Approach Considerations
In treating pediatric sepsis, the initial focus should be on stabilization and correction of metabolic, circulatory, and respiratory derangements. [22] Cardiac output may have to be assessed repeatedly. It may be necessary to use multiple peripheral intravenous (IV), intraosseous, or central venous access devices. Frequent sampling of arterial blood is often required. Ongoing reevaluation is essential.
Antimicrobial agents should be given as soon as possible, according to the most likely pathogens. Surgical intervention (eg, draining an abscess, venous access, appendectomy) is occasionally required. Adjunctive therapies may be needed.
Generally, pediatric patients with sepsis should not be fed until gut hypoxia and hypoperfusion have been excluded. Once feeding can safely begin, immune-enhancing nutrition may reduce mortality. Some studies suggest that arginine, omega-3 fatty acids, and messenger RNA (mRNA) may be beneficial.
Initial Resuscitation and Stabilization
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. [23] Accordingly, fluid resuscitation with crystalloid or colloid parenteral solutions should be initiated immediately. [24] If circulatory derangements do not resolve with 3 IV fluid boluses of 20 mL/kg, vasopressor support should follow.
One study analyzed the outcome of African children who received bolus fluid resuscitation for shock and life-threatening infections and suggested that this practice could be associated with increased mortality in some settings. [11] The study subjects received boluses of 20-40 mL of 5% albumin solution or 0.9% saline solution in quantities of 20-40 mL/kg body weight; the control group received no bolus.
In this study, the 48-hour mortalities were 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 mortalities were 12.2%, 12.0%, and 8.7%, respectively. [11] The results suggest that fluid bolus treatment significantly increases the 48-hour mortality in children with severe febrile illness and impaired perfusion who reside in resource-limited settings.
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.
Empiric Antimicrobial Therapy
Empiric antimicrobial therapy for pediatric sepsis of unclear etiology should be based on the pathogens most frequently encountered 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. Older infants and children most often receive a third-generation cephalosporin, vancomycin, plus clindamycin.
Patients who have indwelling catheters or those who are at high risk for methicillin-resistant S aureus (MRSA) 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, micafungin, fluconazole, foscarnet, ganciclovir, valganciclovir, cidofovir, liposomal amphotericin B, itraconazole, and voriconazole. Posaconazole is also used and is approved by the US Food and Drug Administration (FDA) for use in children aged 13 years or older and for prophylaxis of invasive Aspergillus and Candida infections in adult patients who are at high risk as a consequence of severe immunosuppression.
Risk stratification
In a retrospective case-control study of 350 newborns with early-onset sepsis (EOS) and 1063 matched controls, Escobar et al found that the use of a risk-stratification system incorporating maternal risk and infants' clinical condition in the first hours of birth could reduce the use of antibiotics for as many as a quarter million newborns annually. [25, 26] The maternal risk factors considered were as follows:
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Highest maternal antepartum temperature
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Gestational age
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Length of time that amniotic membranes were ruptured
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Carriage of group B Streptococcus
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Type of intrapartum antibiotic therapy administered
Application of the risk-stratification scheme to the study sample indicated that 4.1% of all live births (60.8% of the EOS cases) should have received systemic antibiotics, pending negative culture results; 11.1% of all live births (23.4% of the EOS cases) warranted more rigorous observation and evaluation with a blood culture; and 84.8% of live births (15.7% of the EOS cases) were low-risk and required only continued observation. [26]
A study reported that antimicrobial utilization and prescription practices in a neonatal intensive care unit decreased the use of ampicillin significantly by 22.5 days of antibiotic therapy per 1,000 patient days. The study also reported an average reduction of 2.65 late-onset sepsis evaluations per year per provider. [27]
A study by Evans et al reported that 1-hour completion of a mandated New York State pediatric sepsis treatment bundle that includes blood cultures, broad-spectrum antibiotics, and a 20-mL/kg intravenous fluid bolus was associated with lower risk-adjusted in-hospital mortality. [28]
Adjunctive Therapies
Adjunctive therapies such as inhaled nitric oxide, extracorporeal membrane oxygenation, [29] corticosteroids (eg, dexamethasone or methylprednisolone), pentoxifylline, and various other mediators of the inflammatory response may be needed. For suspected toxic shock syndrome due to S aureus or GABHS, IVIG is recommended.
In cases of refractory shock, additional adjunctive therapies (eg, terlipressin) have shown potential benefit in initial trials. [30] Further clinical studies are required, but the risks of the drug may be outweighed by its benefits in certain circumstances.
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. [31, 32, 33] Similarly, pentoxifylline adjunctive therapy may reduce mortality from late-onset sepsis. [34] Studies of other such interventions are under way.
A randomized, double-blind study by Panigrahi et al on the use of an oral synbiotic (Lactobacillus plantarum plus fructooligosaccharide) in 4,556 rural Indian newborns reported a 40% reduction in the combined outcome of death and sepsis in the synbiotic combination group compared to the placebo (5.4% vs 9%, risk ratio, 0.60; 95% confidence interval, 0.48 - 0.74). [35]
Withdrawal of drotrecogin alfa
Drotrecogin alfa, a recombinant human-activated protein C indicated for reduction of mortality in adults with severe sepsis, was approved by the FDA for treatment of 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 documented a 28-day all-cause mortality of 26.4% in patients treated with activated drotrecogin alfa, compared with 24.2% in the placebo group. [36, 37, 38, 39]
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Pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS).
