Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study.

OBJECTIVES: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction. DESIGN: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy. SETTING: Six PICUs in Australia and New Zealand. PATIENTS: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021. INTERVENTIONS: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33). MEASUREMENTS AND MAIN RESULTS: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29-120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0-26.0) days in the intervention and 21.0 (0.0-25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5-11.3) days in the intervention group versus 6.9 (3.0-11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6-101.2) hours in the intervention group versus 47.3 (22.4-106.8) hours in the standard care group (median difference -12 hr; 95% CI, -56.8 to 32.7 hr). CONCLUSIONS: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT.

Efficacy and Safety of Parenteral High-Dose Vitamin C Therapy in Pediatric Patients: A Scoping Review.

OBJECTIVES: Recently, several adult trials have investigated the potential benefit of high-dose vitamin C therapy in critically ill patients. In pediatric patients, little is known on the efficacy, safety, and risk of high-dose vitamin C therapy. We aimed to review the efficacy and potential harm associated with high-dose vitamin C treatment. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library, and National Institute of Health Clinical Trials Register. STUDY SELECTION: We included studies in neonatal and pediatric patients who received IV or intra-arterial high-dose vitamin C (ascorbic acid) defined as greater than or equal to 75 mg/kg/d. DATA EXTRACTION: Two independent investigators screened articles and extracted data. DATA SYNTHESIS: We found 1,364 articles, assessed 193 full texts for eligibility, and identified 12 eligible studies. These studies included 855 patients, with 194 receiving high-dose vitamin C. The age of patients who received high-dose vitamin C ranged from 2 hours after delivery to 8.4 years (median 2.4 yr), and the vitamin C dose ranged from 100 to 1,500 mg/kg/d (median 260.5 mg/kg/d). Four studies were double-blind randomized controlled trials, and no clinical efficacy outcome was reported in favor of or against vitamin C. Furthermore, no adverse event or signal of harm was reported with high-dose vitamin C. CONCLUSIONS: In 12 studies with 194 children treated with parenteral high-dose vitamin C, there was no evidence of clinical efficacy or inferior clinical outcomes in double-blind randomized controlled trials, and no reported harmful effects. These findings justify further investigations of this treatment in children.

A critical care pandemic staffing framework in Australia.

BACKGROUND: Pandemics and the large-scale outbreak of infectious disease can significantly impact morbidity and mortality worldwide. The impact on intensive care resources can be significant and often require modification of service delivery, a key element which includes rapid expansion of the critical care workforce. Pandemics are also unpredictable, which necessitates rapid decision-making and action which, in the lack of experience and guidance, may be extremely challenging. Recognising the potential strain on intensive care units (ICUs), particularly on staffing, a working group was formed for the purpose of developing recommendations to support decision-making during rapid service expansion. METHODS: The Critical Care Pandemic Staffing Working Party (n = 21), representing nursing, allied health, and medical disciplines, has used a modified consensus approach to provide recommendations to inform multidisciplinary workforce capacity expansion planning in critical care. RESULTS: A total of 60 recommendations have been proposed which reflect general recommendations as well as those specific to maintaining the critical care workforce, expanding the critical care workforce, rostering and allocation of the critical care workforce, nurse-specific recommendations for staffing the ICU, education support and training during ICU surge situations, workforce support, models of care, and de-escalation. CONCLUSION: These recommendations are provided with the intent that they be used to guide interdisciplinary decision-making, and we suggest that careful consideration is given to the local context to determine which recommendations are most appropriate to implement and how they are prioritised. Ongoing evaluation of recommendation implementation and impact will be necessary, particularly in rapidly changing clinical contexts.

Adherence to standard medication infusion concentrations and its impact on paediatric intensive care patient outcomes.

AIM: To review compliance with the DERS, and to evaluate the impact on daily fluid balances as a standard outcome in paediatric intensive care. METHOD: A prospective audit of patients admitted to our tertiary level PICU over a 10day period. The audit tool collated information on patient's weight, diagnosis, medication infusions, whether standard concentrations were selected, daily fluid balance, target fluid balance, and renal support including use of diuretics. RESULTS: Seventy-seven (84%) of patients weighed less than 10kg. On average, there were seven medication infusions per patient and 98% of the medication infusions adhered to standard concentrations for medication infusions and DERS. In 2% of medication infusions staff opted not to use the DERS, or selected non-standard concentration, and 2% of patients had no labels on the syringe. 90% of patients had a minimal positive balance of 0.5mL/kg/h, averaged over 24h; 48% of patients received renal support and 16% of patients were 24h post cardiac surgery, where a negative fluid balance was recorded. It is standard practice post cardiac surgery to receive diuretics. Standard concentrations did not have a significant impact on patients' daily fluid balance. CONCLUSIONS: The use of standard concentrations and short infusions in PICU using DERS is feasible & achievable as demonstrated by high compliance, and does not have a negative impact on patient outcome, especially fluid balance.

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.

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.

Fosfomycin--investigation of a possible new route of administration of an old drug. A case study.

Patients with cystic fibrosis can develop multi-resistant organisms and may have poor intravenous access making antibiotic treatment difficult. This case discusses the successful use of fosfomycin via the subcutaneous route in a paediatric patient with cystic fibrosis.