Children’s Intensive Care Research Program

ARCH-India ‘Unnati’ Research Collaboration

Globally, critically-ill children are treated in Paediatric Intensive Care Units (PICUs), where clinical practice is informed by high-quality evidence generated by clinical trials. This project aims to deliver education to Indian paediatric intensive care clinicians on clinical trial methodology through a series of workshops, webinars and site visits. The Resuscitation in Paediatric Septic Shock using Mega-Dose Vitamin C and Hydrocortisone (RESPOND) Trial, a University of Queensland-led clinical trial investigating new treatments for paediatric sepsis, will be used as a case study. This work will ensure Indian hospitals can participate in international clinical trials and enhance their international visibility, ultimately benefitting their sickest children.

Contact: k.gibbons@uq.edu.au

RAPIDS; Funded by MRFF

Sepsis and life-threatening infections are one of the most common reasons for children to present to Intensive Care Units and may even result in death. Some of the biggest challenges in treating sepsis are the time required to obtain the accurate diagnosis of the infection (up to 48 hours), and deciding if and what antibiotics are required for treatment.

The RAPIDS multicentre trial is researching a blood test which may provide a test result (i.e., whether a viral or bacterial infection is present) within hours. This involves the use of the most modern tests to assess gene expression in children with a suspected infection as gene-sequencing based (“genomics”) sepsis diagnosis is likely superior to traditional infection testing.

It is the aim of this research to assess whether this new technology could become a standard of care in the future. This would result in faster detection of sepsis and therefore, more timely and efficient treatment of infections, reducing the unnecessary use of antibiotics.

Contact: paedsepsisresearch@uq.edu.au

Funded by PHRT, ETH Domain [Switzerland]

Sepsis is a leading cause of death and disability in children, accounting for an estimated 3 million deaths in children worldwide every year. A major limitation in paediatric sepsis management is the delay in obtaining accurate diagnosis because children with sepsis initially often have symptoms akin to common and mild viral illnesses. Therefore, fast, and reliable diagnosis of sepsis is a major unmet clinical need. Improved diagnostic strategies have great potential to result in better patient outcomes, lower costs, and less inappropriate antimicrobial usage.

Thanks to rapid omics technology, discriminative patterns of host responses to infection can now be tested systematically at transcriptomic, proteomic, and metabolomic levels. These technologies carry huge potential to unravel biological mechanisms underpinning sepsis and to enable discovery of novel biomarkers which can be implemented at the bedside in the future.

This study aims to improve the diagnosis of sepsis through host proteomics and metabolomics. We will build on the unique prospective cohort of critically ill children presenting acutely with suspected sepsis to hospital. Building on our discovery of host gene expression signatures characterizing dysregulated host response to bacterial infection, we will characterize the metabolome and proteome in this high-quality cohort and search for biological phenotypes associated with sepsis. Specifically, we will assess involved pathways leading to severe disease defined by the degree of organ dysfunction, in children with bacterial versus viral infection, compared to non-infected controls. Using machine learning on the multi-omics dataset, we aim to derive novel phenotypes, and subsequently derive signatures characterizing selected disease states of high clinical and prognostic relevance.

Contact: paedsepsisresearch@uq.edu.au

The NITRIC Follow-up Study; Funded by MRFF

Each year, over 1000 children with childhood heart disease (CHD) in Australia require heart surgery. The short and long-term outcomes of these children are determined by the impact of the surgical intervention, the response to cardiopulmonary bypass (CPB), and the direct consequences thereof during their intensive care stay. Neurodevelopmental disabilities remain amongst the most common, and the most damaging, adverse outcomes in children undergoing heart surgery.

One out of four infants undergoing heart surgery develop a harmful response to CPB, which leads to low cardiac output syndrome (LCOS). LCOS results in prolonged (multi-) organ dysfunction and adverse short-term outcomes which can manifesting into poor outcomes at school age. Currently, we do not possess reliable, sensitive, and rapid predictors for LCOS or adverse early and long-term outcomes. Preventive strategies to reduce LCOS remain of limited effectiveness.

We hypothesise that gene expression transcripts identify the harmful response to CPB, which leads to LCOS and prolonged severe organ failure post heart surgery in infants. The combination of transcripts will yield a signature allowing rapid discrimination of patients who will progress to LCOS and adverse outcomes. We will assess both short- and long-term outcomes manifesting into school age. This can ultimately enable the development of biomarkers for point of care testing.

Contact: nitricmrff@uq.edu.au

REDUCE; Funded by Children’s Hospital Foundation

The provision of intravenous fluids is a key component of treatment for a variety of conditions within the paediatric intensive care unit (PICU). However, there is currently a lack of evidence regarding the appropriate amount of fluid that should be administered to critically ill children. Excess fluid causes oedema which can impede oxygen delivery to cells and as such, result in the escalation of respiratory support as well as increase length of PICU stay. The REDUCE trial is aiming to assess whether administering a safe restricted volume of intravenous fluids will assist in achieving better outcomes in comparison to a liberal approach to fluid management.

Contact: sainath.raman@uq.edu.au

MELODY; Funded by Ramaciotti Foundation

Precision medicine—a method of tailoring the treatment approach for the patient by accounting for individual variability—is the future of healthcare. Clinical trials of precision medicine approaches have demonstrated that such an approach can improve clinical outcomes. In the Paediatric Intensive Care Unit (PICU), it is well documented that there is a paucity of high-quality evidence for paediatric critical care interventions and therapies—the sickest children are often excluded from high quality trials, and by consequence are exposed to suboptimal treatment. To date, there has been minimal use of the data rich PICU environment to boost the generation of knowledge at the individual level. Recently, thanks to breakthroughs in the application of computational science in health, the promise of embedded data algorithms to assist clinical decision making is becoming clear. Using advanced machine learning techniques, this project will develop a dynamic risk prediction model for early detection of patient deterioration using extensive, high-resolution data from >32,500 patient admissions across three large PICUs (Brisbane, Melbourne, and Zurich). The provision of resultant targeted treatments will increase the quality of life for children and their families who experience a PICU admission, reducing mortality and the impact of neurodevelopmental sequelae for PICU survivors.

Contact: k.gibbons@uq.edu.au

STAR-PICU; Funded by the ZOLL Foundation

Critically ill children around the world receive life-saving care in Pediatric Intensive Care Units (PICUs). But, 1 in 3 PICU survivors will have ongoing problems with the way they move, learn, think and feel after their ICU admission. For children under five, these problems can impact their developing brain, affecting schooling and causing problems into adulthood. Identifying how to change the care in the ICU can ensure we give children the best chance to reach their full potential. This research will use machine learning to understand what parts of PICU care affected the developmental outcomes of over 2000 PICU survivors in Queensland, Australia, during their first year of school. These results will assist clinicians to create programs to help young PICU survivors thrive at school.

Contact: p.gilholm@uq.edu.au

Funded by the Children’s Hospital Foundation

Over 10,000 children in Australia require life support for critical illness every year. While most children survive, the impact on long-term cognitive and functional outcomes remains poorly understood. We have successfully linked intensive care admission data of the past 20 years with standardised school testing and administrative databases, to investigate the long-term impact of critical illness. This project involves a novel application of data science approaches to this unique data set capturing health and educational trajectories in a large cohort of Queensland children who had critical illness before age five. We will use machine learning techniques to build and test a predictive model to identify, at time of hospital discharge, children at risk of poor educational outcomes in the future. We will for the first time explore the integration of this approach with prospective clinical data. The innovative study will provide urgently needed evidence to guide families, practitioners, and researchers.

Contact: k.gibbons@uq.edu.au

Funded by Metro South Research Support Scheme

Every year more than 200,000 babies, children and adults are admitted to hospital intensive care units (ICUs) in Australia and New Zealand, where they receive care because they are extremely sick. Almost 15,000 of these patients die, and thousands more leave the ICU with ongoing medical problems. Research is desperately needed to find new treatments to help these patients survive their hospital admission and regain their quality of life. One of the most important aspects of conducting research is ensuring the patient, or their family/carer, understands the research project and can provide informed consent before treatment starts. However, an admission to ICU is often one of the most stressful times in a patient’s, and their families, lives, and the added decision to participate in research can be extremely challenging and sometimes distressing. To deliver potentially new life saving treatments, and make sure obtaining consent does not add extra burden to patients and families, clinicians and researchers are now allowed to start some research treatments before obtaining consent, and ask for consent when the patient is in a more stable condition; this is called ‘delayed consent’. The acceptability of this approach—obtaining consent after treatment has started—for patients, carers, and clinicians, may be limited. It has been reported that many patients are surprised to learn it was possible for consent to be sought after treatment was delivered, and clinicians were apprehensive to ask for consent in this situation. Research is urgently needed to understand how patients and families want to be approached for delayed consent, to develop consent materials that are responsive to the high stress situation of an ICU stay, and support clinicians and researchers to have these difficult conversations.

Contact: k.gibbons@uq.edu.au

The diagnostic value of biomarkers in sepsis can only be realised if the results are available to clinicians in a timely way. Currently, many regional and remote facilities in Queensland do not have the on-site laboratory capabilities to accommodate this need. C-reactive protein (CRP) can be measured at the point of care (POC) using the TGA-approved Abbott Afinion CRP assay. We implemented a POC CRP device in Ayr, Charters Towers, Ingham (Townsville HHS), Cooktown and Weipa (Torres and Cape HHS) Emergency Departments (ED). This pilot demonstrated that the POC CRP device is acceptable to clinicians and the use is sustainable. The follow-up project involves the implementation of the POC CRP device across >56 sites with the aim of delivering safe and responsive care to priority populations living in regional, rural and remote areas. The student will undertake the evaluation of the implementation.

Project type: Masters / PhD

Contact: Dr Sai Raman

Health in-equity is unfortunately still prevalent in Australia. One of the key seps to address this problem is describe the burden of the problem. With this current project, we aim to investigate impact of SE status on health outcomes. The project will source data from Australia New Zealand Paediatric Intensive Care Registry, the Office of National Statistics and the Statistical Services Branch. The student will be mentored to source data, analyse the data, and write a manuscript.

Project type: Honours

Contact: Dr Sai Raman

Currently, critically ill children on the paediatric intensive care receive blood transfusion when their blood haemoglobin level drops below 70 gms/L. Children with certain cardiac conditions are administered blood at a level of 100 gms/L. While there is some evidence in the general paediatric intensive care cohort that these thresholds are safe, no clear evidence exists in patients supported on Extracorporeal Life Support. In this project, the student will perform a retrospective cohort study to investigate outcomes based on haemoglobin cut-offs in children placed on ECMO.

Project type: Honours

Contact: Dr Sai Raman

Critically ill children on the paediatric intensive care unit routine receive blood test and Chest X-rays every morning. While majority of these are clinically indicated, it is unclear what proportion of these change management. Using ML techniques, in this project, we aim to develop a clinical decision-making tool that will guide junior doctors to order clinical investigations appropriately. Additionally, we will explore the HE cost efficiency of such an approach. Furthermore, we will cross validate a similar project that is underway in the PICUs in the US.

Project type: Masters

Contact: Dr Sai Raman

Recent evidence suggests early mobility on intensive could augment recovery from severe critical illness. To apply an intervention directed at this facet of intensive care, we need to first observe and document the range of movements that children have on intensive care. In the novel observational study, we will be placing accelerometers (like smart watches) on children’s arms during their stay on PICU. We will then describe the interactions of severity of illness, intensive care procedures and mobility. The follow-up study would incorporate ‘liberation’ principles with an intervention directed at early mobility.

Project type: Masters / PhD

Contact: Dr Sai Raman

Unfortunately, children suffer cardiac arrest due to various reasons before being admitted to intensive care or whilst on PICU. There are some consensus guidelines on how to manage and support these children after return of spontaneous circulation. An international collaborative (Pedi-ResQ) has generated tools and dashboards to assist PICUs to benchmark their practice and improve care delivered to this sick cohort of children. The Queensland Children’s Hospital joined this collaborative earlier this year. We will implement a bundle of care that will include intra-arrest and post arrest goal directed care. This proposed study will have two components 1) a description and evaluation of the implementation of the bundle of care and 2) Objective quantitative analysis of outcomes of children post-cardiac arrest. The second project will be a pre-post cohort study design.

Project type: Masters

Contact: Dr Sai Raman

Our group described the epidemiology sepsis in children admitted to PICUs across ANZ about 10 years ago. Since then, there have been implementation of quality improvement programs in several states directed at early sepsis recognition and management. Now, we aim to explore if there has been any change in the patterns of sepsis presentation and outcomes. Others studies that the student could be part of are around delivery intravenous antibiotic therapy. In this program of research, we are investigating therapeutic drug monitoring, Bayesian forecasting, duration of antibiotic infusion and dosing on extracorporeal life support.

Project type: Masters / PhD

Contact: Dr Sai Raman

In a life-threatening situation when urgent life-saving care in an intensive care unit (ICU) is required, any delay to receiving treatment may increase the likelihood of a poor clinical outcome. In such instances, obtaining prospective informed consent for research from substitute decision makers for adult patients, and the families/carers of a paediatric patient, is challenging. This can lead to suboptimal research participation with acutely ill patients being deprived of the opportunity to benefit from new treatments.

It is largely unknown if a) delayed consent is acceptable to patients, families, and carers, b) clinicians and researchers feel adequately trained to undertake this approach, and c) HRECs have a thorough understanding of how to review projects with this consent approach. This project aims to:

1. Understand the perceptions of a broad range of stakeholders involved in consenting practices in an ICU.
2. Explore how demographic, social and/or clinical factors of patients, carers, families, clinicians researchers and HREC members, influenced satisfaction with the consent approach.

Develop responsive, sensitive, consenting materials that optimise research practices in health research after engaging in meaningful co-design with consumers, clinicians and HREC members.

Project type: Masters

Contact: Professor Kristen Gibbons

Precision medicine tailors therapies for an individual by taking into account the underlying heterogeneity in a population. Many models have been developed, but translation has only been successful in few disciplines. To date, the scarce precision medicine models in paediatric critical care have been limited by small sample sizes, lack of external validation and have not been trialled in clinical practice. However, PICU is optimised for precision medicine due to the large quantity of biomarkers measured, widespread implementation of electronic health records (EHRs), and extensive digitised physiological monitoring. Machine learning models derived from these granular, high-quality PICU datasets, coupled with omics data, will explain the biological heterogeneity. The models will identify children who are more likely to benefit from certain interventions and establish personalised care pathways for consumer-prioritised outcomes. Using the extensive, highly curated databank from the NITRIC clinical trial (largest international trial of infants undergoing heart surgery) and the follow-up study, and the RAPIDS observational cohort investigating better identification of children with sepsis, as sandpits to develop models to establish personalised trajectories, this project will:

1. Derive and validate phenotypes to quantify the heterogeneity of the patient cohort (including infants undergoing heart surgery, and septic patients).
2. Develop prediction models for prioritised short- and long-term outcomes incorporating clinical and omics data.

Project type: Multiple Masters / PhD

Contact: Professor Kristen Gibbons

Tailoring medical treatments to account for a patient’s individual variability is the future of healthcare. Clinical trials have demonstrated that such “precision medicine” approaches can improve clinical outcomes for patients. Recently, breakthroughs in the application of computational science in healthcare have shown the promise of using computer algorithms on health data to assist in clinical decision-making. For the most critically unwell children admitted to hospital, there is a lack of high-quality research for the treatments they receive—the sickest children are often excluded from high quality trials, and thus may not receive treatments that are optimal for them. A large amount of health-related data is generated within paediatric intensive care units (PICUs) but, to date, this data has not been fully utilised. Using extensive, high-resolution data from >32,500 patient admissions across three large PICUs (Brisbane, Melbourne, and Zurich), this project will use advanced machine learning techniques to develop a model to assist clinicians to detect deterioration of a child’s condition early so that they can intervene early. This will result in the right treatments being delivered at the right time — reducing mortality, decreasing neurodevelopmental complications, and ultimately increasing quality of life for children admitted to intensive care.

Project type: Masters/ PhD

Contact: Professor Kristen Gibbons

There is a paucity of high-quality trials to inform the life-saving care of children admitted to PICU. >75% of all PICU trials have ≤100 participants, >80% only recruit from a single centre and only 3% have used an innovative trial design, severely hampering the delivery of robust and generalisable results. The COVID-19 pandemic highlighted the need for agile trial infrastructure and international networks to rapidly generate gold-standard, personalised evidence to inform practice. Adult intensive care researchers demonstrated the feasibility of such an approach in a critical care setting, enrolling thousands of patients into global interventional trials using innovative designs. These learnings need to be translated to the paediatric setting to trial precision medicine approaches in a robust, efficient manner, delivering best care for children. This project will lay the foundations for translating a machine-learning model into clinical practice. Components of the project will include undertaking a systematic review, developing and deploying silent models into clinical care, and collecting and evaluating stakeholder feedback in relation to implementation of such models, and, using implementation science, designing best practice tools to promote the highest level of successful model translation.

Project type: Masters / PhD

Contact: Professor Kristen Gibbons

Sepsis, defined as life-threatening organ dysfunction caused by dysregulated host response to infection, affects an estimated 48.9 million cases every year. Sepsis is not only a leading cause of global mortality, but can result in long-term morbidity related to physical, cognitive, and psychosocial sequelae. This translates into a major health and economic burden to societies. In 2017, the World Health Organisation (WHO) declared sepsis a global health priority. The WHO resolution stated an urgent need to implement measures for the prevention, diagnosis, management, and follow-up support of sepsis. This project will use existing MRFF and NHMRC funded cohorts to identify and explore patterns of responses to long-term follow-up assessments and questionnaires from children and families after an intensive care admission, co-design with stakeholders enhanced methods for conducting long-term follow-up, and implement such strategies through a prospective project.

Project type: Masters / PhD

Contact: Professor Kristen Gibbons