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International albumin use: 1995 to 2006.

Administration of intravenous fluids to maintain or expand intravascular volume is one of the common interventions in pre-hospital and hospital medicine. Despite the widespread use of fluids, especially in intensive care patients, there is ongoing controversy over the type of fluid that should be given (1). Available data suggest that there is wide variation in the type of fluids clinicians use. In a survey of more than 2400 doctors in European countries, 65% of clinicians reported using a mixture of crystalloids and colloids for volume resuscitation, isotonic crystalloids, hydroxy-ethyl starches (HES) and gelatins being the most common fluids used (2). In contrast, in a survey of 364 clinicians in the Canadian province of Ontario in 1998 to 1999, respondents used predominantly crystalloids for volume expansion; albumin was the most commonly used colloid (3). Other surveys confirm significant practice variations and suggest that uncertainty over the choice of fluids remains widespread (4,5).

Little is known about the reasons for heterogeneity in regard to the choice of fluids for intravascular volume expansion. Factors reported to influence the choice of intravenous fluid include local policies, costs, marketing pressure and published evidence on beneficial or deleterious effects of a specific fluid type (2,3). As most data on choice of fluids originate from surveys or point-prevalence studies, it is difficult to assess if these factors have resulted in a change of practice over time.

Human albumin has often been at the heart of the debate on use of different intravenous fluid solutions (6,7). In 1998, the Cochrane Injuries Group Albumin Reviewers published a meta-analysis of 30 randomised controlled trials involving 1419 patients to quantify the effect of fluids containing human albumin on mortality in critically ill patients with hypovolaemia, burns or hypoproteinaemia (8). The investigators included trials in adults, children and neonates and concluded that administration of albumin-containing fluids resulted in a 6% absolute increase in the risk of death (8). In May 2004, the Saline versus Albumin Fluid Evaluation (SAFE) Study investigators reported the first large-scale randomised controlled trial to examine the effect of type of resuscitation fluid on mortality (9). The study, involving 6997 critically ill adult patients, found that use of either 4% albumin or normal saline for fluid resuscitation resulted in similar 28-day mortality. However, the SAFE investigators and an accompanying editorial noted that further study was needed to determine whether albumin or saline conferred benefit in certain sub-populations of critically ill patients (1,9). Subsequently, the same investigators have confirmed that resuscitation with albumin increased mortality in patients with traumatic brain injury (10). Immediately following the 1998 meta-analysis, albumin use in England, Wales, Scotland and Northern Ireland fell by at least 40% (11): whether the publication had a similar effect in other parts of the world is not known.

In recent years the suggestion has emerged that the choice of resuscitation fluid and especially the use of HES might increase the risk of renal failure, particularly in patients with severe sepsis. An increased incidence of renal failure and oliguria in intensive care unit patients with severe sepsis and septic shock who received HES as resuscitation fluid was reported by Schortgen et al in 2001 (12). In the following years the association between occurrence of renal failure and use of a specific fluid has been debated (13,14). Recently, Brunkhorst and colleagues reported that fluid resuscitation with HES increased the incidence of acute renal failure when compared with fluid resuscitation with modified Ringers lactate solution (15).

Given the central role of albumin in this controversy, we sought to determine trends in the use of albumin in a number of countries during the last decade and where possible we report trends in synthetic colloid use for comparison.


Data sources for albumin use

Data on the annual albumin use between 1995 and 2006 were collected from 13 sources representing 15 countries (Australia, Canada, Denmark, England and Wales, Finland, France, Germany, Iceland, New Zealand, Norway, Scotland and Northern Ireland, Sweden and Switzerland). These sources were able to supply data on the amount of albumin issued to hospitals and we make the assumption that any difference between the amounts of albumin supplied to hospitals and the amounts administered to patients is minimal. Data from Australia, New Zealand and Canada were provided by the respective national blood services (Australian Red Cross Blood Service, New Zealand Blood Service and Canadian Blood Service). In Europe, data for Denmark were obtained from Laegemiddelstyrelse (the Danish Drug Administration Agency); for England and Wales combined from BPL Limited; for Finland from the National Registry of Drug Use; for France from the Groupement pour l'elaboration et la realisation des statistiques; for Germany from the Paul Ehrlich Institute; for Iceland from the Icelandic Medicines Control Agency; for Norway from Octapharm; for Scotland and Northern Ireland combined from the Scottish Blood Transfusion Service; for Sweden from the Apoteket (Swedish Drug Administration Agency); and for Switzerland from the Swiss Agency for Therapeutic Products and from individual companies licensed to supply albumin in Switzerland. We also approached USA-based authors of investigator-initiated studies in the field of resuscitation fluid to seek data on national albumin use in the USA.

Albumin use by country

Information on annual albumin use was provided either by number of units and concentration (4%, 5%, 20% or 25%) or by total amount in kilograms. Annual data on the total amount of albumin used by jurisdiction was standardised by converting all data to kilograms of albumin used per year. For comparison of infusion volumes of albumin and synthetic colloids, volume of synthetic colloid was converted to "5% albumin equivalents" based on published intravascular volume expansion properties16-18. We also documented whether data were provided by calendar year or financial year. In the latter case, data are shown by year-end to represent completed use (for example, for the financial year 2000/2001, total is shown in 2001).

Data sources for synthetic colloid use

Data on annual synthetic colloid use between 1995 and 2006 were available for Denmark (Laegemiddelstyrelse [the Danish Drug Administration Agency]), Sweden (Apoteket [Swedish Drug Administration Agency]) and Canada (Canadian Blood Service), whereas in other countries reliable sources could not be identified.

Synthetic colloid use by country

Information on annual use of synthetic colloids was provided by number of units and concentration. Annual data on the total amount of synthetic colloids used was standardised by converting all data to kilograms of dry weight colloid used per year. Due to the different intravascular volume expansion properties of specific fluids, volume equivalents to the intravascular volume expansion of 5% albumin were calculated (referred to as albumin volume equivalents). According to published data we defined the volume expansion of 5% albumin to be equivalent to 6% HES or 4% gelatin solution, whereas for 6% dextran a conversion factor of 1.2 was assumed (16,19-22). Data provided by financial year are shown by year-end to represent completed use.

Population sources

National population statistics were obtained from the country-specific statistics bureaus using data from census years (23-35). For non-census years, population totals were calculated assuming linear growth (or decline).


Total albumin use in kilograms per 10,000 persons per annum was calculated and plotted to document trends in albumin use over time and between jurisdictions. An aggregate figure was calculated for the years 1995 to 2006 across the surveyed countries for which annual data were available. The mass of synthetic colloids per 10,000 persons per annum were calculated, converted to albumin equivalent volumes and plotted over time. The use of albumin and synthetic colloids was standardised to albumin volume equivalents and plotted over time to document trends in total colloid use in the jurisdictions for which data were available. As data were not available for every year in some jurisdictions, we report only the available data and make no assumptions about missing data.


Availability of information on albumin use

Data on annual albumin use were obtained from 13 sources representing 15 countries. Data were provided by calendar year by 11 countries and by financial year for the remaining four countries. Data were incomplete for England and Wales (missing 1995, 1997, 1998 and 2000), Germany (missing 1995 to 1998) and Denmark (missing 1995 to 1996 and 2006). An additional four countries were missing data on 2006 (data not yet available: New Zealand, Norway, Sweden and Switzerland) and four additional countries were missing data for 1995 (Australia, Scotland and Northern Ireland and Sweden). There was no central, national data source for albumin use for the USA and we were unable to identify an alternative reliable data source.

Albumin use between 1995 and 2006

Data on albumin use (kg/10,000 persons) in the individual surveyed countries and the aggregate of the surveyed countries are shown in Table 1 and Figures 1 to 4. The highest national albumin use in any one year was 3.92 kg per 10,000 persons in 1995 in Switzerland, the lowest was 0.43 kg per 10,000 persons in New Zealand in 2005. The aggregate of albumin use in the surveyed countries was decreasing prior to the Cochrane Injuries Group publication in 1998 and decreased further between 1998 and 1999. Since 1999, changes in albumin use in the surveyed countries have generally been less marked. In some countries use has increased (e.g. Australia); in others use has been steady (e.g. New Zealand) or declined (e.g. Germany).

The aggregate use in the surveyed countries decreased from a peak of 2.54 kg per 10,000 persons in 1995 to 1.40 kg per 10,000 persons in 1999. Aggregate albumin use has remained relatively constant since that time, varying between 1.35 kg per 10,000 persons in 2004 and 1.51 kg per 10,000 persons in 2000 (Figures 1 to 4).



Use of synthetic colloids between 1995 and 2006

Data on synthetic colloids was available for Denmark (1997 to 2005), Sweden (1996 to 2005) and Canada (1995 to 2004). In Denmark HES was the

most commonly used synthetic colloid, followed by dextran; use of both colloids increased throughout the observation period. In Sweden, dextran was initially the most frequently used colloid with a decline in use throughout the observation period, whereas HES use increased. In Canada HES use increased throughout the observation period. Data on use of individual synthetic colloids in the surveyed countries are shown in Table 2 and Figure 5.





Total use of colloids between 1995 and 2006

Use of synthetic colloids in albumin volume equivalents increased from 125.5 to 195.1 litres per 10,000 population in Denmark (1997 to 2005), from 127.0 to 188.9 litres per 10,000 population in Sweden (1996 to 2005) and from 11.7 to 71.6 litres per 10,000 population in Canada (1996 to 2004). The total use of colloids (albumin plus synthetic colloids) showed a trend to increase on a per capita basis in the countries for which data were available (Figure 6).


Summary of study findings

We conducted an international study to document annual use of albumin and synthetic colloids in a number of industrialised countries between 1995 and 2006. We found that reliable information on colloid use was difficult to obtain and data were not available for all countries or all years; per capita albumin use varied up to nine-fold between the surveyed countries over time. Synthetic colloid use varied significantly in type and total volume in the few countries for which data were available. Total colloid use (albumin plus synthetic colloids) per capita increased throughout the observation period.

Possible mechanism and comparison with previous studies

We found up to a nine-fold difference in adjusted albumin use between the countries surveyed over time. Although our study cannot explain this variation, possible explanations include differences in the cost of albumin and differences in the availability of alternative fluids in the countries studied. We are unaware of variation in patient demographics between the surveyed countries that might account for the observed variation in albumin use. We have presented the data on a per capita basis using the total population of each country as the denominator. It is possible that differences in the organisation of health care systems and differences in hospitalisation rates between countries may also affect the use of resuscitation fluids.

In 1998, the Cochrane Injuries Group Albumin Reviewers concluded that administration of albumin-containing fluids resulted in a 6% absolute increase in the risk of death (8). A subsequent survey of clinical directors revealed that in many intensive care units in the United Kingdom use of intravenous albumin had been influenced by this review (36). In the present study, we found that albumin use in the surveyed countries was decreasing prior to the publication, but we had insufficient data to conduct time-series analysis to determine whether the publication had a material effect on the trend in albumin use (37).

In contrast to albumin use, use of synthetic colloid increased during the study period. When calculated as volume equivalents, the total volume of albumin and synthetic colloids has remained stable or even increased throughout the observation period. These data do not suggest that clinicians have changed from using colloid solutions to using crystalloids, even though colloids are generally more expensive and meta-analyses report no outcome advantage with colloids (38-40).

We are unaware of any previous study examining the use of colloids across a decade in multiple countries. Two surveys have reported clinicians' preferences in choice of resuscitation fluids (2,3). These studies suggested that most doctors use a combination of crystalloids and colloids to expand plasma volume: in 1998 to 1999, albumin was the most common colloid used in Canada3, whereas in 2001 to 2002, albumin was used infrequently in most European countries (2).

Study strengths and limitations

Our study is international and may be original in documenting changes in colloid use over a tenyear period in individual countries. However, it has several limitations. First, data were collected retrospectively, obtained for 15 countries only and were incomplete for some years. Second, we found it difficult to obtain comprehensive and reliable data on colloid use. Data were available from national blood bank authorities for only five countries. In the remainder, we sourced data from commercial entities, drug administration agencies and pharmacy registries. Data on synthetic colloids was only available for three countries. We found that commercial organisations were less willing or unable to release data because of commercial sensitivity or because of inadequate data storage and retrieval systems. Also, data sources have become more fragmented over time due to the privatisation of national blood services and replacement of monopolies by competing suppliers. Finally, we have reported total albumin use for each of the surveyed countries and have no information on the proportion of albumin used for the treatment of different groups of patients or for particular indications.

Implications for clinicians and policy makers

Administration of intravenous fluid is one of the most common interventions in pre-hospital and hospital medicine. Accordingly, small differences in outcomes and relative costs which result from the use of different fluid preparations may have important consequences. Although we documented a reduction in albumin use and increased synthetic colloid use in those countries for which data were available, we can only speculate that synthetic colloids are being used in place of albumin. Our data suggest that many clinicians continue to use colloid based resuscitation (2), and as synthetic colloids may have adverse effects (12), we do not know whether reduced albumin use has resulted in a net benefit to patients or in harm.

Unanswered questions and future research

Future research should document current fluid resuscitation practices internationally and examine the effects of choice of resuscitation fluid on patient outcomes. Given the widespread use of resuscitation fluids in pre-hospital and hospital medicine, further large-scale international observational studies and randomised controlled trials are warranted.


SAFE TRIPS Investigators

Australian and New Zealand Co-ordinating Committee

Simon Finfer (Chair), Rinaldo Bellomo, D James Cooper, Alisa Higgins, Stephanie Hollis, Daryl Jones, Colin McArthur, Suzanne McEvoy, John Myburgh, and Robyn Norton; The George Institute for International Health, University of Sydney, Sydney; Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne.

SAFE TRIPS Investigators by country


* Joanne Pink; Australian Red Cross Blood Service.

* Simon Finfer, Stephanie Hollis, Suzanne McEvoy, John Myburgh, Robyn Norton; The George Institute for International Health, University of Sydney, Sydney.

* Rinaldo Bellomo, D James Cooper, Alisa Higgins, Daryl Jones; Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne.


* Paul Hebert, Lauralyn McIntyre, Alan Tinmouth; University of Ottawa, Center for Transfusion and Critical Care Research, Ottawa Health Research Institute Ottawa.


* J Duncan Young; Intensive Care Society Trials Group, Oxford.

* Simon Stanworth; National Blood Service/Oxford Radcliffe Hospitals, Oxford.


* Frederique Schortgen; Groupe Hospitalier Albert Chenevier--Henri Mondor, Reanimation Medicale, Creteil.

* Laurent Brochard; Groupe Hospitalier Albert Chenevier--Henri Mondor, Reanimation Medicale, Universite Paris, Creteil.


* Frank Brunkhorst, Konrad Reinhardt; Department of Anaesthesiology and Intensive Care Medicine Friedrich-Schiller-University Jena.

New Zealand

* Colin McArthur; Department of Critical Care Medicine, Auckland City Hospital.

* Peter Flanagan; New Zealand Blood Service.

Scandinavian Critical Care Trials Group

* Anders Perner; Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark.

* Jyrki Tenhunen; Critical Care Medicine, Tampere University Hospital, Finland.

* Sigurbergur Karason; Department of Anaesthesia and Intensive Care, Landspitali University Hospital, Reykjavik, Iceland.

* Anne Berit Guttormsen; Bergen, Norway.

* Anders Aneman; Department of Anaesthesiology and Intensive Care Sahlgrens University Hospital Goteborg, Sweden.

Scotland and Northern Ireland

* Brian McClelland; Scottish Blood Transfusion Service.


* Tobias M Merz, Jukka Takala; Department of Intensive Care Medicine, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

We would like to thank Patrick Robert and Keith Berman of The Marketing Research Bureau, Inc., Orange, CT 06477, USA for supplying the data on worldwide albumin use and for assistance in verifying some country-specific data.


CSL partially funded the original SAFE Study and has refunded travel expenses incurred by SF in presenting the results at industry sponsored and academic meetings. Fresenius Kabi has refunded travel expenses incurred by SF and JM in attending meetings to discuss research into the clinical effects of HES in critically ill patients.

Address for correspondence: Professor S. Finfer, PO Box M201, Missenden Road, Camperdown, NSW 2050. Email:

Accepted for publication on August 13, 2009.


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D. JONES *, S. McEVOY [[dagger]], T. M. MERZ [[double dagger]], A. HIGGINS [[section]], R. BELLOMO **, J. D. COOPER [[double dagger]], S. HOLLIS [[double dagger]][[double dagger]], C. McARTHUR [[section][section]], J. A. MYBURGH ***, C. TAYLOR [[dagger][dagger][dagger]], B. LIU [[double dagger][double dagger][double dagger]], R. NORTON [[section]][section][section]], S. FINFER **** Critical Care and Trauma Division, The George Institute for International Health, Sydney, New South Wales, Australia

* B.Sc. (Hons), M.B., B.S., F.R.A.C.P., Research Fellow, Monash University., Melbourne, Victoria.

[[dagger]] M.B., B.S. (Hons), M.App.Epid., Ph.D., F.A.F.P.H.M., Senior Research Fellow.

[[double dagger]] M.D., Senior Staff Specialist, Department of Intensive Care Medicine, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

[[section]] B.Physio (Hons)., M.P.H., Research Fellow, Monash University, Melbourne, Victoria.

** M.B., B.S. (Hons), M.D., F.R.A.C.P., F.C.C.P., Professor, University of Melbourne, Melbourne, Victoria.

[[dagger][dagger]] B.M., B.S. (Flinders), M.D. (Adel), F.R.A.C.P., F.F.A.R.A.C.S., F.A.N.Z.C.A., Professor, Monash University, Melbourne, Victoria.

[[double dagger][double dagger]] B.Sc., B.Ed., M.Med.Sc., Research Fellow.

[[section][section]] M.B., Ch.B., F.A.N.Z.C.A., F.J.F.I.C.M., Clinical Director, Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand.

*** M.B., B.Ch., Ph.D., F.C.I.C.M., Director.

[[dagger][dagger][dagger]] B.Ph.Ed., M.N.D., Research Fellow.

[[double dagger][double dagger][double dagger]] M.B., B.S., M.P.H., D.Phil., Senior Research Fellow.

[[section][section][section]] M.P.H., Ph.D., Principal Director.

**** M.B., B.S., F.R.C.P., F.C.I.C.M., F.R.C.A., Director.
Table 1
Albumin use in kg per 10,000 persons by jurisdiction, aggregate and
worldwide, 1995 to 2006

Year   Aus            Canada    Den       England       Finland
                                          and Wales

1995                                                    1.37
1996   1.79           2.32                1.93          1.40
1997   1.95           2.05      2.20                    1.44
1998   1.94           1.94      2.02                    1.38
1999   1.97           1.56      1.26      0.89          1.00
2000   1.98           1.63      1.06                    0.87
2001   1.95           1.62      0.92      0.90          0.98
2002   1.76           1.66      0.82      0.86          0.86
2003   1.88           1.68      0.73                    0.71
2004   2.04           1.69      0.59      0.87          0.73
2005   2.04           1.75      1.22      0.90          0.79
2006   2.32           1.88                0.94

Year   France         Germany   Iceland   NZ            Norway

1995   2.55                     1.24      1.40          2.70
1996   1.93                     1.07      1.10          2.24
1997   1.59                     0.93      1.04          2.49
1998   1.50                     0.58      0.69          2.10
1999   1.54           1.4       0.83      0.54          1.68
2000   1.61           1.39      0.68      0.53          1.41
2001   1.70           1.28      0.46      0.50          1.21
2002   1.85           1.21      0.54      0.48          1.11
2003   1.92           1.06      0.77      0.48          1.21
2004   1.92           1.04      0.51      0.45          1.25
2005   2.02           1.03      0.72      0.43          1.16
2006   2.13           0.83      0.96

Year   Scotland and   Sweden    Switz     Aggregate
       Northern                           of surveyed
       Ireland                            countries

1995                            3.92      2.54
1996   2.45           3.43      3.57      2.10
1997   2.66           2.99      2.90      1.95
1998   2.77           2.74      2.55      1.83
1999   1.84           1.70      1.48      1.40
2000   1.37           1.50      1.80      1.51
2001   1.35           1.73      1.71      1.38
2002   1.22           1.49      1.88      1.37
2003   1.35           1.42      1.73      1.45
2004   1.30           1.56      1.67      1.35
2005   1.12           1.63      1.58      1.39
2006   1.08                               1.43

Aus=Australia, Den=Denmark, NZ=New Zealand, Switz=Switzerland

Table 2
Use of synthetic colloids in albumin volume equivalents
(litres per 10,000 persons) by jurisdiction 1995 to 2005

Year   Den,       Den,      Sweden,    Sweden,   Sweden,    Canada,
       starches   dextran   starches   dextran   gelatins   starches

1995                                                        11.7
1996                        18.6       108.4     3.0        22.7
1997   106.3      19.2      30.6       102.7     2.6        32.0
1998   122.8      21.6      37.5       103.0     3.4        40.3
1999   138.6      25.0      43.5       103.5     2.0        49.2
2000   150.3      30.8      46.5       103.7     2.3        54.7
2001   148.3      34.8      53.0       104.8     1.0        57.5
2002   152.4      40.5      44.4       97.0                 60.4
2003   142.8      42.2      81.3       91.7                 64.2
2004   189.3      42.5      95.1       83.4                 71.6
2005   157.4      37.7      112.9      76.0


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Author:Jones, D.; McEvoy, S.; Merz, T.M.; Higgins, A.; Bellomo, R.; Cooper, J.D.; Hollis, S.; McArthur, C.;
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:4E
Date:Mar 1, 2010
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