Editorial

Colloid Use for Fluid Resuscitation: Evidence and Spin

n this issue, Wilkes and Navickis (1) present a metaanalysis of albumin versus crystalloids in seriously ill patients. Their study has many strengths. The comprehensive search strategy minimized the chance of publication bias and English-language bias. Explicit selection criteria were used, including studies with randomized allocation; comparison of albumin administration with crystalloid, no albumin, or lower-dose albumin; and an end point of mortality. The investigators selected trials and abstracted data in duplicate. Other criteria for quality assessment of the trials included treatment allocation, crossovers, and blinding. Blinding of whom (clinicians, researchers, outcome assessors, analysts, or patients) and for what purpose (minimization of co-interventions and outcome ascertainment) is a useful technique for reporting meta-analyses that acknowledges the inherent problems associated with conventional blinding labels (2). The analysis is clear and replicable, and the authors used the QUORUM (Quality of Reporting of MetaAnalyses) format to aid in transparent reporting (3). Wilkes and Navickis conclude that their ndings should serve to allay concerns regarding the safety of albumin (1). However, the pooled relative risk for death was 1.11 (95% CI, 0.95 to 1.28) in all patients receiving albumin, 1.12 (CI, 0.85 to 1.46) in surgery or trauma patients, 1.76 (CI, 0.97 to 3.17) in patients with burns, and 1.59 (CI, 0.91 to 2.78) in patients with hypoalbuminemia. These results are reassuring only insofar as they fail to show a statistically signicant increase in mortality. In each case, the point estimatethe best estimate of the true effect of treatmentshows an increase in the relative risk for death of more than 10% overall and up to 76% in subgroups. Condence intervals estimate the range within which the true effect plausibly lies. These condence intervals indicate that the results are consistent with a relative overall increase in mortality of 28% and a threefold increase in mortality in two of the subgroups. Point estimates that suggest harm and condence intervals that include important increases in mortality cannot allay concerns about the potentially harmful effects of albumin. Even in the subgroup of patients with ascites, in which benet is suggested, the condence intervals indicate considerable uncertainty (relative risk, 0.93 [CI, 0.67 to 1.28]).

Furthermore, two factors weaken the inferences we can draw from these results. First, although a priori subgroup analyses based on methodologic features of individual studies and on subgroups of patients with surgery and trauma, hypoalbuminemia, burns, and ascites were done, other explanations for heterogeneity were not explored. These include study designs with fundamentally different objectives (short-term modication of a physiologic end point or longer-term morbidity end points) and different resuscitation schedules (volume, rate, and duration of administration). Second, to draw appropriate inferences from meta-analyses, the quality of the research that is summarized must be also considered. The trials included in these meta-analyses present myriad limitations, including widely discussed study design issues; outdated uid protocols; and unmeasured effects of red blood cell transfusions, which also inuence the outcome of critically ill patients. Turning to the consistency of the literature, seven other meta-analyses of uid administration and mortality in seriously ill patients have been published (4 10). In 1989 (4) and 1991 (5), two meta-analyses comparing crystalloid and colloid uid resuscitation in heterogeneous seriously ill patients found a trend toward increased mortality associated with colloids. In 1997, Wade and colleagues (6) found no difference in mortality between trauma patients receiving hypertonic saline and those receiving isotonic crystalloid, nor did hypertonic saline and 6% dextran 70 differ from isotonic crystalloid. Using regression techniques to adjust for differences in populations between studies (such as type of injury, and hemodynamic and neurologic status), Wade and colleagues (7) found that hypertonic saline plus dextran conferred a signicant survival advantage compared with isotonic crystalloid in patients with head injury (adjusted odds ratio for hospital survival, 2.12 [CI, 1.01 to 4.49]). In 1998, Schierhout and Roberts (8) evaluated the effect of crystalloids (hypertonic or isotonic) versus colloids on mortality in critically ill patients requiring resuscitation. They observed a trend toward increased mortality overall (relative risk, 1.19 [CI, 0.98 to 1.45]) and in patients with trauma (relative risk, 1.30 [CI, 0.95 to 1.77]) and burns (relative risk, 1.21 [CI, 0.88 to 1.66]) but not in those undergoing surgery (rel7 August 2001 Annals of Internal Medicine Volume 135 Number 3 205

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Editorial

Colloid Use for Fluid Resuscitation: Evidence and Spin

ative risk, 0.55 [CI, 0.18 to 1.65]). Also in 1998, the Cochrane Injuries Group Albumin Reviewers (9) evaluated randomized trials of albumin or plasma protein fraction versus isotonic crystalloids (or no albumin or plasma protein fraction). Risk for death was signicantly increased overall in patients who received albumin (relative risk, 1.68 [CI, 1.26 to 2.23]) and in patients with burns (relative risk, 2.40 [1.11 to 5.19]) and hypoalbuminemia (relative risk, 1.69 [CI, 1.07 to 2.67]); hypovolemic patients had a trend toward increased mortality (relative risk, 1.46 [CI, 0.97 to 2.22]). In 1999, Choi and colleagues (10) compared the effect of colloids with isotonic crystalloids in heterogeneous seriously ill patients. Crystalloids were associated with a trend toward lower mortality overall (relative risk, 0.86 [CI, 0.63 to 1.17]) and a signicantly lower risk for death among patients with trauma (relative risk, 0.39 [CI, 0.17 to 0.89]). As the number of meta-analyses increases, more contradictions among them are inevitable. Meta-analyses may differ in two fundamental ways (11). First, the actual results of meta-analyses results may differ because of the trials that were available or selected. Second, the results of meta-analyses may be very similar, but the authors may interpret the results quite differently. In reviewing the meta-analyses by Schierhout and Roberts (8), the Cochrane Injuries Group Albumin Reviewers (9), and Wilkes and Navickis (1), readers will be struck by the similarity of some of the results and the dissimilarity of the interpretations. Why might authors of one meta-analysis present as alarming results that other authors present as reassuring? Inuences may include different interpretations of point estimates and condence limits, a priori beliefs, knowledge of pathophysiology, variable cost considerations, and conicts of interest. Because funding can inuence how research ndings are interpreted, many journals now appropriately insist that all authors acknowledge their funding sources (12). For example, the Plasma Protein Therapeutics Association (www.plasmatherapeutics.org/ppta_namerica/index.htm), which funded the meta-analysis in this issue, is working closely with consumer groups to ensure continued access to critically needed plasma protein therapeutics . . . taking proactive measures to positively impact reimbursement proposals and address other critical issues that will advance therapeutic access to life-saving medicines. Recently, uid resuscitation as a topic and critical
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appraisal of meta-analysis as a skill became prominent in critical care curricula at rounds, journal clubs, and conferences, in part through publicity surrounding the Cochrane Collaboration meta-analyses (8, 9). Ensuing letters to the editor raised important physiologic, clinical, methodologic, and statistical issues. Some have posed thoughtful calls for more sophisticated preclinical models (13), more contemporary uid schedules (14), and economic evaluations (15). Speculation about whether albumin would be approved today at an inaugural regulatory agency meeting is intriguing (16). These ideas and subsequent statements from professional societies provide the foundation for a qualitative research project, using case study methods and document analysis, to understand how and why meta-analysis results can incite such a range of practice policies. Systematic reviews are beginning to inuence health policy. After the meta-analysis by the Cochrane Injuries Group Albumin Reviewers (9), use of albumin solutions in the United Kingdom decreased by at least 40% by the end of 1998 (17). The role of the intense reaction of the media to the Cochrane meta-analyses in inuencing practice is difcult to prove, but easy to deduce. The methodologic weakness of the available studies and their heterogenous populations and variable treatment regimens suggest that investigators might undertake larger, more rigorous studies based on current physiologic rationale and modern randomized trial methods. In grant proposals, systematic reviews of previous work can highlight what is known and what requires further investigation. For example, on the basis of the Cochrane Injuries Group Albumin Reviewers meta-analysis, which reported a 6% (CI, 3% to 9%) absolute increase in mortality associated with albumin (9), the Australian and New Zealand Intensive Care Society Clinical Trials Group began a randomized, concealed, double-blind trial comparing resuscitation using 4% albumin versus 0.9% normal saline in a heterogeneous sample of patients in the intensive care unit. The trial is designed to detect a 3% difference in 28-day mortality and will enroll 7000 patients in intensive care units in Australia and New Zealand. Stimulated in part by Wade and colleagues meta-regression (7), a second randomized trial from Australia is testing the effect of hypertonic saline versus isotonic crystalloid for prehospital resuscitation of hypotensive patients with head trauma (Cooper J. Personal communication). Recognizing
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Colloid Use for Fluid Resuscitation: Evidence and Spin

Editorial

that morbidity end points must not be overshadowed by a singular focus on vital status, this multicenter trial is evaluating long-term neurologic sequelae of uid choice. Modern trials are less likely than older studies to conate resuscitation uid with either protocolized treatment goals or monitoring technology. The Canadian Critical Care Trials Group (18) recently completed a multicenter randomized trial of therapeutic goals achieved by uid administration and pharmacotherapy guided by a pulmonary artery catheter. Among 1994 elderly high-risk surgical patients, the mortality rate was 7.8% in the treatment group and 7.7% in the control group (19). Currently, the Acute Respiratory Distress Syndrome Network is also enrolling patients with the acute respiratory distress syndrome into a randomized, factorial study of goal-directed therapy and pulmonary artery catheterization (www.nhlbi.nih.gov/funding/inits). Others are testing albumin as a composite intervention to evaluate whether it enhances the diuretic response to furosemide in patients with acute lung injury (20). Thus, both short-term physiologic studies and investigations designed to reduce morbidity are still needed to suggest mechanisms and to generate hypotheses for future testing. Such hypotheses could also be raised by meta-analyses other than those currently published (1, 4 10). We identied four more meta-analyses from the Cochrane Library (20 23), two of which are updates (20, 21) of published work (8, 9). A fth meta-analysis by Wilkes and colleagues (24) addressing a more rened clinical question shows signicantly less blood loss in patients exposed to albumin compared with hydroxyethyl starch (693 350 mL vs. 789 487 mL) within 24 hours of cardiopulmonary bypass. What can we learn from the ongoing debate about uid resuscitation in seriously ill patients? First, rigorously conducted systematic reviews of randomized trials can be valuable in informing practice. Second, to avoid misleading inferences, we must faithfully interpret point estimates and condence intervals when interpreting meta-analyses. Third, while physiologic rationale guides our practice, we need to acknowledge when modern, highquality studies do not support this rationale. Fourth, original research may be more likely to advance this eld than will additional meta-analyses. Finally, participation in well-designed clinical trials represents the optimal approach to resolving continued controversies in patient care.
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Deborah Cook, MD Gordon Guyatt, MD McMaster University Hamilton, Ontario L8N 4A6, Canada
Disclosures: Drs. Cook and Guyatt have received no personal funding

from pharmaceutical agencies producing either colloids or crystalloids. Dr. Cook coauthored a previous meta-analysis of colloids versus crystalloids. Bayer, Inc., paid Dr. Guyatts expenses to attend a conference and provided an honorarium that he contributed to a McMaster University research fund.
Requests for Single Reprints: Deborah J. Cook, MD, Department of

Medicine, St. Josephs Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.
Current Author Addresses: Dr. Cook: Department of Medicine, St. Josephs Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada. Dr. Guyatt: Department of Clinical Epidemiology and Biostatistics, St. Josephs Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Ann Intern Med. 2001;135:205-208.

References
1. Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. 2001; 135:149-64. 2. Devereaux PJ, Manns BJ, Ghali WA, Quan H, Lacchetti C, Montori VM, et al. Physician interpretations and textbook denitions of blinding terminology in randomized controlled trials. JAMA. 2001;285:2000-3. [PMID: 11308438] 3. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999; 354:1896-900. [PMID: 10584742] 4. Velanovich V. Crystalloid versus colloid uid resuscitation: a meta-analysis of mortality. Surgery. 1989;105:65-71. [PMID: 2911805] 5. Bisonni RS, Holtgrave DR, Lawler F, Marley DS. Colloids versus crystalloids in uid resuscitation: an analysis of randomized controlled trials. J Fam Pract. 1991;32:387-90. [PMID: 2010737] 6. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN. Efcacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of controlled clinical studies. Surgery. 1997;122:609-16. [PMID: 9308620] 7. Wade CE, Grady JJ, Kramer GC, Younes RN, Gehlsen K, Holcroft JW. Individual patient cohort analysis of the efcacy of hypertonic saline/dextran in patients with traumatic brain injury and hypotension. J Trauma. 1997;42:S61-5. [PMID: 9191698] 8. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. BMJ. 1998;316:961-4. [PMID: 9550953] 9. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. BMJ. 1998;317:235-40. [PMID: 9677209] 10. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in uid resuscitation: a systematic review. Crit Care Med. 1999;27:200-10. [PMID: 9934917] 11. Jadad AR, Cook DJ, Browman GP. A guide to interpreting discordant
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Colloid Use for Fluid Resuscitation: Evidence and Spin

systematic reviews. CMAJ. 1997;156:1411-6. [PMID: 9164400] 12. Cho MK, Shohara R, Schissel A, Rennie D. Policies on faculty conicts of interest at US universities. JAMA. 2000;284:2203-8. [PMID: 11056591] 13. Sibbald WJ. An alternative pathway for preclinical research in uid management. Crit Care. 2000;4 Suppl 2:S8-S15. [PMID: 11255593] 14. Beale RJ, Wyncoll DL, McLuckie A. Human albumin administration in critically ill patients. Analysis is supercial and conclusions exaggerated [Letter]. BMJ. 1998;317:884. [PMID: 9786698] 15. Vincent JL. Fluid management: the pharmacoeconomic dimension. Crit Care. 2000;4 Suppl 2:S33-5. [PMID: 11255597] 16. Gotzsche PC. Why we need a broad perspective on meta-analysis. It may be crucially important for patients [Editorial]. BMJ. 2000;321:585-6. [PMID: 10977820] 17. Roberts I, Edwards P, McLelland B. More on albumin. Use of human albumin in UK fell substantially when systematic review was published [Letter]. BMJ. 1999;318:1214-5. [PMID: 10221965] 18. Sandham JD, Hull RD, Brant R and the Canadian Critical Care Trials Group. A randomized controlled trial of pulmonary artery catheter use in 1,994 high risk geriatric surgical patients [Abstract]. Am Rev Resp Crit Care Med. 2001;163:A16.

19. Martin GS, Mangialardi RJ, Wheeler AP, Bernard GR. Albumin and diuretics in ARDS [Abstract]. Am J Resp Crit Care Rev. 1999;159:A376. 20. Alderson P, Schierhout G, Roberts I, Bunn F. Colloids versus crystalloids for uid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2000;2: CD000567. [PMID: 10796729] 21. Bunn F, Lefebvre C, Li Wan Po A, Li L, Roberts I, Schierhout G. Human albumin solution for resuscitation and volume expansion in critically ill patients. The Albumin Reviewers. Cochrane Database Syst Rev. 2000;2:CD001208. [PMID: 10796756] 22. Bunn F, Roberts I, Tasker R, Akpa E. Hypertonic versus isotonic crystalloid for uid resuscitation in critically ill patients (Cochrane Review). Cochrane Database Syst Rev. 2000;4:CD002045. [PMID: 11034742] 23. Bunn F, Alderson P, Hawkins V. Colloid solutions for uid resuscitation (Cochrane Review). Cochrane Database Syst Rev. 2001;2:CD001319. [PMID: 11405985] 24. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg. [In press].

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