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Background Intravenous fluid therapy represents the most common intervention critically ill patients are exposed to. Hyperchloremia and metabolic acidosis associated with 0.9% sodium chloride have been observed to lead to worse outcomes, including mortality. Balanced solutions, such as Plasma-Lyte 148 and Compound Sodium Lactate, represent potential alternatives but the evidence on optimal fluid choices in critically ill children remains scarce. This study aims to demonstrate whether balanced solutions, when used as intravenous fluid therapy, are able to reduce the incidence of a rise in serum chloride level compared to 0.9% sodium chloride in critically ill children. Methods This is a single-centre, open-label randomized controlled trial with parallel 1:1:1 assignment into three groups: 0.9% sodium chloride, Plasma-Lyte 148, and Compound Sodium Lactate solutions for intravenous fluid therapy. The intervention includes both maintenance and bolus fluid therapy. Children aged < 16 years admitted to intensive care and receiving intravenous fluid therapy during the first 4 h of admission are eligible. The primary outcome measure is a ≥ 5mmol/L increase in serum chloride level within 48 h post-randomization. The enrolment target is 480 patients. The main analyses will be intention-to-treat. Discussion This study tests three types of intravenous fluid therapy in order to compare the risk of hyperchloremia associated with normal saline versus balanced solutions. This pragmatic study is thereby assessing the most common intervention in paediatric critical care. This is a single-centre open-label study with no blinding at the level of delivery of the intervention. Certain paediatric intensive care unit (PICU) patient groups such as those admitted with a cardiac condition or following a traumatic brain injury are excluded from this study. Trial registration The study has received ethical approval (HREC/19/QCHQ/53177: 06/06/2019). It is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12619001244190) from 9th September 2019. Recruitment commenced on 12th November 2019. The primary results manuscript will be published in a peer-reviewed journal.

Use of extracorporeal membrane oxygenation (ECMO) is expanding, however it is still associated with significant morbidity and mortality. Activation of inflammatory and innate immune responses and hemostatic alterations contribute to complications. Hyperoxia may play a role in exacerbating these responses. Nine ex vivo ECMO circuits were tested using fresh healthy human whole blood, with two oxygen levels: 21% inspired fraction of oxygen (FiO ; mild hyperoxia; n=5) and 100% FiO (severe hyperoxia; n=4). Serial blood samples were taken for analysis of platelet aggregometry, leukocyte activation, inflammatory and oxidative stress markers. ECMO resulted in reduced adenosine diphosphate- (p

Up to 37% of children admitted to the PICU develop acute kidney injury as defined by Kidney Disease: Improving Global Outcomes criteria. We describe the prevalence of acute kidney injury in a mixed pediatric intensive care cohort using this criteria. As tools to stratify patients at risk of acute kidney injury on PICU admission are lacking, we explored the variables at admission and day 1 that might predict the development of acute kidney injury. Single-center retrospective observational study. Thirty-six-bed surgical/medical tertiary PICU. Children from birth to less than or equal to 16 years old admitted between 2015 and 2018. None. Clinical data were extracted from the PICU clinical information system. Patients with baseline creatinine at admission greater than 20 micromol/L above the calculated normal creatinine level were classified as "high risk of acute kidney injury." Models were created to predict acute kidney injury at admission and on day 1. Out of the 7,505 children admitted during the study period, 738 patients (9.8%) were classified as high risk of acute kidney injury at admission and 690 (9.2%) developed acute kidney injury during PICU admission. Compared to Kidney Disease: Improving Global Outcomes criteria as the reference standard, high risk of acute kidney injury had a lower sensitivity and higher specificity compared with renal angina index greater than or equal to 8 on day 1. For the admission model, the adjusted odds ratio of developing acute kidney injury for high risk of acute kidney injury was 4.2 (95% CI, 3.3-5.2). The adjusted odds ratio in the noncardiac cohort for high risk of acute kidney injury was 7.3 (95% CI, 5.5-9.7). For the day 1 model, odds ratios for high risk of acute kidney injury and renal angina index greater than or equal to 8 were 3.3 (95% CI, 2.6-4.2) and 3.1 (95% CI, 2.4-3.8), respectively. The relationship between high risk of acute kidney injury and acute kidney injury needs further evaluation. High risk of acute kidney injury performed better in the noncardiac cohort.

BackgroundSepsis contributes significantly to morbidity and mortality globally. In Australia, 20,000 develop sepsis every year, resulting in 5,000 deaths, and more than AUD$846 million in expenditure. Prompt, appropriate antibiotic therapy is effective in improving outcomes in sepsis. Conventional culture-based methods to identify appropriate therapy have limited yield and take days to complete. Recently, nanopore technology has enabled rapid sequencing with real-time analysis of pathogen DNA. We set out to demonstrate the feasibility and diagnostic accuracy of pathogen sequencing direct from clinical samples, and estimate the impact of this approach on time to effective therapy when integrated with personalised software-guided antimicrobial dosing in children and adults on ICU with sepsis.MethodsThe DIRECT study is a pilot prospective, non-randomized multicentre trial of an integrated diagnostic and therapeutic algorithm combining rapid direct pathogen sequencing and software-guided, personalised antibiotic dosing in children and adults with sepsis on ICU.Participants and interventionsDIRECT will collect microbiological and pharmacokinetic samples from approximately 200 children and adults with sepsis admitted to one of four ICUs in Brisbane. In Phase 1, we will evaluate Oxford Nanopore Technologies MinION sequencing direct from blood in 50 blood culture-proven sepsis patients recruited from consecutive patients with suspected sepsis. In Phase 2, a further 50 consecutive patients with suspected sepsis will be recruited in whom MinION sequencing will be combined with Bayesian software-guided (ID-ODS) personalised antimicrobial dosing.Outcome measuresThe primary outcome is time to effective antimicrobial therapy, defined as trough drug concentrations above the MIC of the pathogen. Secondary outcomes are diagnostic accuracy of MinION sequencing from whole blood, time to pathogen identification and susceptibility testing using sequencing direct from whole blood and from positive blood culture broth.DiscussionRapid pathogen sequencing coupled with antimicrobial dosing software has great potential to overcome the limitations of conventional diagnostics which often result in prolonged inappropriate antimicrobial therapy. Reduced time to optimal antimicrobial therapy may reduce sepsis mortality and ICU length of stay. This pilot study will yield key feasibility data to inform further, urgently needed sepsis studies. Phase 2 of the trial protocol is registered with the ANZCTR (ACTRN12620001122943).Trial registrationRegistered with the Australia New Zealand Clinical Trials Registry Number ACTRN12620001122943

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.

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.

Purpose Paracetamol has been associated with a reduction in blood pressure, especially in febrile, critically-ill adults. We hypothesised that blood pressure would fall following administration of paracetamol in critically-ill children and this effect would be greater during fever and among children with a high body surface area to weight ratio. Methods A 12-month prospective observational study of children (0–16 years) admitted to paediatric intensive care, who underwent pulse contour analysis and received paracetamol concurrently. Results Mean arterial blood pressure decreased significantly by 4.7% from baseline (95% CI 1.75–8.07%) in 31 children following 148 doses of paracetamol. The nadir was 2-hour post-dose. The effect was pronounced in children with fever at baseline (6.4%, 95% CI 2.8–10%), although this was not statistically significant. There was no simple relationship between this effect and body surface area to weight ratio. The association between a change in blood pressure and changes in heart rate or measured stroke volume was poor; therefore it was likely that a change in the systemic vascular resistance contributes most to this effect. Conclusion There is a significant but modest reduction in blood pressure post-paracetamol in critically-ill children. This is likely related to a change in systemic vascular resistance.

Objectives: To derive a relationship between the Spo(2)/Fio(2) ratio and Pao(2)/Fio(2) ratio across the entire range of Spo(2) values (0-100%) and to evaluate whether mortality prediction using the Pediatric Index of Mortality-3 can be improved by the use of Pao(2)/Fio(2) values derived from Spo(2)/Fio(2).Design: Retrospective analysis of prospectively collected data.Setting: A regional PICU transport service.Patients: Children transported to a PICU.Interventions: None.Measurements and Main Results: The relationship between Spo(2)/Fio(2) and Pao(2)/Fio(2) across the entire range of Spo(2) values was first studied using several mathematical models in a derivation cohort (n = 1,235) and then validated in a separate cohort (n = 306). The best Spo(2)/Fio(2) Pao(2)/Fio(2) relationship was chosen according to the ability to detect respiratory failure (Pao(2)/Fio(2) = 200). The discrimination of the original Pediatric Index of Mortality-3 score and a derived Pediatric Index of Mortality-3 score (where Spo(2)/Fio(2)-derived Pao(2)/Fio(2) values were used inplace of missing Pao(2)/Fio(2) values) were compared in a different cohort (n = 1,205). The best Spo(2)/Fio(2)-Pao(2)/Fio(2) relationship in 1,703 Spo(2)/Fio(2)-to-Pao(2)/Fio(2) data pairs was a linear regression equation of ln[PF] regressed on ln[SF]. This equation identified children with a Pao(2)/Fio(2) less than or equal to 200 with a specificity of 73% and sensitivity of 61% in children with Spo(2) less than 97% (92% and 33%, respectively, when Spo(2) = 97%) in the validation cohort. Pao(2)/Fio(2) derived from Spo(2)/Fio(2) (derived Pao(2)/Fio(2)) was better at predicting PICU mortality (area under receiver operating characteristic curve, 0.64; 95% CI, 0.55-0.73) compared with the original Pao(2)/Fio(2) (area under receiver operating characteristic curve, 0.54; 95% CI, 0.49-0.59; p = 0.02). However, there was no difference in the original and derived Pediatric Index of Mortality-3 scores and their discriminatory ability for mortality.Conclusions: Spo(2)-based metrics perform no worse than arterial blood gas-based metrics in mortality prediction models. Future Pediatric Index of Mortality score versions may be improved by the inclusion of risk factors based on oxygen saturation values, especially in settings where Pao(2) values are missing in a significant proportion of cases.