Intensive Care Med (2004) 30:22222229 DOI 10.

1007/s00134-004-2415-1

ORIGINAL

Frdrique Schortgen Nicolas Deye Laurent Brochard for the CRYCO Study Group

Preferred plasma volume expanders for critically ill patients: results of an international survey

Received: 23 June 2003 Accepted: 26 July 2004 Published online: 28 September 2004  Springer-Verlag 2004 This study was presented in part at the 15th Annual Congress of the European Society of Intensive Care Medicine, Barcelona, 29 September2 October 2002. This study was supported by grant Projet Hospitalier de Recherche Clinique AOM00120 from the Assistance Publique-Hpitaux de Paris (Paris Teaching Hospital Network). Electronic Supplementary Material Supplementary material is available in the online version of this article at http:// dx.doi.org/10.1007/s00134-004-2415-1. F. Schortgen ()) Medical and Infectious Diseases Intensive Care Unit, Bichat-Claude Bernard Teaching Hospital, 75018 Paris, France e-mail: frederique.schortgen@bch.ap-hop-paris.fr Tel.: +33-1-40257703 Fax: +33-1-40258837 N. Deye L. Brochard Medical Intensive Care Unit, Henri Mondor Teaching Hospital, 94000 Crteil, France

Abstract Objective: Criteria for plasma volume expander selection in critically ill patients remain controversial. This study evaluated preferences of intensivists regarding plasma volume expanders. Design: International survey using a 75-item questionnaire. Participants and setting: All members of the European and French Societies of Intensive Care Medicine (n=2,415 in 1,610 adult ICUs in Europe and elsewhere) were invited to participate, and 577 (24%) working in 515 ICUs (32%) returned completed questionnaires. Results: Among respondents, 17% used crystalloids alone as their firstchoice strategy, 18% colloids alone, and 65% both. Colloids alone were often chosen in patients with cirrhosis (42%), coagulation disorders (42%), or adult respiratory distress syndrome (39%); and crystalloids in patients with dehydration (85%), drug overdose (59%), or acute renal failure (49%). First-line plasma expanders were as follows: isotonic crystalloids (81%), starches (55%), gelatins

(35%), albumin (7%), plasma (6%), dextrans (4%), and hypertonic crystalloids (2%). Colloids alone were used more frequently in the United Kingdom (40%), starches in Germany (81%) and The Netherlands (66%), and gelatins in the United Kingdom (68%). The main factors behind preferences for first-line plasma volume expanders were time to volume loss correction, duration of effect, adverse events, and cost. Conclusions: Colloids are widely used as first-line treatment, usually in combination with crystalloids. Starches are the most widely used colloids in Europe, where albumin use is declining. However, strategies vary widely across clinical situations and countries. Keywords Survey Intensive care unit Colloids Crystalloids Fluid resuscitation Practices

Introduction
Intravascular fluid administration is a cornerstone of the treatment of hypovolemic shock. Despite 30 years of research in animals and humans the best plasma volume expander (PVE) among the many available compounds remains a matter of debate [1]. Colloids and crystalloids are often contrasted with each other. Advantages of col-

loids include rapid reversal of hemodynamic disorders and preservation of colloid osmotic pressure [2]. Crystalloids have fewer side effects and lower costs than do colloids. However, larger volumes are needed with crystalloids, and it has been argued that this may promote pulmonary and peripheral edema [2, 3, 4]. Comparative studies are old and methodologically flawed. More recently, systematic reviews failed to find convincing evi-

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dence that either class of compounds was superior over the other [5, 6]. In addition, the development of synthetic colloids has added vigor to the debate regarding selection of the optimal colloid [7, 8, 9]. Because no conclusive studies are available, a consensus regarding PVE selection cannot be reached. None of the colloids has been proven to yield better outcomes as than crystalloids. In addition, colloids are costly, and cost-containment efforts in several countries have included measures to restrict the use of albumin [10, 11]. Although national guidelines on first-line PVEs have been developed, there is no international consensus, and preference is given to crystalloids in some countries and to colloids in others [12, 13]. In addition, the efficacy of PVEs may vary from one clinical situation to another, further complicating identification of the best first-line compound. Few studies have sought to determine how intensivists deal with the uncertainty surrounding first-line PVE therapy. National surveys showed a preference for crystalloids in Canada and starches in Germany [14, 15]. The absence of evidence that one PVE class is superior over the other, together with the differences across national guidelines, probably translates into heterogeneity in practices within and across ICUs. Choices made by individual intensivists may be influenced by personal preferences, ICU-wide or hospital-wide policies, or national guidelines. However, little is known about the extent of and reasons for heterogeneity regarding PVE selection in the ICU. The aim of this international survey (the CRYCO Study) was to evaluate the preferences of intensivists for PVE therapy in various clinical situations and to identify the reasons behind these preferences.

intensivists by electronic mail or fax in November 2001. A reminder was sent in February 2002, and the survey was completed in March 2002. The research project complied with French law regarding the protection of individuals from information technology-based intrusion into their private life and was approved by the appropriate authorities (Commission Nationale Informatique et Liberts). The statistical analysis included descriptive statistics and frequency analyses. To investigate the rationale for the choice of PVE we used the c2 test to compare proportions of colloid users and nonusers. Values of p less than 0.05 were considered significant.

Results
Characteristics of respondents The overall response rate was 24% (577/2,415), 23% among intensivists in Europe, and 29% among intensivists outside Europe. The 577 respondents worked in 515 ICUs in 41 countries; the vast majority of respondents worked in ICUs in Europe (Table 1). Plasma volume expanders used in the ICUs The types of PVEs used in the study ICUs are indicated in Fig. 1. Isotonic crystalloids (90%), starches (66%), and gelatins (57%) were the three most widely used PVEs (i.e., reported as often or always used). Strategy for choosing the first-line plasma volume expander Among respondents 65% used a combination of crystalloids and colloids as the first-line PVE strategy, 18% used colloids alone, and 17% used crystalloids alone (Fig. 2).
Table 1 Characteristics of the 577 ICU physicians who returned completed questionnaires (ICU intensive care unit, IQR 25th to 75th interquartile range) Region European Non-European Type of hospital (% of respondents) University hospital Public community hospital Private hospital Other Median number of beds per hospital (IQR) Median number of beds per ICU (IQR) Type of ICU (% of respondents) Medical-surgical ICU Surgical ICU Medical ICU Time working in an ICU Less than 5 years 510 years More than 10 years 90% 10% 54% 35% 7% 4% 700 (2041024) 12 (818) 58% 22% 20% 6% 28% 66%

Methods
The study questionnaire was developed by the investigators. The 75 items were closed questions exploring six main areas: hospital and ICU characteristics, awareness of guidelines for the use of PVEs, PVEs used in the respondents ICU, recent changes in the ICUs policy for PVE use, respondents preferred PVE in general and in ten clinical situations characterized by hypovolemic shock, and reasons underlying the respondents preferences. The items explored the respondents strategy for volume expansion (i.e., the choice between colloids and crystalloids) and the respondents preferences among PVEs (i.e., starches, albumin, gelatins, dextrans, plasma, isotonic crystalloids, and hypertonic crystalloids). A covering letter attached to the questionnaire explained the rationale for the survey, indicated that no pharmaceutical company was supporting the study, and explained that the study was not driven by financial considerations. Before initiation of the survey, the clarity of the items and the questionnaire completion time were evaluated by ten intensivists who were not involved in designing the study. The questionnaire could be completed in about 10 min. Using the databases of the European Society of Intensive Care Medicine and of the French Society of Intensive Care Medicine (Socit de Ranimation de Langue Franaise) we identified 2,415 intensivists working in 1,610 medical, surgical, or specialized adult ICUs in 71 countries. We sent the questionnaire to each of these

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Fig. 1 Type of plasma volume expanders used in the ICU. Percentages based on 577 respondents Fig. 3 Strategy for plasma volume expansion across countries. Countries with at least 30 respondents were taken into account. Answers from the 16 non-European countries (Argentina, Australia, Bolivia, Brazil, Canada, Chile, Hong Kong, Israel, Japan, Jordan, Mexico, Peru, Russia, Tunisia, Turkey, United States) were pooled, as were answers from the 25 European countries. Results are expressed as the percentage of respondents in each country. The total number of respondents is indicated for each country

Choice of the types of plasma volume expander The types of PVE preferred for first-line therapy are indicated in Table 2. Starches were the PVE of first choice reported by more than half the respondents and were the most frequently chosen colloids, followed by gelatins (35%); albumin was rarely used as the first-line PVE (7%). Among the many reported PVE combinations, the most widely used was starch plus isotonic crystalloid (31% of respondents). The choice among colloids varied across clinical situations (Table 2). Most respondents included starches in the first-line treatment of patients with sepsis, trauma, hemorrhage, or adult respiratory distress syndrome. Albumin was the most widely used colloid in patients with cirrhosis or burns. Differences across countries are reported in Table 3. Only countries with more than 30 respondents were included in this analysis. Starches were preferred by 81% of respondents in Germany and gelatins by 68% of those in the United Kingdom. Hypertonic crystalloids and dextrans were never or rarely used in these countries. Respondents working in Italy had the highest rate of plasma use as first-line treatment (18%). Outside Europe, albumin was more likely, and starch less likely, to be selected for first-line therapy. Fifty ICUs had more than one respondent. The strategy for first-line therapy differed across physicians working in the same ICU in 28% of these 50 units.

Fig. 2 Strategy for selecting first-line plasma volume expanders in general and in ten specific clinical situations

Differences in first-line PVE strategies were found across clinical situations (Fig. 2). Colloids were often used alone in patients with cirrhosis (42%), coagulation disorders (42%), or acute respiratory distress syndrome (39%). Crystalloids were often used alone in patients with dehydration (85%), drug overdose (59%), or renal failure (49%). Strategies also varied across countries (Fig. 3). Crystalloids alone were almost never used in the United Kingdom (2%) or The Netherlands (3%) but were used by 32% (19/60) of respondents working in countries outside Europe. Use of colloids alone was twice as common in the United Kingdom (40%) as overall.

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Table 2 Type of plasma volume expanders used by respondents in general and in ten specific clinical situations. Results are expressed as percentages based on 577 respondents; some respondents gave more than one answer (ARDS acute respiratory distress syndrome)

Crystalloids Isotonic In general Sepsis Trauma Burns Hemorrhage Dehydration Drug intoxication ARDS Renal failure Coagulation disorders Cirrhosis 81 70 71 83 63 98 86 60 82 57 58 Hypertonic 2 4 14 7 10 1 2 3 2 1 5

Colloids Starches 55 58 55 30 58 7 23 52 20 14 28 Gelatins 35 34 39 19 40 8 20 30 25 17 23 Albumin 7 12 5 32 6 0 2 6 10 7 56 Plasma 6 10 14 16 26 0 0 4 1 65 24 Dextrans 4 5 5 3 3 1 3 3 2 1 2

Table 3 Type of plasma volume expanders used by respondents according to country (parentheses total number of respondents in each country). Countries having at least 30 respondents were taken into account and answers coming from the 16 non-European countries were pooled (i.e., Argentina, Australia, Bolivia, Brazil, Crystalloids Isotonic France (n=162) Germany (n=63) United Kingdom (n=40) The Netherlands (n=35) Italy (n=33) European countries (n=517) Non-European countries (n=60) 72 84 60 91 88 80 82 Hypertonic 0 0 0 2 0 2 0

Canada, Chile, Hong Kong, Israel, Japan, Jordan, Mexico, Peru, Russia, Tunisia, Turkey, United States), as were answers from the 25 European countries. Results are expressed as the percentage of respondents in each country

Colloids Starches 51 81 35 66 54 58 25 Gelatins 40 19 68 46 42 35 35 Albumin 6 5 5 3 6 5 22 Plasma 2 6 0 3 18 5 10 Dextrans 0 0 0 0 0 3 5

Table 4 Reasons for selecting plasma volume expanders: comparison of colloid users and nonusers. Results are shown as numbers and percentages of respondents. The number of respondents varies with the number of unanswered items

All respondents (n=577) n Rapidity of reversal of intravascular volume loss* Long-lasting volume expansion* Efficacy in reversing damage to the microcirculation Reduced risk of pulmonary edema* Reduced risk of interstitial fluid accumulation* Low risk of adverse events* No risk of infectious agent transmission Low cost* 527/569 326/566 332/566 251/560 114/565 287/568 463/568 358/568 % 93 58 59 45 20 50 82 63

Colloid nonusers (n=99) n 75/97 18/97 61/98 23/96 10/96 89/97 81/96 83/97 % 77 19 62 24 10 92 84 86

Colloid users (n=478) n 452/472 308/469 271/468 228/464 104/469 198/471 382/472 275/471 % 96 66 58 49 22 42 81 58

* p<0.001 between colloid users and nonusers

Reasons behind the selection of first-line plasma volume expanders Intensivists who included colloids in their first-line strategy were more likely to work in ICUs admitting surgical patients (82% vs. 67%, p<0.001) than were intensivists who used crystalloids alone. The other characteristics of the respondents did not differ according to the strategy for fluid resuscitation. The main reasons for

choice of the first-line treatment differed between colloid users and colloid nonusers (Table 4). The three main reasons for using colloids were their ability to correct volume loss rapidly, the long duration of their effect, and the need to select the PVE according to the clinical situation. Respondents who used only crystalloids stated that these compounds were as effective as colloids when given in sufficiently large amounts, had fewer adverse effects, and were less expensive (Table 5).

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Table 5 Respondents agreed with the following controversial statements. Results are shown as numbers and percentages of respondents. The number of respondents varies with the number of unanswered items All respondents (n=577) n Crystalloids are as effective as colloids if the volume administered is sufficient* The choice of plasma volume expander is strongly dependent on the clinical situation* Colloids have more adverse effects than crystalloids* Starches are the most effective synthetic colloids Among colloids, starches have the fewest adverse effects The newer starches have significantly fewer adverse effects than the older compounds The use of colloids improves the outcome of critically ill patients in comparison to crystalloids* The use of crystalloids improves the outcomeof critically ill patients in comparison to colloids* The use of albumin worsens the outcome of critically ill patients * p<0.001 between colloid users and nonusers 389/567 437/568 383/568 338/568 257/563 335/563 117/567 86/565 150/566 % 69 77 67 60 46 60 21 15 26 Colloid nonusers (n=99) n 88/98 55/98 87/96 52/98 40/97 50/97 8/97 27/97 24/97 % 90 56 91 53 41 52 8 28 25 Colloid users (n=478) n 301/469 382/470 296/472 286/470 217/466 285/466 109/470 59/468 126/469 % 64 81 63 61 47 61 23 13 27 Do not know n 28 20 27 76 88 187 191 206 177

Changes in ICU policy for plasma volume expander use Of the 577 respondents 311 (57%) reported changes in the policy for PVE use in their ICU over the last 5 years. Nearly one-half these changes (137 of 311 respondents, 45%) targeted the PVE most widely used in the ICU; among these changes 98 (98/137, 72%) consisted in broader indications for crystalloids and 39 (39/137, 28%) in broader indications for colloids. The most common changes were discontinuation of albumin use (135 of 577 respondents, 24%) and start of starches for first-line therapy (87 of 577 respondents, 15%). According to the respondents, the reasons behind these changes were evidence in the literature (99%), adverse effects of expanders (72%), personal experience of the physician (68%), guidelines developed by panels of experts (65%), risk of infectious agent transmission (53%), cost containment (52%), and guidelines developed in the ICU and/or hospital (33%).

Discussion
Our survey was the first international study on PVE selection by intensivists for patients with hypovolemic shock. Our study design could not provide accurate information on the reasons underlying practices. It did generate data allowing intensivists to compare their practices to those of their colleagues. This may be useful given the absence of an international consensus on PVE use in critically ill patients. Recently published guidelines on the management of severe sepsis emphasize that fluid administration for volume expansion must be clearly separated from increasing maintenance fluids. This distinction was made in our questionnaire. Several terms are used to designate

fluid resuscitation products given to correct hypovolemia in patients with shock. We used plasma volume expander and plasma expansion in our questionnaire. We did not use plasma substitute because we felt that this term might create confusion with products used to supply coagulation factors. The term volume expansion has been used in recommendations on the management of severe sepsis to indicate that crystalloids, colloids, or both may be used [16]. The results of our survey indicate considerable heterogeneity among intensivists in Europe and elsewhere regarding PVE use. Regarding first-line strategies for plasma volume expansion, two-thirds of respondents reported a preference for combining colloids and crystalloids. In the absence of evidence that one of these PVE classes is superior over the other, the two seem to be used with similar frequencies, and combining colloids and crystalloids appears to be empirically considered the best strategy for ICU patients. The widespread use of colloids, most notably starches, is in accordance with an earlier survey showing that two thirds of German intensivists used starches for first-line volume expansion [14]. On the other hand, in Canada, 61% of intensivists and other physicians prescribing plasma expansion reported using crystalloids at least 90% of the time, whereas albumin was the most widely used colloid [15]. These differences in clinical practices across countries reflect both the lack of conclusive data in the literature and the impact of local factors. Among these latter, the price of starches is five times higher in the United States than in Europe [7]. Also, time on the market probably influences practices. Medium-molecular-weight starches are widely used in European countries, but the dates of market authorization vary markedly across countries, i.e., 1980 in Germany, 1991 in France, and 1998 in Spain. Starches were first produced by a German firm, a fact that may contribute to the high

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level of use of starches in Germany. Dextrans are used mainly in northern Europe [17] although dextrans were selected for first-line therapy by only 21 (4%) respondents overall. In the absence of strong evidence supporting the superiority of one product over the others, marketing pressure may also influence the choices made by individual intensivists and by national panels of experts. A Canadian survey on the choice between albumin and starches found that physicians who reported high use of starches were more likely to report a visit from a drug detailer for pentastarch [15]. Our questionnaire included items on reasons for PVE selection. Because all items were closed questions, however, the survey did not collect detailed information on this point. PVE selection is often based on a complex combination of knowledge from the literature and clinical judgment that cannot be explored in depth by closed questions. As expected, the reasons behind PVE selection differed markedly between colloid users and nonusers. Intensivists who preferred crystalloids reported that the adverse event profile and the cost contributed in equal measure to this preference; they felt that the difference in efficacy could be overcome by using larger volumes of crystalloids. Surprisingly, most of the colloid users agreed that crystalloids were as effective as colloids when given in sufficiently large amounts. The faster volume expansion and longer duration of the effect were often listed among reasons for preferring colloids. Interestingly, intensivists managing surgical patients were more likely to use colloids than those in medical ICUs. Shock requiring rapid correction of severe volume depletion from bleeding is common among surgical ICU patients. When crystalloids are given in this situation, large amounts must be administered over a long period of time. The number of respondents using hypertonic crystalloids in patients with trauma and bleeding was very small. One possible explanation is that the survey focused on PVE use in the ICU, whereas small volume resuscitation using hypertonic crystalloids have been advocated mainly for prehospital treatment. Possible differences across PVEs regarding patient outcomes were rarely considered relevant to PVE selection. One-half the respondents considered that colloids and crystalloids were similar in terms of patient outcomes. By contrast, a large majority of respondents reported that PVE selection was highly dependent on the clinical situation. The high level of colloid use in situations carrying a risk of low colloid osmotic pressure is not a surprise. For patients with adult respiratory distress syndrome 39% of respondents reported use of colloids alone. Although a higher risk of pulmonary edema with crystalloids has been documented in a single, old, randomized controlled trial [4], concern about the risk of pulmonary edema was among the most commonly reported reasons for preferring colloids. None of the comparative studies in the literature indicates that one PVE is

superior over the others in improving lung physiology in patients with acute lung injury [5]. Albumin use in combination with furosemide has recently produced encouraging results in patients with hypoproteinemia and acute lung injury [18]. Although fewer than 10% of respondents selected albumin as the first-line PVE, only 27% reported that albumin was never used in their department. Albumin was almost entirely reserved for patients with cirrhosis or burns. Discontinuation of albumin use was also the most commonly reported change in PVE policies over the past 5 years. Evidence in the literature was reported as the main factor driving policy changes; this is somewhat surprising given the discrepancies between results of published studies. The lack of convincing evidence that one PVE is better than the others may make cost seem more relevant than clinical considerations as a criterion for PVE selection. There is strong evidence that starches are as effective as albumin in expanding the plasma volume [7]. Thus the main reason for albumin discontinuation may be cost containment. More than half the colloid users reported that cost was an important factor in PVE selection, although they did not use the cheapest PVE (i.e., crystalloids). This suggests that the high cost of albumin has contributed to the increasing use of starches. In addition, in several hospitals, albumin is not available at the bedside but must be ordered via a special procedure [15]. Two recently published studies have given new vigor to the debate on albumin use and patient outcomes. One is a meta-analysis by Wilkes and Navickis [8], indicating that albumin is safe, in contradiction with the higher mortality associated with albumin use in an earlier Cochrane review [19]. The other is a vast retrospective study comparing albumin and nonprotein colloids (i.e., dextrans or first-generation hetastarches) in patients undergoing coronary artery bypass graft surgery. After adjustment on severity, albumin was significantly associated with a reduction in mortality [20]. In our survey 43% of respondents disagreed with the statement that albumin administration was associated with worse patient outcomes and 31% did not have an opinion on this issue. Other factors, such as the potential risk of infectious agent transmission, may lead to a preference for starches over natural colloids and gelatins. Most of the respondents reported recent changes in PVE policies in their ICU. These changes often affected the most frequently used class of PVE and tended to decrease colloid use and to increase crystalloid use. Adverse effects of PVEs were often reported among reasons for changing PVE policies. Recent systematic reviews suggest that colloids may have no advantages over crystalloids, and that colloids may be harmful in specific patient populations. In contrast to crystalloids, colloids have been reported to induce adverse effects specific for each compound and including anaphylactoid reactions, coagulation disorders, acute renal failure, liver failure, and

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pruritus [21, 22, 23, 24, 25]. The safety profile of starches may be better with the newly developed compounds characterized by more rapid degradation [7]. Our survey has several limitations. The respondents were members of societies for intensive care, a characteristic that may have introduced a bias as compared to the overall population of intensivists. Furthermore, intensivists with unusual clinical practices regarding fluid resuscitation and those not interested in the specific characteristics of PVEs may have been less likely to participate in the survey. The number of respondents is a major limitation to clinical practice surveys. To our knowledge, our survey has larger numbers of potential participants and of respondents than other surveys of PVE use. Although the response rate was only 24% of intensivists and 32% of ICUs, these figures are similar to those in several recent international surveys [26, 27, 28]. Nevertheless, we do not know whether our sample was representative of the intensivist population in each of the participating countries. Because of the large number of countries the number of respondents per country was limited. Therefore we compared practices across the five countries with the largest numbers of respondents and

pooled the answers from the 16 non-European countries. Despite the probable heterogeneity in the non-European group, we found major differences in practice between European and non-European countries. Lastly, the results of this study are based on statements made by intensivists rather than on observed practices. In conclusion, we found considerable heterogeneity in clinical practices regarding PVE selection by intensivists. The survey respondents reported using colloids widely for first-line therapy, chiefly in combination with crystalloids. Starches were reported as the most frequently used colloids in Europe and albumin use as being in decline. PVE selection varied across clinical situations, across countries, and in 25% of cases across intensivists in a given ICU. Patterns of actual PVE use and differences in efficacy across PVEs in clinical practice remain to be assessed.
Acknowledgements We thank the European Society of Intensive Care Medicine and the French Society of Intensive Care Medicine (Socit de Ranimation de Langue Franaise) for providing the databases used to identify the study participants and Sophie Jacques-Weber for her secretarial assistance throughout the survey.

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