Efficacy of albumin in critically ill patients
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7389.559 (Published 15 March 2003) Cite this as: BMJ 2003;326:559Data supplement
- [posted as supplied by authors]
The Saline vs. Albumin Fluid Evaluation (SAFE) Study (ISRCTN76588266): Design and conduct of a multi-centre, blinded randomised controlled trial of intravenous fluid resuscitation in critically ill patients.
Authors: ANZICS Clinical Trials Group and Institute for International Health SAFE Study Investigators.
A joint initiative of the:
Australian and New Zealand Intensive Care Society Clinical Trials Group
Australian Red Cross Blood Service
Institute for International Health, University of Sydney
Corresponding author:
Simon Finfer
Chair, ANZICS Clinical Trials Group Executive
ANZICS House
233 Rathdowne Street
Carlton,
Vic 3053
Australia
e-mail: ctg@anzics.com.au
Summary Points
- Whether albumin administration to critically ill patients increases or decreases mortality remains unknown.
- Two recent meta-analyses have produced conflicting results.
- A 7000-patient blinded randomised controlled trial is being conducted in Australia and New Zealand in an effort to resolve this controversy.
- Since the main study started in March 2002, almost 3000 patients have been recruited and the trial is scheduled to complete recruitment in mid 2003.
- The trial will provide important information to those treating patients in intensive care.
Introduction
In 1998, the BMJ published a meta-analysis by the Cochrane Injuries Group Albumin Reviewers that compared the effect of using albumin-containing fluid versus crystalloid on mortality rates in critically ill patients. 1 The paper reviewed 24 studies and concluded that there was "no evidence that albumin reduced mortality and a strong suggestion that it might increase the risk of death". Despite the fact that the reviewers themselves advised that their "results must be interpreted with caution", an accompanying editorial called for a total halt to the use of albumin in the critically ill. 2, 3 In the following weeks, numerous editorials and letters published in the BMJ debated the various merits of albumin use. 4, 5, 6, 7
The Cochrane Injury Group Albumin Reviewers publication was of particular interest to intensive care practitioners in Australia. In Australia, human albumin is produced by the fractionation of blood from volunteer blood donors. Through the Australian Red Cross Blood Service (ARCBS), it is supplied free of charge to hospitals. This contrasts with other countries, where hospitals pay for the albumin they use, and where albumin is generally viewed as an expensive product. Possibly because of these local circumstances, albumin is widely used as a resuscitation fluid in Australian Intensive Care Units (ICUs). Despite the concerns raised by the Cochrane Injury Group Albumin Reviewers publication, many Australian intensive care practitioners did not consider the evidence provided to be strong enough to change their usual practice.
The results of a subsequent meta-analysis published in 2001 contributed further to the clinical uncertainty about the effects of albumin. In that analysis, 55 randomised controlled trials comparing albumin therapy with crystalloid therapy, no albumin or lower doses of albumin were reviewed and graded. Overall, the authors reported no difference in mortality (relative risk 1.11, 95% CI 0.95 to 1.28). However, in the subgroups of trials that were judged to be of high quality (relative risk 0.73, 95% CI 0.48 to 1.12) or of larger sample size (n>100) (relative risk 0.94, 95% CI 0.77 to 1.14), the estimates of treatment effect and the lower confidence limits were consistent with albumin being beneficial. The upper confidence limits however, remained consistent with a moderate adverse effect. The authors concluded that further well-designed clinical trials were required to resolve the uncertainty about the true effects of albumin use in critically ill patients. 8
After considering the available evidence, the Committee on Safety of Medicines issued advice to doctors in the United Kingdom that they take care with the use of Albumin ("Human albumin therapy in critically ill patients," CEM/CMO/98/11). In Australia, State Health Departments also considered issuing such advice. The Australian and New Zealand Intensive Care Society, in collaboration with the Institute for International Health of the University of Sydney, and the Australian Red Cross Blood Service, proposed that a better response would be to conduct a large-scale randomised controlled trial. This proposal was supported by the Health Departments of all Australian States and Territories, the Australian Commonwealth Government, the National Health and Medical Research Council of Australia, and the Health Research Council of New Zealand.
Study Design
The Saline versus Albumin Fluid Evaluation (SAFE) study is a randomised, controlled, blinded trial comparing intravenous albumin with saline for fluid resuscitation in critically ill patients. The study intends to recruit 7,000 patients over 18 years of age from 16 ICUs throughout Australia and New Zealand over 18 months. Eligible ICU patients who require fluid resuscitation will be randomised to receive either 4% human albumin solution (AlbumexÒ ) or 0.9% sodium chloride (saline). The primary study outcome measure is 28-day all-cause mortality. Secondary outcomes include length of stay in the ICU, length of hospital stay, organ dysfunction as measured by the components of the Sepsis-related/Sequential Organ Failure Assessment (SOFA) score,9 and other physiological measures of response to fluid therapy.
Patients who satisfy the diagnostic criteria for severe sepsis and the acute respiratory distress syndrome at study entry are identified to allow a priori subgroup analysis.
Subjects
All ICU patients requiring fluid for intravascular volume depletion who do not have a clear indication or contraindication for albumin or saline are eligible for the study. (See Table 1 for a complete list of inclusion criteria.)
Information from the ANZICS bi-national database of intensive care patient admissions and outcomes indicates that when cardiac surgical patients are excluded, the mortality of patients admitted to Australian and New Zealand ICUs is 15%. Since the mortality of cardiac surgical patients is less than 1%, they are excluded from the trial. Their inclusion would significantly increase the number of patients to be studied without the likelihood of demonstrating a mortality benefit of either fluid in that group of patients. Patients admitted to intensive care because of burns or immediately following liver transplant surgery are also excluded as their accepted treatment protocols call for the routine use of albumin-containing solutions.
Patients are also excluded if there is an objective reason to believe choice of fluid resuscitation can not influence the primary outcome of death at 28 days. For example, if a patient is moribund and expected to die and the treating clinicians are not committed to full supportive care, the patient is not eligible for study entry.
Finally, patients are excluded if they have previously been enrolled and completed follow up in the SAFE study, or they have previously received non-study fluid resuscitation that was prescribed within an ICU, during the current ICU admission. (See Table 1 for the complete list of exclusion criteria.)
Study treatments
The two study treatments are 4% Albumin (AlbumexÒ ,CSL Ltd., Melbourne, Australia) or 0.9% Sodium Chloride BP (Saline). The allocated study treatment is used for all fluid resuscitation requirements during the first 28 days of the patients’ ICU stay. There is no attempt to influence which intravenous fluids are used prior to a patient’s admission to the ICU or after discharge from the ICU. (Surveys of albumin use in major Australian teaching hospitals before the study demonstrated only 4% of ICU patients received albumin outside the ICU. R. Bellomo and M. Chapman – unpublished data)
Blinding
In order to blind the study, special materials have been produced to ensure that the two fluids are indistinguishable to both the treating clinicians and the patients receiving the fluids. Effectiveness of the blinding materials was confirmed by a formal study.
Study fluid containers
Both study fluids are packaged in identical 500ml glass bottles and shipped in specially produced cardboard masking cartons with a translucent yellow plastic window (See Figure 1). The plastic windows allow the administering nurse to see the amount of fluid remaining in the bottle yet obscure the colour of the fluid.
Study IV fluid administration sets
Specially manufactured IV fluid administration sets, (TUTA Laboratories, Sydney, Australia), are used to administer both study fluids. The administration set is similar to a standard Australian blood administration set. It has a double drip chamber (one of which has a blood filter), and a pump chamber between the flow regulator and the Luer connection to the patient’s cannula (See Figure 2).
The tubing is made of clear dark green plastic to mask the fluid colour while allowing air bubbles to be seen. Both the drip chamber and hand pump are masked with opaque black plastic so that frothing of albumin in these chambers is not visible. The middle 2cm of the drip chamber are not masked with black plastic; this allows the nurse or clinician to ensure that fluid has been extruded from the bottle into the administration set at priming and also allows staff to see the drip rate.
Internet based study management
The study is managed using an Internet based system which enables two-way data transfer in a secure, password protected, encrypted environment. Access to this function is available 24 hours a day, seven days week to participating ICUs and is administered by the data and coordinating centre with full back up service.
Randomisation
Randomisation is conducted by clinical staff (both doctors and nurses) via the website (Figure 3). Randomisation is stratified within intensive care unit and by a diagnosis of trauma at ICU admission. This system ensures that treatment allocation can not be detected pre-randomisation. All attempts at randomisation are logged by the central web server and this facilitates analysis of study outcomes on an intention-to-treat basis.
Data submission and management
Direct data entry is performed at each study hospital by research coordinators. Logical data checks are performed as data are entered and queries for out-of-range, missing or inconsistent data are raised in real time. This system is designed to minimise errors in data transcription and the time taken for completed and accurate data to reach the coordinating centre.
Study fluid distribution and logistics
Fluid distribution and usage is managed via the study web site to ensure there is sufficient fluid of both types at each participating centre. At randomisation, the study web site allocates a unique patient study number and a unique fluid code number (Figure 3). The fluid code number corresponds to a box containing four bottles (two litres) of either Albumex or saline that has already been distributed to the ICU of the hospital in which the patient is being treated. When a patient requires further fluid, a web-based function allocates another unique fluid code number that corresponds to a further box containing two litres of the same fluid that has been distributed to the same ICU at the same hospital.
The hospital research ethics committee at each participating hospital has approved the study. All local hospital ethics committees have allowed delayed consent where direct consent cannot be obtained from a critically ill patient in a timely fashion. 10 As soon as possible, the patient, or their proxy or surrogate decision-maker is contacted, they are informed of the patient’s inclusion in the study and given the opportunity to withdraw from the study should they so wish.
Based on a 15% mortality rate in the control group, at 90% power, 7,000 patients will be required to detect a 3% or larger difference in the absolute risk of death between the two treatment groups. An absolute risk reduction of this magnitude is based upon the approximate minimal effect suggested by the lower confidence interval in the Cochrane Injury Group Albumin Reviewers Paper. 1
Analysis
The primary analysis will be performed on all randomised patients according to the intention to treat principle. For the primary outcome of 28 day all cause mortality, a stratified Cochran-Mantel-Haenszel chi-square test will be employed. For the contrast of overall duration of survival, curves will be plotted using the Kaplan-Meier Product-Limit method. Duration of ICU stay and duration of hospital stay will be compared using Poisson models. Other secondary outcome measures will be analysed using Poisson models, t-tests, chi-square tests, non-parametric tests or other methods where appropriate.
Data and safety monitoring
An independent Data and Safety Monitoring Committee (DSMC), comprising experts in clinical trials, biostatistics and intensive care, has been established. The DSMC will review data segregated into two blinded study groups when outcome data are available for one third (2,333 patients) and two thirds of participants (4,666 patients).
The SAFE study will be stopped if the randomised comparisons provide evidence beyond reasonable doubt of a difference between groups in all cause mortality. Using the Haybittle-Peto approach, a three standard deviation difference would constitute such evidence. 11, 12
Funding
The funding bodies are listed in Table 2. The funding bodies had no input into the design of the trial. CSL Limited provides the study fluids and reviewed the protocol to ensure that the study complies with Good Clinical Research Practice and with their obligations to local regulatory authorities. Funding bodies receive updates on trial progress but have no access to trial data and will not be involved in data handling or analysis. All study reports will be produced by the independent investigators under the direction of the study management committee and without input or interference from the funding bodies.
Current status
Following a pilot phase in November and December 2001, the main study commenced in March 2002. On August 18, 2002, the 2,333rd patient was randomised marking one third of the target recruitment. At this rate of recruitment, which is higher than anticipated (see Figure 4), 7000 patients would be enrolled by May or June of 2003.
Summary
Publication of the Cochrane Injuries Group Albumin Reviewers paper in the BMJ generated great controversy in the critical care community. As a direct result, a 7000 patient randomised controlled trial, the SAFE Study, was designed to determine the relative place of albumin and saline in the resuscitation of critically ill patients. To date this is the largest study attempted in the intensive care unit population.
In addition to answering the question posed by the BMJ paper, the collaborations forged to conduct the SAFE study, involving the research group of a professional society, a university research, multiple arms of government, and a supportive commercial organisation can serve as a model for the conduct of further large-scale trials in critical care, and in other areas of medicine. 13
Figure 1. Study fluid in masking carton.
Figure 2. Study giving set.
Figure 3: Web page showing successful randomisation and allocation of patient identifier and first fluid box number .
Table 1 Selection criteria for SAFE
Patients are eligible for inclusion in the study if ALL the following requirements are met:- Fluid resuscitation is required for intravascular fluid depletion that is in addition to intravenous fluid that is required for nutrition or to replace ongoing insensible losses, urinary losses, ongoing losses from other sites (eg. fistula losses from the gastrointestinal tract, urinary losses from diabetes insipidus, cerebral salt wasting syndrome or the polyuric phase of acute renal failure) or to restore normonatraemia.
- The ICU clinician considers that both 4% human albumin solution and 0.9% sodium chloride are equally appropriate for the patient and that no specific indication or contraindication for either exists.
- The requirement for fluid resuscitation must be supported by AT LEAST ONE of the following clinical signs:
- Heart rate > 90 beats per minute
- Systolic blood pressure (SBP) < 100mmHg or mean arterial pressure (MAP) < 75mmHg or a 40mmHg decrease in SBP or MAP from the baseline recording. Or requirement for inotropes or vasopressors to maintain blood pressure at those levels.
- Central venous pressure < 10mmHg
- Pulmonary artery wedge pressure < 12 mmHg
- Respiratory variation in systolic or mean arterial blood pressure of >5 mmHg
- Capillary refill time > one second
- Urine output < 0.5 ml/kg for one hour
Patients are excluded from the study if ONE OR MORE of the following are present: - A known previous adverse reaction to human albumin solution
- Any known religious objection to the administration of human blood products (for example if patient is a Jehovah’s Witness)
- A requirement for the patient to receive plasmapheresis during this ICU admission
- An admission to the ICU following cardiac surgery.
- An admission to the ICU for the treatment of body burn.
- An admission to the ICU following liver transplantation surgery.
- Age less than 18 years.
- Brain death or brain death that is likely to be diagnosed within in the next 24 hours of fluid resuscitation being required.
- If the patient is moribund and expected to die within the next 24 hours - defined as having a treatment limitation order in place that exceeds a ‘not for resuscitation’ order and that indicates the treating clinicians are not committed to full supportive care.
- If the patient has previously been enrolled and has completed follow up in the SAFE study.
- If the patient has previously received fluid resuscitation that was prescribed within the study ICU and during this current ICU admission.
- If the patient has been transferred to the study ICU from a non-study ICU and received a fluid bolus or fluid resuscitation for the treatment of volume depletion in that non-study ICU.
Table 2: Funding bodies (In alphabetical order, Australia unless stated)Auckland District Health Board, New Zealand;
Commonwealth Department of Health and Aged Care;
CSL Limited, Melbourne;
Middlemore Hospital, New Zealand;
National Health and Medical Research Council;
Health Department of Western Australia;
Health Research Council of New Zealand;
New South Wales Health Department;
Northern Territory Health Services;
Queensland Health Services Department,
Royal Hobart Hospital, Tasmania;
South Australia Department of Human Services;
Victorian Department of Human Services;
1. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998;317:235-40.2. Offringa M. Excess mortality after human albumin administration in critically ill patients. Clinical and pathophysiological evidence suggests albumin is harmful. BMJ 1998;317:223-4.
3. Mills H. 330 die as health chiefs dither. Observer, 1. 6-26-1998.
4. Shwe KH, Bhavnani M. Human albumin administration in critically ill patients. Some patients may benefit. BMJ 1998;317:885-6.
5. Beale R, Wyncoll D, McLuckie A. Human albumin administration in critically ill patients. Analysis is superficial and conclusions exaggerated. BMJ 1998;317:884.
6. McClelland B. Albumin: don't confuse us with the facts. Rather than fulminating, seek to answer the questions raised. BMJ 1998;317:829-30.
7. White C. Action on human albumin not swift enough. BMJ 1998;317:367.
8. Wilkes MM, Navickis RJ. Patient survival after human albumin administration: A meta-analysis of randomized controlled trials. Ann Intern Med 2001;135:149-64.
9. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996;22:707-10.
10. National Health and Medical Research Council. National Statement on Ethical Conduct in Research Involving Humans. Canberra: 1999.
11. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol 1971;44:793-7.
12. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976;34:585-612.
13. Smith R. Maintaining the integrity of the scientific record. Editors make a move. BMJ 2001;323:588.Guarantors: Simon Finfer and Robyn Norton.
Writing committee: (In alphabetical order, CTG = Australian and New Zealand Intensive Care Society Clinical Trials Group, IIH = Institute for International Health).
Rinaldo Bellomo (CTG), Gordon Doig (CTG), Simon Finfer (CTG), Julie French (IIH), John Myburgh (CTG), Stephen MacMahon (IIH), Bruce Neal (IIH), Robyn Norton (IIH).
SAFE Investigators (Alphabetically by Institution, Australia unless stated, NSW = New South Wales, NZ = New Zealand):
Alfred Hospital, Melbourne, Victoria - Julie Charlton, Jamie Cooper, Andrew Davies, Catherine Harry, Shirley Vallance.
Auckland Hospital, Auckland (NZ) - Janine Chadderton, Lynette Newby, Colin McArthur
Austin & Repatriation Medical Centre, Melbourne, Victoria - Samantha Bates, Rinaldo Bellomo, Donna Goldsmith,
Australian Red Cross Blood Service, Melbourne, Victoria - Neil Boyce
Fremantle Hospital, Freemantle, Western Australia - David Blythe, Annamaria Palermo,
Institute for International Health, Sydney, NSW - Julie French, Mary Hayek, Kathy Jayne, Stephen MacMahon, Mamta Merai, Bruce Neal, Robyn Norton, Sameer Pandey
John Hunter Hospital, Newcastle, NSW – Rosemary Carroll, Peter Saul,
Middlemore Hospital, Auckland - Jane Clarke, Juliet Powell, Tony Williams
Nepean Hospital, Penrith, NSW – Louise Cole, Ian Seppelt, Michele Thomson, Leonie Weisbrodt,
Princess Alexandra Hospital, Queensland - Lisa Bradley, Chris Joyce, Theresa Kelly, Tony Limpus, Robyn Moore,
Royal Adelaide Hospital, South Australia - Marianne Chapman, Stephanie Creed, Justine Rivett
Royal Darwin Hospital, Northern Territory - Dianne Stephens, Jane Thomas,
Royal Hobart Hospital, Tasmania - Anthony Bell, Kathy Marsden, Andrew Turner,
Royal Melbourne Hospital, Victoria - Catherine Boyce, Kerry Byron, John F Cade, Belinda Howe, Jeffrey J Presneill
Royal North Shore Hospital, Sydney, NSW – Gordon S Doig, Simon Finfer, Anne O’Connor, Julie Potter,
Royal Prince Alfred Hospital, Sydney, NSW – Catherine Powell, Dorrilyn Rajbhandari, Clive Woolfe
St George Hospital, Sydney, NSW - Marie Hodgetts, Kathryn Girling, John Myburgh
Western Hospital, Melbourne, Victoria - Craig French, Lorraine Little
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