"The MRINZ now has the capability to act autonomously as the trial coordinating centre in New Zealand for large scale pivotal multicentre, multi-national trials in intensive care and respiratory medicine."
"The MRINZ is the most productive independent medical research organisation in New Zealand."
"Despite its relatively small size the MRINZ produces about one peer-reviewed publication every week, which is a remarkable output."
The MRINZ is part of an international collaborative group which has proposed a paradigm shift in the approach to the management of asthma and COPD. It is based on the concept that asthma and COPD represent a continuum of different diseases that share biological mechanisms and present with distinct clinical, pathophysiological and psychosocial features that can be observed and which require individualised treatment. This allows treatments to be targeted to the needs of individual patients on the basis of such clinical characteristics that distinguish a given patient from other patients. This ‘precision medicine’ approach has been adopted in the Asthma & Respiratory Foundation (New Zealand) Adult Asthma Guidelines: a quick reference guide, released in 2016.
Comment: Recognition of ‘treatable traits’ will allow an individualised approach to the management of asthma and COPD.
Treatment of mild asthma
In New Zealand about 20% of adults have asthma, of whom 60% have mild disease. Guideline-based treatment of mild asthma is regular inhaled corticosteroids (ICS), with a short-acting beta agonist (SABA) as a separate inhaler used when needed for symptom relief. The benefits of regular ICS use are limited in actual clinical practice by poor ICS adherence and low prescription rates. The MRINZ is coordinating two large 12 month randomised controlled trials of patients with mild asthma to determine if a novel regimen of a combination ICS/fast onset long-acting beta agonist inhaler taken as required for relief of symptoms is superior to regular ICS therapy with SABA as required. One of these studies (Novel START) is being undertaken in sites in the United Kingdom, Italy, Australia and New Zealand, while the other study (PRACTICAL) is being undertaken in multiple sites in New Zealand.
Comment: These studies have the potential to change practice in New Zealand and internationally and to improve outcomes in patients with mild asthma who have a poorly recognised yet important burden of disease.
Avoidance of hyperoxaemia during cardiac surgery
Multi-organ damage and dysfunction is common in patients who have undergone open heart surgery using cardiopulmonary bypass (CPB). One of the mechanisms that is thought to play a part in this process is through the production of reactive oxygen species (ROS). Previous studies have suggested that the production of ROS is more marked in the presence of hyperoxaemia, which commonly occurs during CPB. We randomised 298 patients to a strategy that avoided hyperoxaemia during CPB or standard care. Despite producing a significant reduction in the extent of the hyperoxaemia we did not demonstrate any signal of clinical benefit.
Comment: This is an important initial study investigating the avoidance of hyperoxaemia in patients undergoing cardiac surgery, but further work is required to fully assess if this approach is beneficial.
Use and timing of tranexamic acid and aspirin in patients having cardiac artery bypass surgery
Aspirin is used to reduce the chances of arterial blockages in patients with several conditions including coronary artery disease. Cardiac arterial bypass grafting is the definitive treatment for coronary artery disease yet it is a major surgical procedure with significant risk of blood loss. The traditional approach to these patients has been to stop aspirin at least 5 days before surgery and to use an antifibrinolytic agent, most commonly tranexamic acid, to reduce perioperative bleeding. It was unknown if this approach produced the best patient outcomes by minimising the risk of bleeding whilst potentially increasing the risk of thrombotic events. The ATACAS trial sought to address this in 4,631 patients from 31 sites in 7 countries. Two New Zealand sites participated and together enrolled more than 600 patients. The study had two important findings; firstly that continuing aspirin until the day of surgery neither increased the risk of thrombosis nor bleeding and secondly that the administration of tranexamic acid significantly reduced bleeding without any higher risk of thrombotic complications.
Comment: We now know that it is safe for patients undergoing coronary artery surgery to continue their aspirin until the time of surgery and that the routine use of tranexamic acid in these patients is beneficial.
The New Zealand Improving Outcomes After Cardiac Surgery Network
Following its establishment last year IOACSNet has reached some important milestones in 2016. TRiCS III became the first clinical trial in cardiac surgical patients to recruit from all five public hospital cardiac surgery centres in New Zealand with our total recruitment now exceeding 570 patients in this landmark trial of 5,000 patients that will finish in early 2017. The New Zealand component of this international study has been funded by the Health Research Council of New Zealand.
The Fluid after Bypass study received funding from the Heart Foundation and commenced recruitment in Auckland in 2016 and will expand to all five centres in early 2017. The LAAOS III study now has three New Zealand centres and the ITACS study will commence recruitment in New Zealand in 2017.
Comment: IOACSNet has achieved its primary aim of involving all five public hospitals that undertake cardiac surgery in high quality collaborative research.
Alternative and Complementary Medicine
An important priority for the MRINZ is supporting the New Zealand biotechnology industry by undertaking randomised controlled trials of novel therapies or devices. 2016 has seen the expansion of the programme with a 950 participant randomised controlled trial, looking at a novel honey-based treatment for cold sores. The MRINZ has developed a novel methodology for this study, establishing a Pharmacy Research Network of over 50 pharmacists across New Zealand who conduct the study at the pharmacist/patient interface. The success of the network has paved the way for affordable, community-based studies that look to provide an evidence base for over-the-counter alternative and complementary treatments for common ailments.
Comment: The Pharmacy Research Network has provided the opportunity to undertake clinical research of alternative and complementary medicines developed in New Zealand.
Chronic obstructive pulmonary disease (COPD)
The chronic breathlessness of COPD is physically limiting, socially isolating and associated with depression and anxiety. Pulmonary rehabilitation improves quality of life, exercise tolerance and breathlessness in patients with COPD. Adding to and sustaining these benefits are much needed topics of research. Singing has reported health benefits, and some data suggest beneficial effects on hyperinflation and mood in patients with COPD.
Having established a free community-based singing group, Sing Your Lungs Out (SYLO), in Newtown, Wellington in 2014, we conducted qualitative and quantitative studies to evaluate the potential health benefits for patients with COPD who had previously completed a pulmonary rehabilitation programme. These published studies have demonstrated that participation in a weekly community singing group is feasible for patients with COPD of varying severity, resulting in clinically important improvements in respiratory function and mood. Patients themselves reported enjoyment, purpose and connectedness. A third study is underway, comparing weekly singing group (Porirua SYLO) participation with a hospital-based standard pulmonary rehabilitation programme.
Therapeutic singing groups for COPD patients have now been established in Masterton and Motueka using the SYLO-study model.
A short documentary film is being made outlining the story of the Sing Your Lungs Out group. We hope this might encourage, inspire and inform other centres considering similar initiatives.
Comment: This community singing group is an example of a low-cost, community-based, patient-centred, non-pharmacological intervention for COPD.
Alongside our strong programmes of investigator-led research, the MRINZ has a stream of research supporting clinical trials of new therapeutic agents developed by the pharmaceutical industry. A particular focus is on new monoclonal antibodies which may offer a chance for personalised therapy for patients with severe asthma or COPD. Over the last year we have been recruiting participants in three studies exploring the short and medium term benefits offered by these new agents.
Comment: These novel medicines represent the future of respiratory medicine for many patients with severe disease and in some cases participation in clinical research can provide access to new treatments for people who have not responded to current funded therapies.
The MRINZ is committed to improving medical practice through the development and implementation of evidence-based management guidelines. A key initiative in 2016 was the senior role in the drafting of guidelines of the Asthma & Respiratory Foundation (New Zealand) Adult Asthma Guidelines: a quick reference guide. The guidelines are designed to aid health professionals in delivering asthma care in the community, providing simple evidence-based recommendations for the diagnosis, assessment and treatment of asthma in adults. Prior to this initiative New Zealand asthma guidelines had not been updated since 2002.
Comment: Many of the key recommendations are based on landmark research undertaken at the MRINZ which has led to improvements in the management of asthma worldwide.
Delirium is a problem with brain function that develops when patients are acutely unwell. It is characterised by vivid hallucinations, delusions, and an inability to focus. Patients requiring life support in intensive care units are particularly likely to become delirious and often become agitated and aggressive. When delirium occurs it is often terrifying for patients and their families. Until now, there was no specific treatment, and doctors often resorted to masking the symptoms with heavy doses of sedatives. Ground-breaking research involving MRINZ Intensive Care researchers has demonstrated the first effective treatment for agitated ICU patients with delirium. The research found that for patients on life support with agitated delirium, a medicine called dexmedetomidine allowed them to come off life support sooner, hastened resolution of delirium, and was safe and well-tolerated. Dexmedetomidine reduces the amount of time that patients spend on life support by around a day. Each day that a patient spends in ICU on life support costs around $4,000. In comparison, a day of dexmedetomidine treatment costs only around $140.
Comment: Dexmedetomidine is the first effective treatment for delirium in ICU patients. This treatment has been incorporated into standard clinical practice and patients in New Zealand and around the world are benefiting from this important therapeutic advance.
Community-acquired pneumonia that is of sufficient severity to require admission to an ICU is associated with substantial mortality. For many of the treatments provided to patients with community-acquired pneumonia, different options are available currently and it is not clear which treatment is best. For example, several antibiotics exist that are active against the bacteria that cause pneumonia but it is not known if one antibiotic strategy is best or whether all suitable antibiotic strategies have similar levels of effectiveness. Using current conventional clinical trials methods to assess the efficacy of treatments for pneumonia, in a series of separate and sequential trials would take an inordinate length of time to study and it would not be possible to evaluate interactions between treatment options. Instead, MRINZ investigators, under the leadership of Dr Colin McArthur, are participating in the global clinical trial that is designed to optimise treatments for patients with severe community-acquired pneumonia. The trial is called REMAP-CAP which stands for Randomised Embedded Multifactorial Adaptive Platform – Community-Acquired Pneumonia. The trial is very exciting because the particular design of the trial means that information obtained from previous trials participants is used to increase the chances that current patients will receive the best treatments. Recruitment of patients into REMAP-CAP will begin in 2017.
Comment: The pneumonia platform trial is an exciting trial that is designed to improve outcomes for patients with community-acquired pneumonia around the world.
Fever is a common clinical problem in the critically ill and clinicians currently make decisions about how to manage fever on the basis of a very limited evidence base. Establishing the appropriate management strategy for dealing with fever in critically ill patients will directly inform clinical decision-making to strengthen healthcare practice. Dr Paul Young has been awarded a Clinical Practitioner Research Fellowship from the Health Research Council of New Zealand to support and expand his programme of research investigating the management of fever in ICU patients. Specifically, the programme will evaluate fever management strategies in: (i) adults with fever who are expected to require prolonged life support; (ii) adults with traumatic brain injury who require management in an ICU; and (iii) adults admitted to ICU following an out-of-hospital cardiac arrest.
Comment: The MRINZ ICU fever research programme is an expanding one. This programme has developed from our previous research, published in the New England Journal of Medicine in 2015, that established that it was safe to use paracetamol to treat fever in ICU patients with infections.
Acutely ill patients are commonly treated with intravenous fluids. A randomised controlled trial of commonly used intravenous fluids in ICU which was led by the MRINZ and conducted in four ICU’s in New Zealand was published in the prestigious Journal of the American Medical Association in 2015. The study, funded by the Health Research Council of New Zealand, was undertaken because doctors were troubled by the emerging evidence suggesting that using saline might increase the risk of kidney failure in critically ill patients, yet struck by the lack of data from clinical trials of the safety of newer intravenous fluids such as PlasmaLyte. The trial showed that outcomes for patients who received saline and PlasmaLyte were similar. These findings provide reassurance about the safety of intravenous saline, which is administered to around one million patients in the world every day.
Following on from the publication of this trial in 2015 Dr Young has contributed to three editorials and two review articles about intravenous fluid therapy in 2016. These contributions have been important to ensuring translation of the research findings into practice and have included publications in three of the four highest impact Intensive Care journals in the world.
Comment: The MRINZ, in partnership with the George Institute for Global Health, is currently undertaking an 8,800 participant clinical trial that is designed to determine whether using 0.9% saline or PlasmaLyte for fluid resuscitation in ICU alters the risk of death. This trial is likely to inform clinical practice in relation to intravenous fluid therapy for decades to come.
Nutrition therapy is an essential standard of care for all ICU patients who require life support and remain in ICU for more than a few days. There is a substantial and well-established dissociation between the recommended calorie requirement and calories actually delivered to ICU patients. Nevertheless, while it remains logical that energy delivery should match energy consumption, the benefits of such matching remain to be confirmed by a robust, high quality clinical trial. With funding from the Health Research Council of New Zealand, we are currently undertaking the TARGET study in collaboration with Australian and other New Zealand investigators to determine if delivery of the full recommended calorie (energy) requirement to critically ill patients improves 90-day survival when compared to standard practice.
Comment: The TARGET study will include patients from nearly every New Zealand ICU and will enrol 4,000 ICU patients overall. We expect that the TARGET study will be published in 2018.
Stress ulcer prophylaxis
The administration of stress ulcer prophylaxis (SUP), either with a Proton Pump Inhibitor (PPI) or a Histamine-2 Receptor Blocker (H2RB) is recommended in international guidelines and incorporated into quality-oriented checklists for care of ICU patients. Our recent data show that PPIs and H2RBs are routinely used for SUP in Australia and New Zealand with the choice of medication probably not based on patient factors, but instead dependent on clinician preference or unit policy. This practice variation reflects the lack of definitive evidence comparing PPIs to H2RBs in the ICU setting. Although data suggest PPIs are more effective at reducing upper GI bleeding risk in ICU patients than H2RBs, it also appears that using PPIs in ICU patients is associated with an increase in pneumonia risk compared to H2RBs, and that PPI use but not H2RB use is associated with increased risk of Clostridium difficile infection. The overall influence of the opposing risks of upper GI bleeding and SUP-related infectious complications on in-hospital mortality is unknown. We are currently leading the PEPTIC study, a Health Research Council of New Zealand-funded study which is a multicentre, multi-national trial comparing the safety and efficacy of PPIs versus H2RBs in 40,000 mechanically ventilated ICU patients.
Comment: The PEPTIC study will be the largest clinical trial ever undertaken in critically ill patients.
The MRINZ has a long-standing collaboration with researchers from the University of Auckland and University of Otago, working to identify associations between various lifestyle factors and obesity in children and adolescents. The collaboration utilises data on over 250,000 children from 71 centres in 35 countries, from the ISAAC programme. In 2016 we published a major study investigating the association between birthweight and body mass index (BMI) in the ISAAC children. We found that the higher the birthweight, the greater the BMI at age 6 to 7 years.
Comment: The ISAAC programme is the largest asthma epidemiology study ever undertaken. It has provided the opportunity to investigate the risk factors for childhood obesity, as well as for asthma, which was the original intent of the research programme.
Oxygen therapy has been demonstrated to place patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) at risk of carbon dioxide retention and poor clinical outcomes. This has led to a change in practice with more careful use of oxygen given to such patients transferred by ambulance to hospital. However an audit of management in Wellington has shown that while oxygen therapy is more carefully controlled, its use to drive bronchodilator nebulisers still leads to inappropriately excessive delivery of oxygen. This has led to a Health Research Council of New Zealand-funded study which has shown that the use of air is safer than oxygen in the nebulisation of bronchodilators in acute exacerbations of COPD.
Comment: This study is an example of how clinical research is guided by the findings of audits of clinical practice.
High Flow Delivery Devices
MRINZ has also been investigating the use of a device from Fisher & Paykel Healthcare called AIRVO which delivers high flow humidified air through nasal prongs to patients with respiratory conditions. In two clinical trials we have shown that the AIRVO device is safe to use in patients with stable COPD and in those admitted to hospital with an acute exacerbation of COPD. We are now coordinating an international study to observe whether COPD patients may find it beneficial to take a device home after admission to hospital with an exacerbation.
Comment: The collaboration with Fisher & Paykel Healthcare represents an important priority for the MRINZ, in its commitment to support the New Zealand biotechnology industry.
More than 20,000 New Zealanders (and 20M people globally) are admitted to an intensive care unit (ICU) annually. ICU patients are the sickest patients in the hospital, most require life support (invasive mechanical ventilation), and many die from their critical illness. Supplemental oxygen is universally administered to patients who require life-support but the correct dose of oxygen to provide is currently not known. We are undertaking a 1000-participant randomised controlled trial to establish whether careful titration of oxygen to avoid exposure to either abnormally high or low levels of oxygen (conservative oxygen therapy) improves outcomes compared to standard oxygen therapy in ICU patients who require life support.
Comment: This study will not only inform clinical practice in the use of oxygen therapy in the ICU, but also oxygen therapy in other clinical situations.
The MRINZ has had a key role in setting up and coordinating the largest randomised controlled trial of the treatment of pneumothorax (collapsed lung). It challenges current dogma that the preferred treatment is an invasive approach based primarily on the insertion of a chest drain. The study, which has been undertaken across 33 hospitals in Australia and New Zealand, is nearing completion and the results will be available in 2017.
Comment: Through this study a strong network of trial centres in pleural disease has been built in Australia and New Zealand, and this will facilitate ongoing research.
2016 was a significant year for the Stroke/Rehabilitation programme with the set-up and commencement of the Heath Research Council of New Zealand-funded randomised controlled trial ‘Taking Charge After Stroke – the TaCAS study’. This clinical trial will test whether the ‘Take Charge session’, developed in a previous clinical trial by the MRINZ, is effective for a wide range of stroke-affected individuals. This multicentre study based in seven district health boards in New Zealand has now recruited over 250 of the planned 400 people discharged to community living after stroke. Discussions are also under way about a ‘Take Charge’ study in Australia.
Comment: If the results of this study back up the previously positive randomised controlled trial of the ‘Take Charge session’ in Māori; and Pacific people with stroke (the MaPSS study, also run by MRINZ), this simple, cheap, safe intervention could make a very significant impact on stroke outcomes in New Zealand and elsewhere.
Research from the MRINZ has recently shown that prolonged seated immobility at work is an important yet previously unrecognised risk factor for venous thromboembolism, comprising deep vein thrombosis and/or pulmonary embolism (aka blood clots). The focus has now turned to preventive measures to reduce this risk.
This year we assessed the effectiveness of a small footstool (the Legflow device) at increasing the flow of blood in the legs while sitting in a work chair. We found that using the Legflow device resulted in a significantly better blood flow in the legs compared to sitting still. We are now in the process of assessing the feasibility of implementing the Legflow device in a work office environment.
In line with this, we have been investigating the risk of blood clots in patients who have injured their lower leg and have been placed in a leg cast as part of their treatment plan. We have found that this patient group contributes to one in every seven cases of blood clots, representing the largest potentially preventable risk factor for blood clots.
Comment: Through this research programme, we aim to develop a comprehensive package of interventions for the prevention of venous thromboembolism in situations in which prolonged seated immobility cannot be avoided.