Landmark IV Fluid Study Findings Set to Save Lives  

Saline, a 200-year-old medical therapy given to millions of patients around the world each day, appears to increase the risk of death in patients who are acutely ill.

A landmark intravenous (IV) fluid study, and a comprehensive systematic review paper, both published today in the New England Journal of Medicine (NEJM), are of major significance for global public health, and set to change clinical practice worldwide.

Together the ‘PLUS Study’ and the ‘The choice between balanced crystalloids and normal saline: a systematic review and meta-analysis’ evidence paper provide compelling proof that for most people who are critically ill, using balanced crystalloids for intravenous fluid therapy rather than saline saves lives.

Medical Research Institute of New Zealand (MRINZ) deputy director, PLUS Study lead, and intensive care (ICU) specialist, Professor Paul Young, says “A patient receiving an IV fluid drip is perhaps one of the most enduring images in medicine. These recent findings will change practice for one of the most fundamental therapies applied to acutely unwell patients.”

IV fluids are one of the most common treatments for patients who are acutely ill. Such fluids are given for many reasons including treating dehydration and when blood pressure is low.

Saline, a low-cost salt and water solution, is among the most used IV fluids, first administered during the cholera epidemics of the 1830s. Today alone, more than a million litres of IV saline will be given to patients worldwide. Balanced crystalloids, an alternative to saline used in hospitals worldwide, are salt-based solutions with an electrolyte composition that mimics human plasma.

“ICU and emergency physicians have long debated the choice of IV fluid therapy in critically ill adult patients, with ongoing controversy over the relative effectiveness and safety of balanced crystalloids compared with saline.” says Professor Young.

Because saline was introduced into clinical practice almost two hundred years ago, it was not initially subjected to the same rigorous testing as is applied to new drugs. While studies globally have consistently suggested that balanced crystalloids might reduce the risk of death compared to saline, each study, by itself, has been too small to demonstrate a statistically significant mortality reduction, with worldwide discourse and uncertainty around best practice.

Over the past decade the MRINZ has run a landmark programme of research evaluating whether using a balanced crystalloid called Plasma Lyte® improves patient outcomes compared with saline.

MRINZ’s most recent trial, the ‘PLUS Study’, funded by the Health Research Council of New Zealand, enrolled 5037 critically ill patients across Aotearoa New Zealand and Australia to test the hypothesis that fluid resuscitation and therapy with Plasma Lyte® would decrease 90-day mortality, when compared to saline. Participants received study fluids for longer and in greater volume than in previous trials.

The PLUS study has significantly added to an overall research documentation base, and, when combined with data from previous studies, provides compelling evidence that using balanced crystalloid treatment instead of saline fluid in acutely ill adults saves lives.

“The PLUS study is hugely important because it is the final piece of the puzzle. When the data from PLUS was combined with other study data, the uncertainty around IV fluid choice is finally resolved. This is really the last word on the dangers associated with a 200-year-old medical therapy that is still widely used.” says Professor Young.

“Professor Young and his MRINZ ICU Research team have dedicated years to examining the safety and efficacy of intravenous fluids, and these latest findings are likely to be regarded as the definitive word on this topic.” says Professor Richard Beasley, MRINZ director. “This is a significant landmark in critical care research which will greatly serve the medical community and change clinical practice worldwide.”

KEY POINTS AT A GLANCE

1. The ‘PLUS study’ and the ‘The choice between balanced crystalloids and normal saline: a systematic review and meta-analysis’ evidence paper provide compelling proof that for most people who are critically ill, using balanced crystalloids for intravenous fluid therapy rather than saline saves lives.

2. Combined analysis from existing studies comparing patient outcomes across saline and balanced crystalloid treatment demonstrates that crystalloid fluid treatment reduces the risk of death in patients who are acutely ill compared to saline, except for those with traumatic brain injury.

3. Historic studies have consistently demonstrated that balanced crystalloids reduce the risk of death compared to saline, however, each study, by itself, was too small to demonstrate a statistically significant mortality reduction.

4. Challenging a worldwide two-hundred-year-old treatment, the recent MRINZ-led ‘PLUS study’ adds to an overall evidence base, that when combined with other data, provides compelling evidence that using balanced crystalloids in acutely ill adults can save lives.

5. Medical Research Institute of New Zealand (MRINZ) deputy director, ICU specialist, Professor Paul Young, co-authored the ‘PLUS Study’ and ‘The choice between balanced crystalloids and normal saline: a systematic review and meta-analysis’, both published in the NEJM.

BACKGROUND TRIAL DETAIL

PLUS Study
The MRINZ-led PLUS Study looked at whether using a balanced multi-electrolyte solution (Plasma-Lyte 148®) in preference to 0.9% sodium chloride (saline) in critically ill patients reduces the risk of acute kidney injury or death.

In a concealed, blinded trial patients critically ill patients were randomly assigned Plasma-Lyte 148®, a balanced multi-electrolyte solution (BMES), or saline for fluid therapy in the intensive care unit (ICU) during the ensuing 90 days.

Of the 5037 patients recruited from 53 ICUs in Australia and New Zealand, 2515 were assigned to receive BMES and 2522 to saline. There were 530 deaths in both the BMES and saline groups; mortality rates 21.8% and 22.0% respectively (difference -0.15, 95% confidence interval [CI] -3.60 to 3.30; P=0.90).

Evidence Paper: ‘The choice between balanced crystalloids and normal saline: a systematic review and meta-analysis'
To provide an updated summary of significant available evidence, a collective of ICU specialists from Australia, the United Kingdom, Brazil and New Zealand conducted a review to examine to what extent currently documented information allows intensivists and emergency physicians to choose the right fluid for their patients.

‘The choice between balanced crystalloids and normal saline: a systematic review and meta-analysis' reviewed thirteen significant randomised clinical trials with 35,884 participants. The combined analysis showed that the estimated effect of using balanced crystalloids versus saline in critically ill adults ranges from a 9% relative reduction to a 1% relative increase in risk of death with a high probability that the average effect of using balanced crystalloids is to reduce mortality.

MEDICAL RESEARCH INSTITUTE OF NEW ZEALAND
Rangahautia Te Ora

The Medical Research Institute of New Zealand (MRINZ) is Aotearoa New Zealand’s leading independent medical research institute. MRINZ research is guided by a simple philosophy: it must challenge dogma, increase knowledge, and have the potential to improve clinical practice and outcomes, both in Aotearoa New Zealand, and internationally.

The MRINZ’s research teams are dedicated to investigating important public health problems, delivering high quality evidence on which to improve the management of disease and patient care. An internationally recognised academic institution, the MRINZ operates under a charitable trust pursuing advances in clinical practice and providing a base for specialist training in medical research. The MRINZ is committed to contributing toward a more equitable society that celebrates Te Ao Māori and upholds Te Tiriti o Waitangi.

Professor Paul Young
Deputy Director, MRINZ; Co-clinical leader and Intensive Care Specialist, Wellington Hospital Intensive Care Unit; Medical Director, Wakefield Hospital Intensive Care Unit, Wakefield Hospital, BSc (Hons), MBChB, PhD, Grad Cert Crit Care Echo, Clinical Associate Professor, University of Melbourne, Adjunct Professor, Monash University.

Professor Young is a member of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) and leading member of the New Zealand ICU research community. His primary interest is in the design and conduct of large-scale multicentre randomised controlled trials in the field of Intensive Care Medicine. He has published over 150 peer-reviewed journal articles including numerous high impact publications in the New England Journal of Medicine, the Lancet, and the Journal of the American Medical Association. He is involved in research collaborations with scientists from Australia, the UK, Canada, the USA, Italy, Scandinavia, Saudi Arabia, and Brazil. He is the Associate Editor for Critical Care and Resuscitation.

Follow Paul’s clinical trial research on Twitter @DogICUma