Hydrocortisone–Ascorbic Acid–Thiamine Use Associated with Lower Mortality in Pediatric Septic Shock

Wald, Eric; Sanchez-Pinto, L. Nelson; Smith, Craig; Moran, Thomas M.; Badke, Colleen M.; Barhight, Matthew; Malakooti, Marcelo

doi:10.1164/rccm.201908-1543le

Cited by 35 publications

(35 citation statements)

References 12 publications

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“… 29 Our group at Lurie Children’s Hospital published a single-center retrospective, propensity-scored matched analysis of 129 children with septic shock comparing patients who received HAT therapy to those receiving hydrocortisone only and those who received no adjuvant therapies. 6 We reported a decreased mortality associated with HAT therapy, particularly early in the course and in patients with severe hypoxemia, although we did not find a difference in length of stay or use of vasopressors. 6 Using a similar retrospective design with propensity matching, investigators found improved ICU mortality for adult patients treated with HAT therapy.…”

Section: Vitamin Ccontrasting

confidence: 57%

“… 6 We reported a decreased mortality associated with HAT therapy, particularly early in the course and in patients with severe hypoxemia, although we did not find a difference in length of stay or use of vasopressors. 6 Using a similar retrospective design with propensity matching, investigators found improved ICU mortality for adult patients treated with HAT therapy. 37 In contrast to these findings in observational studies, multiple RCTs of HAT therapy in adults with septic shock have failed to show clinical benefits, with treated patients experiencing no difference in vasopressor needs, ventilator days, or other clinical outcomes compared to controls 38 – 42 (Table 2 ).…”

Section: Vitamin Ccontrasting

confidence: 57%

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Vitamin therapy in sepsis

et al. 2021

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Vitamins are essential micronutrients with key roles in many biological pathways relevant to sepsis. Some of these relevant biological mechanisms include antioxidant and anti-inflammatory effects, protein and hormone synthesis, energy generation, and regulation of gene transcription. Moreover, relative vitamin deficiencies in plasma are common during sepsis and vitamin therapy has been associated with improved outcomes in some adult and pediatric studies. High-dose intravenous vitamin C has been the vitamin therapy most extensively studied in adult patients with sepsis and septic shock. This includes three randomized control trials (RCTs) as monotherapy with a total of 219 patients showing significant reduction in organ dysfunction and lower mortality when compared to placebo, and five RCTs as a combination therapy with thiamine and hydrocortisone with a total of 1134 patients showing no difference in clinical outcomes. Likewise, the evidence for the role of other vitamins in sepsis remains mixed. In this narrative review, we present the preclinical, clinical, and safety evidence of the most studied vitamins in sepsis, including vitamin C, thiamine (i.e., vitamin B 1 ), and vitamin D. We also present the relevant evidence of the other vitamins that have been studied in sepsis and critical illness in both children and adults, including vitamins A, B 2 , B 6 , B 12 , and E. Impact Vitamins are key effectors in many biological processes relevant to sepsis. We present the preclinical, clinical, and safety evidence of the most studied vitamins in pediatric sepsis. Designing response-adaptive platform trials may help fill in knowledge gaps regarding vitamin use for critical illness and association with clinical outcomes.

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Section: Vitamin Ccontrasting

confidence: 57%

Section: Vitamin Ccontrasting

confidence: 57%

Vitamin therapy in sepsis

et al. 2021

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“…To date, only one study on metabolic resuscitation has been published (Table 1). This propensity-matched retrospective single center cohort study on 557 children with septic shock reported good safety of metabolic resuscitation in 43 children with septic shock (44). In adjusted analyses, HAT therapy was associated with decreased 30-and 90-day mortality (P<0.05) compared to hydrocortisone alone, and compared to standard care without hydrocortisone.…”

Section: Pediatric Studies On Ascorbic Acid and Hat Resuscitation-the Respond Picu Studymentioning

confidence: 90%

“…Thiamine in general has an excellent safety profile, and adverse events are exceedingly rare (43). Wald et al used 4 mg/kg/d (maximum 200 mg/dose, not stating the number of doses per day) for a duration of four days in children with septic shock and did not observe adverse effects (44). Weiss et al retrospectively reviewed children admitted to a single PICU with septic shock who had received intravenous thiamine therapy over a sevenyear study period (42).…”

Section: Thiamine In Sepsismentioning

confidence: 99%

Metabolic resuscitation in pediatric sepsis: a narrative review

Schlapbach¹,

Oliveira²,

Raman

et al. 2021

Transl Pediatr

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“…Children may be more prone to vitamin C deficiency during sepsis due to comorbidities, malnutrition, a higher metabolic rate, and a higher proportion of patients with a rapidly progressive disease course. A propensity-matched cohort study from the USA reported excellent safety and feasibility of metabolic resuscitation in children with septic shock ( 31 ). Adjusted analyses showed decreased 30- and 90-day mortality ( p < 0.05) in the intervention group compared to hydrocortisone alone and compared to standard care without hydrocortisone.…”

Section: Introductionmentioning

confidence: 99%

Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation–A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU): Study Protocol and Analysis Plan

et al. 2021

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Introduction: Septic shock remains amongst the leading causes of childhood mortality. Therapeutic options to support children with septic shock refractory to initial resuscitation with fluids and inotropes are limited. Recently, the combination of intravenous hydrocortisone with high dose ascorbic acid and thiamine (HAT therapy), postulated to reduce sepsis-related organ dysfunction, has been proposed as a safe approach with potential for mortality benefit, but randomized trials in paediatric patients are lacking. We hypothesize that protocolised early use of HAT therapy (“metabolic resuscitation”) in children with septic shock is feasible and will lead to earlier resolution of organ dysfunction. Here, we describe the protocol of the Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation–A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU).Methods and Analysis: The RESPOND PICU study is an open label randomized-controlled, two-sided multicentre pilot study conducted in paediatric intensive care units (PICUs) in Australia and New Zealand. Sixty children aged between 28 days and 18 years treated with inotropes for presumed septic shock will be randomized in a 1:1 ratio to either metabolic resuscitation (1 mg/kg hydrocortisone q6h, 30 mg/kg ascorbic acid q6h, 4 mg/kg thiamine q12h) or standard septic shock management. Main outcomes include feasibility of the study protocol and survival free of organ dysfunction censored at 28 days. The study cohort will be followed up at 28-days and 6-months post enrolment to assess neurodevelopment, quality of life and functional status. Biobanking will allow ancillary studies on sepsis biomarkers.Ethics and Dissemination: The study received ethical clearance from Children's Health Queensland Human Research Ethics Committee (HREC/18/QCHQ/49168) and commenced enrolment on June 12th, 2019. The primary study findings will be submitted for publication in a peer-reviewed journal.Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12619000829112). Protocol Version: V1.8 22/7/20.

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Hydrocortisone–Ascorbic Acid–Thiamine Use Associated with Lower Mortality in Pediatric Septic Shock

Cited by 35 publications

References 12 publications

Vitamin therapy in sepsis

Vitamin therapy in sepsis

Metabolic resuscitation in pediatric sepsis: a narrative review

Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation–A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU): Study Protocol and Analysis Plan

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