Plasma-Lyte 148® versUs Saline Study (PLUS)

Comparison of Plasmalyte 148® and Saline for Fluid Resuscitation and Intravenous Fluid Therapy in Critically Ill Adults

The aim of PLUS is to conduct a multi-centre, blinded, randomised, controlled trial (RCT) to determine whether fluid resuscitation and therapy with a "balanced" crystalloid solution (Plasma-Lyte 148®) decreases 90-day mortality in critically ill patients requiring fluid resuscitation when compared with the same treatment using 0.9% sodium chloride (saline)

Study Overview

• Status: Completed
• Conditions: Hypovolemia
• Intervention / Treatment: Drug: Plasma-Lyte 148®; Drug: 0.9% sodium chloride

Detailed Description

Fluid resuscitation is a fundamental component of the management of acutely and critically ill patients and the choice of fluid is a longstanding issue of debate.

Worldwide, 0.9% saline has traditionally been the most widely used resuscitation fluid, however its use is increasingly challenged by emerging evidence that suggests its high chloride content may have clinically important adverse effects and that resuscitation with so-called "balanced" or "buffered" crystalloids (such as Plasma-Lyte 148®) offer patients better outcomes.

Given the limitations of current evidence, there is now a scientific, ethical and health economic imperative to provide an accurate and reliable estimate of the comparative risks versus benefit of Plasma-Lyte 148® versus 0.9% saline.

The PLUS study is a prospective, multi-centre, parallel group, concealed, blinded, randomised, controlled trial.

The study will test the hypothesis that in a heterogeneous population of critically ill adults, random assignment to Plasma-Lyte 148® for intravascular volume resuscitation and crystalloid fluid therapy in the Intensive Care Unit (ICU) results in different 90-day all-cause mortality when compared with random assignment to 0.9% sodium chloride (saline) for the same treatment.

Each patient who meets all inclusion criteria and no exclusion criteria will be randomised to receive either Plasma-Lyte 148® or 0.9% saline for all resuscitation episodes and for all compatible crystalloid therapy while in ICU for up to 90 days after randomisation. Other crystalloid fluids may be used as carrier fluids for the infusion of any drug for which either Plasma-Lyte 148® or 0.9% saline is considered incompatible.The study treatments will be supplied in identical 1000 ml bags and treatment assignment will be concealed.

The volume of study fluid being administered will be titrated against clinical endpoints determined by the treating clinicians and reviewed as clinically appropriate during the period of resuscitation and ICU treatment.

• Study Type: Interventional
• Enrollment (Actual): 5037
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Caringbah, New South Wales, Australia, 2229
      • The Sutherland Hospital
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
    • Hornsby, New South Wales, Australia, 2077
      • Hornsby Ku-Ring-Gai Hospital
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Penrith, New South Wales, Australia, 2751
      • Nepean
    • St Leonards, New South Wales, Australia
      • Royal North Shore Hospital
    • Wagga Wagga, New South Wales, Australia, 2650
      • Wagga Wagga Rural Referral Hospital
    • Wahroonga, New South Wales, Australia, 2076
      • The Sydney Adventist Hospital
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
    • Wollongong, New South Wales, Australia, 2500
      • Wollongong Hospital
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • The Wesley Hospital
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Redcliffe, Queensland, Australia, 4020
      • Redcliffe Hospital
    • Robina, Queensland, Australia, 4226
      • Robina Hospital
    • South Brisbane, Queensland, Australia, 4101
      • Mater Misericordiae
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Toowoomba, Queensland, Australia, 4350
      • Toowoomba Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
    • Launceston, Tasmania, Australia, 7250
      • Launceston General Hospital
  • Victoria
    • Ballarat, Victoria, Australia, 3350
      • Ballarat Health Services
    • Bendigo, Victoria, Australia, 3550
      • Bendigo Hospital
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Dandenong, Victoria, Australia, 3175
      • Dandenong Hospital
    • Footscray, Victoria, Australia, 3011
      • Footscray Hospital, Western Health
    • Frankston, Victoria, Australia, 3199
      • Frankston Hospital
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • Ringwood East, Victoria, Australia, 3135
      • Maroondah Hospital
    • St Albans, Victoria, Australia, 3021
      • Sunshine Hospital, Western Health
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • St John of God Murdoch Hospital
    • Murdoch, Western Australia, Australia, 6165
      • Fiona Stanley Hospital
• New Zealand
  • Auckland, New Zealand, 1142
    • Auckland City Hospital (DCCM)
  • Auckland, New Zealand, 1640
    • Middlemore Hospital
  • Auckland, New Zealand, 1023
    • Auckland City Hospital (CVICU)
  • Hamilton, New Zealand, 3240
    • Waikato Hospital
  • Nelson, New Zealand, 7010
    • Nelson Hospital
  • Tauranga, New Zealand, 3110
    • Tauranga Hospital
  • Auckland
    • Takapuna, Auckland, New Zealand, 740
      • North Shore Hospital
  • Bay Of Plenty
    • Rotorua, Bay Of Plenty, New Zealand, 3010
      • Rotorua Hospital
  • Camberley
    • Hastings, Camberley, New Zealand, 4120
      • Hawkes Bay
  • Canterbury
    • Christchurch, Canterbury, New Zealand, 8140
      • Christchurch Hospital
  • Wellington
    • Lower Hutt, Wellington, New Zealand, 5014
      • Hutt Hospital
    • Newtown, Wellington, New Zealand, 6021
      • Wellington Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• The patient will receive fluid resuscitation defined as a bolus of fluid, prescribed to be administered over one hour or less to increase or maintain intravascular volume that is in addition to maintenance fluids, or specific fluids used to replace non-physiological fluid losses
• The patient is expected to be in the ICU the day after tomorrow
• The patient is not expected to be well enough to be eating tomorrow
• An arterial or central venous catheter is in situ, or placement is imminent as part of routine management
• Both Plasma-Lyte 148® and 0.9% saline are considered equally appropriate for the patient
• The requirement for fluid resuscitation is supported by at least one of seven pre-specified clinical signs: heart rate > 90 beats per minute; systolic blood pressure < 100 mmHg or mean arterial pressure < 75 mmHg; central venous pressure < 10 mmHg; pulmonary artery wedge pressure < 12 mmHg; capillary refill time > 1 second; OR urine output < 0.5 ml/kg for at least one hour

Exclusion Criteria:

• Age less than 18 years
• Patients who have received more than 500mls of fluid resuscitation (as defined above) prescribed in the ICU during this current ICU admission
• Patients transferred directly from another ICU who have received more than 500mls of fluid resuscitation (as defined above) during that ICU admission
• Contraindication to either study fluid e.g. previous allergic reaction to Plasma-Lyte 148®
• Patients admitted to the ICU with specific fluid requirements: the treatment of burns; following liver transplantation surgery; for correction of specific electrolyte abnormalities
• Patients with traumatic brain injury or those considered at risk of developing cerebral oedema
• Patients in whom death is deemed imminent and inevitable
• Patients with an underlying disease process with a life expectancy of <90 days
• Patients in whom it is unlikely the primary outcome can be ascertained
• Patients who have previously been enrolled in PLUS
• Known or suspected pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Plasma-Lyte 148®; Following randomisation, each study participant will receive either Plasma-Lyte 148® or 0.9% saline alone for all resuscitation episodes and for all compatible intravenous crystalloid therapy while in ICU (for up to 90 days).	Drug: Plasma-Lyte 148®; Plasma-Lyte 148 (approx pH 7.4) IV infusion is a sterile, clear nonpyrogenic isotonic solution & when administered intravenously it is a source of water, electrolytes & calories. Plasma-Lyte 148 intravenous infusion is indicated as a source of water & electrolytes or as an alkalinising agent.; Other Names: Balanced crystalloid solution
Active Comparator: 0.9% sodium chloride; Following randomisation, each study participant will receive either Plasma-Lyte 148® or 0.9% saline alone for all resuscitation episodes and for all compatible intravenous crystalloid therapy while in ICU (for up to 90 days).	Drug: 0.9% sodium chloride; The active ingredient is sodium chloride formulated in Water for Injections. The chemical name is sodium chloride with molecular formula NaCl. Sodium Chloride (0.9%) intravenous infusion preparation is a sterile & non-pyrogenic solution & is indicated for extracellular fluid replacement & in the management of metabolic alkalosis in the presence of fluid loss, & for restoring or maintaining the concentration of sodium & chloride ions. As sodium chloride intravenous infusion is administered to the systemic circulation by intravenous infusion, the bioavailability (absorption) of the active components is complete (100 per cent).; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Death from all causes	At 90 days after randomisation

Secondary Outcome Measures

Outcome Measure	Time Frame
Mean and peak serum creatinine concentration	First seven days
ICU, hospital and 28 day all-cause mortality	28 days and 6 months after randomisation
Duration of ICU stay	28 days and 90 days after randomisation
Duration of Hospital stay	28 days and 90 days after randomisation
Proportion of patients newly treated with renal replacement therapy	up to 90 days after randomisation.
Duration of mechanical ventilation in ICU	90 days after randomisation
Proportion of patients treated with and duration of treatment with vasoactive drugs	90 days after randomisation
Quality of life assessment using the EQ-5D-5L questionnaire	At 6 months after randomisation
Maximum post-randomisation increase in serum creatinine in ICU during the index hospital admission.	90 days after randomisation
Healthcare services usage during the six months after randomisation by healthcare record linkage using state and national data linkage units	During the six months after randomisation

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: Baxter Healthcare Corporation; Australian and New Zealand Intensive Care Society Clinical Trials Group
• Investigators: Study Chair: Simon Finfer, Professor, The George Institute

Publications and helpful links

General Publications

• Finfer S, Micallef S, Hammond N, Navarra L, Bellomo R, Billot L, Delaney A, Gallagher M, Gattas D, Li Q, Mackle D, Mysore J, Saxena M, Taylor C, Young P, Myburgh J; PLUS Study Investigators and the Australian New Zealand Intensive Care Society Clinical Trials Group. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. 2022 Mar 3;386(9):815-826. doi: 10.1056/NEJMoa2114464. Epub 2022 Jan 18.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2017
• Primary Completion (Actual): March 30, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: March 15, 2016
• First Submitted That Met QC Criteria: March 22, 2016
• First Posted (Estimated): March 29, 2016

Study Record Updates

• Last Update Posted (Actual): August 8, 2023
• Last Update Submitted That Met QC Criteria: August 6, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Critical care; Fluid resuscitation; Saline; Critically ill; Sodium chloride; Plasma-Lyte; Intravenous fluid therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Hypovolemia; Pharmaceutical Solutions; Ophthalmic Solutions; Plasma-lyte 148
• Other Study ID Numbers: GI-CCT7587; U1111-1178-8334 (Other Identifier: World Health Organisation (WHO) Universal Trial Number (UTN))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No