 clinical criteria may suggest sepsis. The practitioner must then decide if the triage assessment correlates with the patient's clinical condition. The AAP Shock Trigger tool also lists vital signs for various ages of infants and children.

One of the earliest publications establishing the safety of rapid fluid administration was published by Carcillo et al.14 in 1991. They looked at both the timing and volume of isotonic fluid administration in three groups of patients who presented with septic shock and had pulmonary artery catheters in place. They concluded that rapid fluid resuscitation in excess of 40 mL/kg in the first hour was associated with improved survival, decreased occurrence of persistent hypovolemia, and no increase in the risk of cardiogenic pulmonary edema or acute respiratory distress syndrome. An article by Rivers et al.15 in 2001 described what has been termed early goal-directed therapy. It was a systematic regimen to treat septic shock in adult patients and, although it has come under recent criticism, the group demonstrated a statistically significant decrease in mortality in patients who received a protocolized approach (placement of a central venous catheter capable of reading mixed venous O2 saturations, multiple fluid boluses to attain a central venous pressure of 8 to 12 mm Hg, vasopressors for mean arterial pressure <65 mm Hg; patients with a mixed venous saturation <70% were transfused with packed red blood cells to achieve a hematocrit of 30%) versus standard therapy (fluids, antibiotics). Many authors have subsequently developed or modified recognition and management protocols and continue to examine their performance.16–21 Early recognition, aggressive volume resuscitation, and antibiotics definitely make a difference.

Pathophysiology

Both the host response and characteristics of the infecting organism influence the outcome of sepsis. Sepsis with organ dysfunction occurs primarily when host responses to infection are inadequate. In addition, sepsis often progresses when the host cannot contain the primary infection, a problem most often related to characteristics of the organism, such as a high burden of infection and the presence of super-antigens and other virulence factors, resistance to opsonization and phagocytosis, and antibiotic resistance.22 Host defenses can be categorized according to innate and adaptive immune responses, neither of which are fully developed in young pediatric patients who are the most susceptible to sepsis.23 There is also an alteration of the procoagulant–anticoagulant balance favoring the procoagulant state, which can lead to microthromboses that contribute to the development of organ failure.

Pediatric septic shock is caused by a combination of decreased intravascular volume (either absolute or relative hypovolemia), myocardial dysfunction, and abnormalities in peripheral vasoregulation. Absolute hypovolemia (ie, decreased intravascular volume secondary to poor oral intake, vomiting, diarrhea, or increased insensible losses) or relative hypovolemia (ie, decreased intravascular volume secondary to capillary leak, increased venous capacitance) is the most common cause of shock in children. In contrast to adults, in whom septic shock is characterized by high cardiac output and low systemic vascular resistance (SVR), pediatric patients commonly have low cardiac output and normal to elevated SVR. There are other significant developmental differences in both myocardial structure and function that compromise the pediatric compensatory response to sepsis, and these are discussed in more detail elsewhere.9Figure 2 is the ACCM/PALS Pediatric Shock Algorithm, and it details the most current management recommended by the American College of Critical Care Medicine.9

Pediatric septic shock algorithm. BP, blood pressure; HR, heart rate; ICU, intensive care unit; IO, intraosseous; IV, intravenous; ScvO2, central venous oxygen saturation. Reprinted with permission from the Pediatric Advanced Life Support Provider Manual ©2016 American Heart Association, Inc., page 221, Figure 40.32

Figure 2.

Pediatric septic shock algorithm. BP, blood pressure; HR, heart rate; ICU, intensive care unit; IO, intraosseous; IV, intravenous; ScvO2, central venous oxygen saturation. Reprinted with permission from the Pediatric Advanced Life Support Provider Manual ©2016 American Heart Association, Inc., page 221, Figure 40.32

Adequate treatment during the first hour after the onset of symptoms is critical to maximize a good outcome for the pediatric patient with septic shock. The second half of the algorithm (after the first hour) is the PICU management guidelines for ongoing care of the septic patient and will not be discussed in detail here. Initial fluid resuscitation should include two to three rapid boluses of isotonic fluids at 20 mL/kg using a three-way stopcock to allow rapid administration. The patient should be reassessed frequently after each bolus and fluids should be adjusted if the patient develops rales, respiratory distress, or hepatomegaly. A blood culture should be obtained and broad-spectrum antibiotics administered within the first hour. Each hour of delay of antibiotic administration is associated with, on average, a 7.6% increase in mortality.24 Metabolic derangements need to be addressed, as hypoglycemia and hypocalcemia occur frequently in critically ill patients. If the patient fails to respond to fluid therapy (ie, >40 mL/kg), treatment of fluid-refractory shock should be undertaken and a vasoactive agent should be administered within the first hour. Epinephrine is the preferred vasoactive agent to treat shock with cold extremities (ie, cold shock) as it has potent inotropic effects that can increase stroke volume. Norepinephrine is the agent of choice for the child with fluid-refractory shock who presents with warm extremities (ie, warm shock) due to its vasoconstricting effects that can elevate diastolic blood pressure via its effects on SVR. If the child remains refractory to both fluids and vasoactive agents, one should consider that the child might have adrenal insufficiency and administer 1 to 2 mg/kg of hydrocortisone. Vasopressors can be administered via peripheral venous or intraosseous access, so there should be no delay in administering them as needed within the first hour. Therapeutic endpoints include improving perfusion (decreased capillary refill time), improved level of consciousness, good distal pluses, normalizing heart rate, appropriate urine output, and improving metabolic acidosis.9

The diagnosis of sepsis, severe sepsis and septic shock is primarily a clinical one. There is no gold standard laboratory test currently available to make the diagnosis of sepsis. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic process, or pharmacologic responses to a therapeutic intervention. The function of biomarkers includes diagnosis, monitoring, stratification, prediction, and surrogate endpoint. There is strong adult literature using lactate as a biomarker; however, the data for pediatrics have shown that it is neither sensitive nor specific, and thus it is not currently mandated in our protocols. Other biomarkers under consideration include C-reactive protein, which is an acute phase reactant synthesized in the hepatocyte, and production may be triggered by interleukin-6, tumor necrosis factor-alpha, and other cytokines. Procalcitonin is a precursor to calcitonin synthesis, and conversion of procalcitonin to calcitonin is inhibited by various cytokines and bacterial endotoxin, and thus its elevation suggests bacterial infection. In 2007, Wong et al.25 first published genome-wide expression patterns looking at 42 patients with septic shock versus 15 normal controls. More than 2,000 genes were differentially expressed or repressed in the septic patient versus the controls. Many of the upregulated genes corresponded with functional annotations related to immunity and inflammation, and a large number of the repressed genes (>1,000) corresponded to functional annotations related to zinc biology. Of note is the fact that patients who did not survive had significantly lower serum zinc levels compared with survivors. Newer biomarkers are currently under study and some look at genes and specific proteins that are produced in response to sepsis. Combinations of these potential biomarkers may the yield the higher sensitivity and specificity we need for these patients.

We must carefully analyze the data concerning sepsis protocols. One such initiative is an unprecedented set of New York State regulations implemented in 2013 and collectively known as “Rory's regulations.” Named after Rory Staunton, who died at age 12 years from sepsis resulting from a soft-tissue infection, these regulations mandate that all hospitals in the state of New York use evidence-based protocols for sepsis identification and management and that they report to the state government data on their sepsis-protocol adherence and clinical outcomes.26–28

The first New York State Department of Health (NYSDOH) public report was made available online in March 2017.28 In summary, the pediatric data demonstrated an 85% use of an evidence-based protocol. Specific measured bundles included antibiotics started in the first hour (52.5%), fluid bolus of at least 20 mL/kg in first hour (32%), blood cultures obtained prior to antibiotics (53%), and completion of all three tasks in the 1-hour bundle (16.5%). We need to continue to examine the data and make appropriate changes in protocols. As other states such as Illinois and Pennsylvania entertain mandatory reporting, we need to continue to analyze that data as well. A recent report by Cvetkovic et al.3 emphasizes that the sepsis resuscitation bundles need to move out of the PICU and emergency departments and into the field. It is well established that pediatric sepsis resuscitation is time sensitive, so every effort must be made to identify the patient with sepsis as early as possible to initiate the earliest resuscitative measures. PICU transport teams can facilitate experienced goal-directed resuscitation at referring sites, and this approach may be augmented by telemedicine while awaiting arrival of the transport team.

Conclusion

We have made great strides in recognizing and treating pediatric sepsis in the past half-century, but the NYSDOH data suggest we have room for improvement. Awareness programs should teach health care workers to recognize sepsis and to understand it is medical emergency in which time is critical. Government reports and patient stories consistently identify delayed treatment as a major cause of preventable death and disability.29 In August of 2016, the Centers for Disease Control and Prevention labelled sepsis a medical emergency.30 Lastly in the words of Rory's dad, Ciaran Staunton, one needs to always ask the simple question: could this be sepsis?

References

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Basic Pediatric Definitions Involving Sepsis

Systemic inflammatory response syndrome
  The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count <list-item>

Core temperature of >38.5°C or <36°C

</list-item><list-item>

Tachycardia, defined as a mean heart rate >2 standard deviations above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli; or otherwise unexplained persistent elevation over a 0.5 to 4-hour time period OR for children younger than age 1 year. Bradycardia, defined as a mean heart rate <10th percentile for age in the absence of external vagal stimulus, beta-blocker drugs, or congenital heart disease; or otherwise unexplained persistent depression over a 0.5-hour time period

</list-item><list-item>

Mean respiratory rate >2 standard deviations above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or receipt of general anesthesia

</list-item><list-item>

Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) of >10% immature neutrophils

</list-item>
Infection
  A suspected or proven (by positive culture, tissue stain, or polymerase chain reaction test) infection caused by any pathogen OR a clinical syndrome associated with a high probability of infection. Evidence of infection includes positive findings on clinical examination, imaging, or laboratory tests (eg, white blood cells in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia, petechial or purpuric rash, or purpura fulminans).
Sepsis
  Systemic inflammatory response syndrome in the presence or as a result of suspected infection or proven infection
  Life-threatening organ dysfunction due to dysregulated host response to infection11
Severe sepsis
  Sepsis plus one of the following: cardiovascular organ dysfunction OR acute respiratory distress syndrome OR two or more organ dysfunctions involving the hepatic, renal, neurologic, or hematologic systems
Septic shock
  Sepsis and cardiovascular organ dysfunction
Authors

Edward E. Conway Jr., MD, MS, FAAP, FCCM, is a Professor of Pediatrics, Albert Einstein College of Medicine; and the Chief, Division Pediatric Critical Care Medicine, and an Associate Vice-Chairman, Lewis M. Fraad Department of Pediatrics, Jacobi Medical Center.

Address correspondence to Edward E. Conway Jr., MD, MS, FAAP, FCCM, Jacobi Medical Center, 1400 Pelham Parkway South, Bronx, NY; email: conwaye@NYCHHC.org.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/19382359-20180620-02

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