Pediatric Sepsis 

Generally, sepsis is considered to comprise a spectrum of disorders that result from infection by bacteria, viruses, fungi, or parasites or the toxic products of these microorganisms. Bacteremia, viremia, fungemia, and parasitemia refer to bloodstream invasions that may be associated with fever but have no other signs or symptoms of circulatory compromise or end-organ malperfusion or dysfunction.

Sepsis is a problem that presents a management challenge to those who care for infants and children; however, early recognition and intervention clearly improves the outcome for infants and children with infections or intoxications that lead to sepsis.

Most infants and children with sepsis require monitoring and treatment in an intensive care setting. Initial focus should be on stabilization and correction of metabolic, circulatory, and respiratory derangements. Appropriate antimicrobial therapy should be started as soon as possible after evaluation occurs. Ongoing re-evaluation is essential.

Critical care expertise is essential for moderate-to-severe cases. Consultation with an infectious disease specialist may be necessary. Other consultations should be made based on the clinical circumstances.

For more information, see the Medscape Reference article Neonatal Sepsis.

Definition of pediatric sepsis

The spectrum of sepsis ranges from microbial invasion of the bloodstream or intoxication with early signs of circulatory compromise, including tachycardia, tachypnea, peripheral vasodilation, and fever (or hypothermia), to full-blown circulatory collapse with multiorgan system failure and death (see the image below).

All these manifestations are part of what is more appropriately termed the systemic inflammatory response syndrome (SIRS), which is used interchangeably with sepsis to signify any of these manifestations, whatever the etiology. SIRS results from an insult, whether infectious, traumatic, chemical, malignant, autoimmune, or idiopathic, and the host response that follows. The outcome depends on the intricate interplay of upregulating and downregulating cytokines and inflammatory cells and the direct effects of the insult itself.

In recent years, experts have come together to develop a consensus on the definitions of sepsis, SIRS, severe sepsis and septic shock.^[1] Age-related variables have been applied to the definition of SIRS and sepsis. The definition of SIRS now requires either fever or white blood cell (WBC) involvement to meet the criteria.

Clinical course of pediatric sepsis

The earliest, mildest manifestation of SIRS is typified by the triad of hyperthermia (or hypothermia), tachypnea, and tachycardia. If SIRS is identified and reversed early, the subsequent inflammatory cascade can often be avoided or mitigated. However, in some situations, further damage occurs because the insult or the resultant host immune response is too great. This damage can result in increased cardiac output, peripheral vasodilation, increased tissue oxygen consumption, and a hypermetabolic state (ie, warm shock).

If SIRS is not identified and reversed early, cardiac output may fall, peripheral vascular resistance may increase, and shunting of blood may ensue (ie, cold shock). This results in tissue hypoxia, end-organ dysfunction, metabolic acidosis, end-organ injury and/or failure, and death.

Bacterial causes of pediatric sepsis in specific age groups

Myriad bacteria, viruses, fungi, and parasites can cause SIRS. Among the bacterial causes of sepsis, the following age-related patterns are observed.

In patients with early-onset neonatal sepsis, Streptococcus agalactiae, Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes are the most frequent organisms encountered.

In patients with late-onset neonatal sepsis, coagulase-negative Staphylococcus, Staphylococcus aureus, E coli, Klebsiella species, Pseudomonas aeruginosa, Enterobacter species, Candida species, S agalactiae, Serratia species, Acinetobacter species, and various anaerobes are some of the most commonly involved organisms.

In most infants worldwide, the most frequent causes of bacterial sepsis are H influenzae type b (Hib), Streptococcus pneumoniae, Neisseria meningitidis, and Salmonella species are. In the United States and the developed world, S pneumoniae and Nmeningitidis predominate because conjugate Hib vaccination has essentially eliminated disease caused by that organism. In regions where malaria occurs, Plasmodium falciparum is a frequent cause of SIRS in infancy.

The same pathogens that cause SIRS in infancy also cause it in childhood, although the presence of encapsulated organisms generally becomes less frequent as a child’s immune response to polysaccharide antigens improves with age.

Risk factors for pediatric sepsis

Underlying conditions predispose to infection with particular pathogens, such as the following:

• Acquired immunodeficiency syndrome (AIDS) predisposes to SIRS from various usual and unusual pathogens, particularly pneumococcus.
• Children with hemoglobin SS disease have a 400-fold increased risk of sepsis due to pneumococcus and Salmonella, among other pathogens.
• Congenital heart disease is a risk factor for endocarditis and SIRS, and genitourinary anomalies often increase the risk of urosepsis.
• Infants and children with significant burns are at risk for SIRS, caused by skin flora and nosocomial gram-negative pathogens in particular.
• Splenic dysfunction or absence, as well as complement, immunoglobulin, and properdin deficiency, predispose to sepsis due to encapsulated organisms.
• Infants and children with hematologic and solid-organ malignancies (before or during treatment) are at increased risk for SIRS from a considerable variety of organisms.
• Neonates, infants, and children who are hospitalized (particularly in the intensive care unit [ICU]) are at increased risk of SIRS.
• Those with indwelling devices or prosthetic material and other breaches in barrier protective function are also at increased risk of SIRS.

The systemic inflammatory response syndrome (SIRS) remains an infrequent but significant cause of death among infants and children in the United States. The incidence of sepsis in the developing world is somewhat higher than that in the United States. However, reports are fewer, and precise figures are unavailable.

The risk of sepsis is inversely related to age. Neonates are at the highest risk, with bacterial sepsis occurring in 1-10 per 1000 live births in the United States.

Except for urosepsis, which may be more common in females, no sex predilection for sepsis is known.

No particular racial predilection is noted for sepsis, except that invasive bacterial infections are more common in Eskimos, American Indians, and individuals with hemoglobin SS disease.

Mortality from pediatric systemic inflammatory response syndrome (SIRS) ranges from 9-35%. Different insults are associated with different outcomes. Host immune status is important in determining outcome. Aggressive fluid resuscitation early in the course of SIRS results in decreased mortality rates.

Almost half of neonatal deaths are caused by sepsis, although advances in diagnosis and treatment have caused this rate to considerably decrease, especially in preterm infants. Again, the mortality rate tends to decrease as age increases in the pediatric population.

Parents of newborns should understand that any fever in the first few months of life necessitates immediate evaluation. The importance of fever as a marker of possible serious infection, rather than a concerning symptom itself, should be emphasized.

Front-line providers must recognize the importance of aggressive resuscitation for the patient with early signs of systemic inflammatory response syndrome (SIRS).

Vaccination is the key to preventing many of these infections. Travelers should be warned of the possibility of serious infections during travel.

For patient education information, see the Infections Center, as well as Sepsis.

Patient history

Obtain a complete history as part of the evaluation of the infant or child with possible systemic inflammatory response syndrome (SIRS).

Fever is the most common presenting symptom of children with SIRS. A parental report of measured (not tactile) fever can generally be assumed to be reliable.

Ask the caregiver whether any of the following have been noted: a racing heart, rapid or labored breathing, cool extremities, or color changes. Identify exposures to infectious illnesses and other sources of insult.

Discuss the child’s activity level. Perform an age-appropriate evaluation of mental status. Ask about urine output because it is the most sensitive historical marker of dehydration and potential renal hypoperfusion.

Verify immunization and drug allergy statuses.

Physical examination

Perform a complete physical examination of the infant or child with suspected SIRS.

Subtle changes in vital signs (eg, minimal tachycardia, widened pulse pressure, minimal tachypnea, minimally delayed capillary refill) may be the first signs of impending SIRS. Hypotension, mental status changes, and anuria are late signs of SIRS. Hypothermia is often a more ominous sign than fever.

Elicit localizing signs of infection. A petechial or purpuric rash associated with fever is of particular concern.

Frequent reassessment during interventions is required.

Complications

Because the manifestations of SIRS are protean, possible complications are as well. Complications depend on the nature of the triggering insult and the resultant host response.

The differential diagnosis of pediatric sepsis includes the following conditions:

• Acidosis, Metabolic
• Adrenal Insufficiency
• Bacteremia
• Candidiasis
• Endocarditis, Bacterial
• Endocarditis, Fungal
• Enterococcal Infection
• Escherichia Coli Infections
• Haemophilus Influenzae Infection
• Herpes Simplex Virus Infection
• Influenza
• Meningitis, Aseptic
• Meningitis, Bacterial
• Meningococcal Infections
• Necrotizing Enterocolitis
• Pericarditis, Bacterial
• Pneumococcal Infections
• Q Fever
• Salmonella Infection
• Shigella Infection
• Staphylococcus Aureus Infection
• Streptococcal Infection, Group A
• Urinary Tract Infection

Other problems to be considered in the diagnosis of pediatric sepsis include cardiogenic shock, coagulase-negative Staphylococcus,c omplement deficiency, congenital heart disease, fungal infections, hemophagocytic syndromes, inborn errors of metabolism, infections after solid organ transplantation, macrophage activation syndromes, neoplasms, poisoning, pulmonary embolus, and S agalactiae.

Whenever possible, obtain a blood culture before starting antibiotics. The yield is clearly correlated to the volume of blood sampled. Culture of bone marrow may have a higher yield for certain pathogens (eg, Histoplasma capsulatum).

Obtain a urine culture unless, in an older child, a genitourinary source of infection can be reliably excluded.

Obtain a cerebrospinal fluid (CSF) culture before initiating antibiotic therapy in a child whose condition is stable in whom clinical evaluation cannot exclude central nervous system (CNS) infection. Many pathogens can be recovered from CSF cultures several hours after a dose of antibiotics; thus, the child whose condition is unstable should receive antibiotics and be stabilized before lumbar puncture. Once the patient’s condition is stable, identification of CSF pleocytosis is helpful, even if prolonged antibiotic therapy is likely to have rendered culture results negative.

Culture of skin lesions, eye drainage, throat, vagina, rectum, cellulitic areas, nasal secretions, sputum, tracheal aspirates, and stool may be helpful in the appropriate clinical context.

Viral cultures may have a role in certain contexts, although many viral infections are diagnosed serologically.

Obtain a complete blood count (CBC). In the era of pneumococcal occult bacteremia, the likelihood of a positive blood culture result for pneumococcus increased as the white blood cell (WBC) count increased. However, whether an elevated WBC count will continue to be predictive of bacteremia with widespread pneumococcal conjugate vaccination is not clear.

Elevated band and other immature counts, toxic granulation, toxic vacuolation, Dohle bodies, and, particularly, low white blood cell counts are findings of particular concern. Hemoconcentration may be present and helpful as a gauge of hydration status.

Measures of clotting function and coagulation parameters may be helpful. Disseminated intravascular coagulopathy, hypercoagulability, and other clotting dysfunctions may be seen in infants and children with systemic inflammatory response syndrome (SIRS).

Electrolyte level tests, renal and liver function tests, and other chemistry tests may have a role. Serum transaminase levels and other measures of liver dysfunction are often elevated in cases such as disseminated viral and anaerobic infections.

Etiology-specific serologies may be helpful, and urinalysis may have a role in clarifying the level of risk of urinary tract infection in infants and children. In addition, nonculture-based molecular modalities and other diagnostic methods are becoming increasingly important.^[2]

The use of inflammatory markers and acute phase reactants (eg, erythrocyte sedimentation rate, C-reactive protein, interleukin (IL)-1b, IL-6, IL-8, tumor necrosis factor–alpha, leukotriene B4, procalcitonin) in the diagnosis and management of SIRS is unclear.

Obtain a chest radiograph; pneumonia, pleural effusions, adenopathy, and other conditions may be revealed. Pursue other imaging modalities as the clinical context dictates. Echocardiography may be indicated in certain clinical settings.

Lumbar puncture may be indicated for cerebrospinal fluid evaluation. Sampling of other fluids or biopsy of various organs or tissues may be necessary.

Initial focus should be on stabilization and correction of metabolic, circulatory, and respiratory derangements.^[3] Cardiac output may have to be assessed repeatedly. Multiple peripheral intravenous, intraosseous, and/or central venous access devices are likely necessary. Frequent sampling of arterial blood is often required. Ongoing re-evaluation is essential.

Rapid restoration of circulation, tissue perfusion, and oxygen delivery via aggressive volume replacement therapy is the single most important intervention in the acute management of septic shock.^[4] Accordingly, fluid resuscitation with crystalloid or colloid parenteral solutions should be initiated immediately. If circulatory derangements do not resolve with 3 intravenous (IV) boluses of 20 mL/kg of fluids, vasopressor support should follow.

One study analyzed the outcome of African children who received bolus fluid resuscitation for shock and life-threatening infections. The study subjects received boluses of 20-40 ml of 5% albumin solution or 0.9% saline solution per kilogram of body weight; the control group received no bolus. The 48-hour mortality rate was 10.6% (111 of 1050 children) in the albumin-bolus group, 10.5% (110 of 1047 children) in the saline-bolus group, and 7.3% (76 of 1044 children) in the control group. The 4-week mortality rates were 12.2%, 12.0%, and 8.7% in the 3 groups, respectively. The results suggest that fluid bolus treatment significantly increases the 48-hour mortality rate in children with severe febrile illness and impaired perfusion who reside in resource-limited settings.^[5]

Ventilatory support with supplemental oxygen therapy, aggressive fluid resuscitation and support of cardiac output, maintenance of adequate hemoglobin concentration, correction of physiologic and metabolic derangements, and monitoring of urine output and other end-organ functioning are often vital.

Patients with pediatric sepsis whose circulatory, metabolic, and respiratory derangements are not rapidly corrected should be cared for in an intensive care setting. Transfer should be arranged if the appropriate specialists and intensive care settings are not locally available.

Antimicrobial agents should be given as soon as possible, according to the most likely pathogens.

Empiric antimicrobial therapy for the infant or child with systemic inflammatory response syndrome (SIRS) of unclear etiology should be based upon the most frequently encountered pathogens in each age group. For example, newborns and infants in the first 6-8 weeks of life should generally receive ampicillin and gentamicin, ampicillin and cefotaxime, or ampicillin and ceftriaxone for empiric therapy of sepsis without a clear etiology. Older infants and children most often receive a third-generation cephalosporin (or ampicillin/sulbactam) alone in this situation.

Patients who have indwelling catheters or those who are at high risk for methicillin-resistant S aureus infection may require vancomycin as well. Patients who have fever and neutropenia should receive broad-spectrum coverage with an emphasis on gram-negative rods.

Antimicrobial agents that are used less frequently include caspofungin, fluconazole, foscarnet, ganciclovir, liposomal amphotericin B, itraconazole, and voriconazole. Posaconazole (Noxafil) is also used and was recently approved by the US Food and Drug Administration (FDA) in children aged 13 years or older and in adults for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk due to severe immunosuppression.

Adjunctive therapies such as inhaled nitric oxide, extracorporeal membrane oxygenation, corticosteroids (eg, dexamethasone or methylprednisolone), pentoxifylline, intravenous immunoglobulin, and various other mediators of the inflammatory response may be needed.

In cases of refractory shock, newer adjunctive therapies (such as terlipressin) have shown potential benefit in initial trials.^[6] Further clinical studies are required, but the risks of the drug may be outweighed by its benefits in certain circumstances.

Surgical intervention (eg, draining an abscess, venous access, appendectomy) is occasionally required.

Bovine lactoferrin supplementation (alone or in combination with the probiotic Lactobacillus rhamnosus GG) for very low birth weight neonates reduces the incidence of a first episode of late-onset sepsis.^{[7, 8]} Similarly, pentoxifylline adjunctive therapy may reduce mortality from late-onset sepsis.^[9] Studies of other such interventions are underway.

Generally, patients with the systemic inflammatory response syndrome (SIRS) should not be fed until gut hypoxia and hypoperfusion have been ruled out. Once feeding can safely begin, immune-enhancing nutrition may reduce the mortality rate in sepsis. Arginine, omega-3 fatty acids, and messenger RNA (mRNA) have been identified in preliminary studies to be of potential benefit.

Withdrawal of drotrecogin-alfa

Drotrecogin alfa (Xigris), a recombinant human-activated protein C indicated for reduction of mortality in adults with severe sepsis, was approved by the FDA for sepsis in adults, but enrollment in its phase III clinical trial for use in pediatric patients was halted in March 2005 after it was determined that the drug was unlikely to demonstrate improvement over placebo. The drug was withdrawn from the worldwide market on October 25, 2011, after the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa, compared with 24.2% in the placebo group.^{[10, 11, 12, 13]}