Colloid Use for Fluid Resuscitation

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Colloid Use for Fluid Resuscitation: Evidence and Spin

In this issue, Wilkes and Navickis (1) present a meta-analysis of albumin versus crystalloids in seriously illpatients. Their study has many strengths. The compre-hensive search strategy minimized the chance of publi-cation bias and English-language bias. Explicit selectioncriteria were used, including studies with randomizedallocation; comparison of albumin administration withcrystalloid, no albumin, or lower-dose albumin; and anend point of mortality. The investigators selected trialsand abstracted data in duplicate. Other criteria for qual-

ity assessment of the trials included treatment allocation,crossovers, and blinding. Blinding of whom (clinicians,researchers, outcome assessors, analysts, or patients) andfor what purpose (minimization of co-interventions andoutcome ascertainment) is a useful technique for report-ing meta-analyses that acknowledges the inherent prob-lems associated with conventional blinding labels (2).The analysis is clear and replicable, and the authorsused the QUORUM (Quality of Reporting of Meta-

Analyses) format to aid in transparent reporting (3).Wilkes and Navickis conclude that their findings

should serve to allay concerns regarding the safety ofalbumin (1). However, the pooled relative risk fordeath was 1.11 (95% CI, 0.95 to 1.28) in all patientsreceiving albumin, 1.12 (CI, 0.85 to 1.46) in surgery ortrauma patients, 1.76 (CI, 0.97 to 3.17) in patients withburns, and 1.59 (CI, 0.91 to 2.78) in patients withhypoalbuminemia. These results are reassuring only in-sofar as they fail to show a statistically significant in-crease in mortality. In each case, the point estimatethebest estimate of the true effect of treatmentshows anincrease in the relative risk for death of more than 10%overall and up to 76% in subgroups. Confidence inter-vals estimate the range within which the true effectplausibly lies. These confidence intervals indicate thatthe results are consistent with a relative overall increasein mortality of 28% and a threefold increase in mortal-ity in two of the subgroups. Point estimates that suggestharm and confidence intervals that include importantincreases in mortality cannot allay concerns about thepotentially harmful effects of albumin. Even in the sub-group of patients with ascites, in which benefit is sug-gested, the confidence intervals indicate considerableuncertainty (relative risk, 0.93 [CI, 0.67 to 1.28]).

Furthermore, two factors weaken the inferences wecan draw from these results. First, although a priori sub-group analyses based on methodologic features of indi-vidual studies and on subgroups of patients with surgeryand trauma, hypoalbuminemia, burns, and ascites weredone, other explanations for heterogeneity were not ex-plored. These include study designs with fundamentallydifferent objectives (short-term modification of a physi-ologic end point or longer-term morbidity end points)and different resuscitation schedules (volume, rate, and

duration of administration). Second, to draw appropri-ate inferences from meta-analyses, the quality of the re-search that is summarized must be also considered. Thetrials included in these meta-analyses present myriadlimitations, including widely discussed study design is-sues; outdated fluid protocols; and unmeasured effectsof red blood cell transfusions, which also influence theoutcome of critically ill patients.

Turning to the consistency of the literature, sevenother meta-analyses of fluid administration and mortal-ity in seriously ill patients have been published (410).

In 1989 (4) and 1991 (5), two meta-analyses comparingcrystalloid and colloid fluid resuscitation in heteroge-neous seriously ill patients found a trend toward in-creased mortality associated with colloids. In 1997,

Wade and colleagues (6) found no difference in mortal-ity between trauma patients receiving hypertonic salineand those receiving isotonic crystalloid, nor did hyper-tonic saline and 6% dextran 70 differ from isotonic crys-talloid. Using regression techniques to adjust for differ-ences in populations between studies (such as type ofinjury, and hemodynamic and neurologic status), Wadeand colleagues (7) found that hypertonic saline plus dex-tran conferred a significant survival advantage compared

with isotonic crystalloid in patients with head injury(adjusted odds ratio for hospital survival, 2.12 [CI, 1.01to 4.49]). In 1998, Schierhout and Roberts (8) evalu-ated the effect of crystalloids (hypertonic or isotonic)versus colloids on mortality in critically ill patients re-quiring resuscitation. They observed a trend toward in-creased mortality overall (relative risk, 1.19 [CI, 0.98 to1.45]) 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 (rel-

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ative risk, 0.55 [CI, 0.18 to 1.65]). Also in 1998, the

Cochrane Injuries Group Albumin Reviewers (9) evalu-ated randomized trials of albumin or plasma proteinfraction versus isotonic crystalloids (or no albumin orplasma protein fraction). Risk for death was significantlyincreased overall in patients who received albumin (rel-ative risk, 1.68 [CI, 1.26 to 2.23]) and in patients withburns (relative risk, 2.40 [1.11 to 5.19]) and hypoalbu-minemia (relative risk, 1.69 [CI, 1.07 to 2.67]); hypo-volemic patients had a trend toward increased mortality(relative risk, 1.46 [CI, 0.97 to 2.22]). In 1999, Choiand colleagues (10) compared the effect of colloids with

isotonic crystalloids in heterogeneous seriously ill pa-tients. Crystalloids were associated with a trend towardlower mortality overall (relative risk, 0.86 [CI, 0.63 to1.17]) and a significantly lower risk for death amongpatients with trauma (relative risk, 0.39 [CI, 0.17 to 0.89]).

As the number of meta-analyses increases, morecontradictions among them are inevitable. Meta-analy-ses may differ in two fundamental ways (11). First, theactual results of meta-analyses results may differ becauseof the trials that were available or selected. Second, theresults of meta-analyses may be very similar, but theauthors may interpret the results quite differently. Inreviewing the meta-analyses by Schierhout and Roberts(8), the Cochrane Injuries Group Albumin Reviewers(9), and Wilkes and Navickis (1), readers will be struckby the similarity of some of the results and the dissimi-larity of the interpretations. Why might authors of onemeta-analysis present as alarming results that other au-thors present as reassuring? Influences may include dif-ferent interpretations of point estimates and confidencelimits, a priori beliefs, knowledge of pathophysiology,variable cost considerations, and conflicts of interest. Be-cause funding can influence how research findings are

interpreted, many journals now appropriately insist thatall authors acknowledge their funding sources (12). Forexample, the Plasma Protein Therapeutics Association(www.plasmatherapeutics.org/ppta_namerica/index.htm),

which funded the meta-analysis in this issue, is workingclosely with consumer groups to ensure continued accessto critically needed plasma protein therapeutics . . . tak-ing proactive measures to positively impact reimburse-ment proposals and address other critical issues that willadvance therapeutic access to life-saving medicines.

Recently, fluid resuscitation as a topic and critical

appraisal of meta-analysis as a skill became prominent in

critical care curricula at rounds, journal clubs, and con-ferences, in part through publicity surrounding theCochrane Collaboration meta-analyses (8, 9). Ensuingletters to the editor raised important physiologic, clini-cal, methodologic, and statistical issues. Some haveposed thoughtful calls for more sophisticated preclinicalmodels (13), more contemporary fluid schedules (14),and economic evaluations (15). Speculation about whetheralbumin would be approved today at an inaugural reg-ulatory agency meeting is intriguing (16). These ideasand subsequent statements from professional societies

provide the foundation for a qualitative research project,using case study methods and document analysis, to un-derstand how and why meta-analysis results can incitesuch a range of practice policies.

Systematic reviews are beginning to influence healthpolicy. After the meta-analysis by the Cochrane InjuriesGroup Albumin Reviewers (9), use of albumin solutionsin the United Kingdom decreased by at least 40% by theend of 1998 (17). The role of the intense reaction of themedia to the Cochrane meta-analyses in influencingpractice is difficult to prove, but easy to deduce.

The methodologic weakness of the available studiesand their heterogenous populations and variable treat-ment regimens suggest that investigators might under-take larger, more rigorous studies based on current phys-iologic rationale and modern randomized trial methods.In grant proposals, systematic reviews of previous work canhighlight what is known and what requires further investi-gation. For example, on the basis of the Cochrane InjuriesGroup Albumin Reviewers meta-analysis, which reported a6% (CI, 3% to 9%) absolute increase in mortality asso-ciated with albumin (9), the Australian and New Zea-land Intensive Care Society Clinical Trials Group began

a randomized, concealed, double-blind trial comparingresuscitation using 4% albumin versus 0.9% normal sa-line in a heterogeneous sample of patients in the inten-sive care unit. The trial is designed to detect a 3% dif-ference in 28-day mortality and will enroll 7000 patientsin intensive care units in Australia and New Zealand.Stimulated in part by Wade and colleagues meta-regres-sion (7), a second randomized trial from Australia is testingthe effect of hypertonic saline versus isotonic crystalloid forprehospital resuscitation of hypotensive patients with headtrauma (Cooper J. Personal communication). Recognizing

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that morbidity end points must not be overshadowed by

a singular focus on vital status, this multicenter trial isevaluating long-term neurologic sequelae of fluid choice.

Modern trials are less likely than older studies toconflate resuscitation fluid with either protocolizedtreatment goals or monitoring technology. The Cana-dian Critical Care Trials Group (18) recently completeda multicenter randomized trial of therapeutic goalsachieved by fluid administration and pharmacotherapyguided by a pulmonary artery catheter. Among 1994elderly high-risk surgical patients, the mortality rate was7.8% in the treatment group and 7.7% in the control

group (19). Currently, the Acute Respiratory DistressSyndrome Network is also enrolling patients with theacute respiratory distress syndrome into a randomized,factorial study of goal-directed therapy and pulmonaryartery catheterization (www.nhlbi.nih.gov/funding/inits).Others are testing albumin as a composite interventionto evaluate whether it enhances the diuretic response tofurosemide in patients with acute lung injury (20).Thus, both short-term physiologic studies and investiga-tions designed to reduce morbidity are still needed tosuggest mechanisms and to generate hypotheses for fu-ture testing. Such hypotheses could also be raised bymeta-analyses other than those currently published (1,410). We identified four more meta-analyses from theCochrane Library (2023), two of which are updates(20, 21) of published work (8, 9). A fifth meta-analysisby Wilkes and colleagues (24) addressing a more refinedclinical question shows significantly less blood loss inpatients exposed to albumin compared with hydroxy-ethyl starch (693 350 mL vs. 789 487 mL) within24 hours of cardiopulmonary bypass.

What can we learn from the ongoing debate aboutfluid resuscitation in seriously ill patients? First, rigor-

ously conducted systematic reviews of randomized trialscan be valuable in informing practice. Second, to avoidmisleading inferences, we must faithfully interpret pointestimates and confidence intervals when interpretingmeta-analyses. Third, while physiologic rationale guidesour practice, we need to acknowledge when modern, high-quality studies do not support this rationale. Fourth, orig-inal research may be more likely to advance this field than

will additional meta-analyses. Finally, participation inwell-designed clinical trials represents the optimal ap-proach to resolving continued controversies in patient care.

Deborah Cook, MD

Gordon Guyatt, MDMcMaster 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 crystal-

loids. 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.

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Medicine

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Colloid Use for Fluid Resuscitation