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Metabolic resuscitation in pediatric sepsis: a narrative review

ABSTRACT: Sepsis, defined as infection with associated organ dysfunction, accounts for most childhood deaths due to infection globally. Evidence for the optimal support of children with septic shock refractory to the initial sepsis management bundle remains minimal. There is an urgent need for more effective interventions. Administration of hydrocortisone in children with septic shock might fasten shock resolution, and has been shown to dampen the systemic host immune response, augment adrenergic effects, and support the stress response. Ascorbic acid (vitamin C) is one of the most powerful naturally occurring antioxidants and has beneficial effects on multiple pathways which are severely deranged during septic shock. A regimen combining hydrocortisone, ascorbic acid, and thiamine termed “metabolic resuscitation” or “HAT therapy” has been tested in large trials in critically ill adults with sepsis with conflicting results. Available information on intravenous ascorbic acid indicates an excellent safety profile even at very high doses both in adults and children. Given the pharmacological properties and beneficial effects shown both in vitro and in animal studies, and its safety profile, ascorbic acid either as a single therapy or as part of HAT treatment represents a promising candidate for future pediatric sepsis treatments. While pediatric age groups may be more susceptible to ascorbic acid deficiency during sepsis, there is a lack of high-quality trial data on HAT therapy in this age group. A single centre retrospective study identified potential for mortality benefit in children with septic shock, and the results from a randomized controlled pilot trial are being awaited. It is imperative for pediatric research on ascorbic acid and HAT in children with sepsis to critically investigate key questions related to pharmacology, dosing, timing, feasibility, safety, effects on short- and long-term outcomes, and generalisability in view of the global burden of sepsis.

SUBMITTER: Schlapbach L

PROVIDER: S-EPMC8578751 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo determine the associations of demographic, clinical, laboratory, organ dysfunction, and illness severity variable values with: 1) sepsis, severe sepsis, or septic shock in children with infection and 2) multiple organ dysfunction or death in children with sepsis, severe sepsis, or septic shock.Data sourcesMEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2004, and November 16, 2020.Study selectionCase-control studies, cohort studies, and randomized controlled trials in children greater than or equal to 37-week-old postconception to 18 years with suspected or confirmed infection, which included the terms "sepsis," "septicemia," or "septic shock" in the title or abstract.Data extractionStudy characteristics, patient demographics, clinical signs or interventions, laboratory values, organ dysfunction measures, and illness severity scores were extracted from eligible articles. Random-effects meta-analysis was performed.Data synthesisOne hundred and six studies met eligibility criteria of which 81 were included in the meta-analysis. Sixteen studies (9,629 patients) provided data for the sepsis, severe sepsis, or septic shock outcome and 71 studies (154,674 patients) for the mortality outcome. In children with infection, decreased level of consciousness and higher Pediatric Risk of Mortality scores were associated with sepsis/severe sepsis. In children with sepsis/severe sepsis/septic shock, chronic conditions, oncologic diagnosis, use of vasoactive/inotropic agents, mechanical ventilation, serum lactate, platelet count, fibrinogen, procalcitonin, multi-organ dysfunction syndrome, Pediatric Logistic Organ Dysfunction score, Pediatric Index of Mortality-3, and Pediatric Risk of Mortality score each demonstrated significant and consistent associations with mortality. Pooled mortality rates varied among high-, upper middle-, and lower middle-income countries for patients with sepsis, severe sepsis, and septic shock (p < 0.0001).ConclusionsStrong associations of several markers of organ dysfunction with the outcomes of interest among infected and septic children support their inclusion in the data validation phase of the Pediatric Sepsis Definition Taskforce.

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Metabolic resuscitation in pediatric sepsis: a narrative review

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