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Fluid Resuscitation in the Intensive Care Unit

to the editor: The Saline versus Albumin Fluid Evaluation (SAFE) Study (May 27 issue)1 debunks a 1998 meta-analysis associating albumin with increased mortality in critical care populations.2 Regrettably, this trial may spawn a new misconception: that albumin and saline are equivalent for resuscitating a heterogeneous mix of patients in intensive care units. Patients with trauma are generally young and healthy and should not be grouped for evaluation with older patients without trauma, many of whom have preexisting cardiopulmonary disease. The incidence of pulmonary edema is low in patients with hemorrhagic trauma, and studies have not demonstrated a benefit of albumin over saline.3 Consequently, crystalloids are the accepted standard for volume replacement in patients with trauma.4 When patients with trauma are excluded, use of albumin in the SAFE Study yielded a relative risk of death of 0.96, as compared with saline use. More specifically, the analysis of the patients with sepsis revealed a stronger mortality trend favoring albumin (relative risk, 0.87). The SAFE investigators should enroll additional patients with sepsis to resolve whether 1 of every 10 lives could be saved simply by using albumin for fluid resuscitation. Stratifying patients according to the baseline albumin level could answer another fundamental question: whether, as some suggest,5 supplementation with albumin improves outcomes in patients with severe hypoproteinemia. Gary R. Haynes, M.D., Ph.D.
Medical University of South Carolina Charleston, SC 29425 haynesg@musc.edu
1. The SAFE Study Investigators. A comparison of albumin and sa-

line for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. 2. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998;317:235-40. 3. Moss GS, Lowe RJ, Jilek J, Levine HD. Colloid or crystalloid in the resuscitation of hemorrhagic shock: a controlled clinical trial. Surgery 1981;89:434-8. 4. Committee on Trauma. Advanced trauma life support manual. Chicago: American College of Surgeons, 1997:103-12. 5. Vincent J-L, Dubois MJ, Navickis RJ, et al. Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg 2003;237:319-34.

to the editor: The SAFE Study investigators provide evidence of an increase in the risk of death among trauma patients with concomitant brain injury who received albumin as compared with those who were treated with saline. These results, obtained from a subgroup analysis, support our own findings in a prospective, randomized, controlled trial of the safety of large doses of mediummolecular-weight hydroxyethyl starch (HES 130/

THIS WEEKS LETTERS

1905 Fluid Resuscitation in the Intensive Care Unit 1908 Doxorubicin-Induced Myocardial Injury 1909 Rituximab for Rheumatoid Arthritis 1910 Arterial Thrombosis in Systemic Lupus Erythematosus 1911 Drug Therapy in Alzheimers Disease 1913 Dislocation of the Lenses 1914 Ventricular Tachycardia Complicating Alcohol Septal Ablation

Keith E. Berman, M.P.H., M.B.A.

Health Research Associates Pasadena, CA 91106

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0.4) in patients with traumatic brain injury.1 The control group, which received albumin as an addon colloid to HES 200/0.5, had a significantly higher incidence of intracranial-pressure peaks above 30 mm Hg and more cumulative hours of elevated intracranial pressure. These differences between groups could be linked neither to the underlying brain trauma nor to intracranial bleeding complications. We hypothesized that albumin, which unlike HES is suspected to leak from a regionally disrupted bloodbrain barrier,2-4 might have caused an increase in intracranial volume and therefore excessive intracranial pressure. Our hypothesis appears to be endorsed by the findings of the SAFE Study and may also explain the finding by the SAFE investigators of higher mortality among patients who had trauma involving brain injury when they were treated with albumin. Thomas A. Neff, M.D.
University of Michigan Medical School Ann Arbor, MI 48109 thneff@umich.edu

vere hypovolemia. The study may merely show that in mildly unstable, critically ill patients, the choice of fluid does not matter. James E. Barone, M.D.
Lincoln Hospital and Mental Health Center Bronx, NY 10451

to the editor: The SAFE Study demonstrates sim-

Reto Stocker, M.D.

University Hospital Zurich CH-8001 Zurich, Switzerland

Donat R. Spahn, M.D.

University Hospital Lausanne CH-1011 Lausanne, Switzerland Dr. Spahn reports having served on a data and safety monitoring board for Fresenius Kabi and as a consultant for B. Braun.
1. Neff TA, Doelberg M, Jungheinrich C, Sauerland A, Spahn DR,

Stocker R. Repetitive large-dose infusion of the novel hydroxyethyl starch 130/0.4 in patients with severe head injury. Anesth Analg 2003;96:1453-9. 2. Fukuda K, Tanno H, Okimura Y, Nakamura M, Yamaura A. The blood-brain barrier disruption to circulating proteins in the early period after fluid percussion brain injury in rats. J Neurotrauma 1995; 12:315-24. 3. Peters T. All about albumin: biochemistry, genetics, and medical applications. San Diego, Calif.: Academic Press, 1995. 4. Dieterich HJ, Reutershan J, Felbinger TW, Eltzschig HK. Penetration of intravenous hydroxyethyl starch into the cerebrospinal fluid in patients with impaired blood-brain barrier function. Anesth Analg 2003;96:1150-4.

ilar clinical outcomes whether 4 percent albumin or normal saline is used for fluid resuscitation. The authors and the editorialist1 both describe well the limitations and applicability of this study. However, neither authors nor editorialist comments on the difference in the cost of the two therapies. On the basis of data from the SAFE Study and published information on average wholesale prices2 $232 for 1 liter of 5 percent albumin and $2.32 for 1 liter of saline the cost for each patient treated with albumin would be $521.30, as compared with $6.90 for each patient treated with saline, a 75-fold difference. This calculation may overstate the difference, since somewhat less of the 5 percent albumin preparation available in the United States might have been required. Nevertheless, intensivists should be aware of the substantial difference in costs, especially since the cost of fluid resuscitation with 5 percent albumin will often not be reimbursed by insurers. William A. Primack, M.D. Kristina Estes, Pharm.D.
University of Massachusetts Medical School Worcester, MA 01655 william.primack@fallon-clinic.com
1. Cook D. Is albumin safe? N Engl J Med 2004;350:2294-6. 2. Drug topics red book. Montvale, N.J.: Thomson PDR, 2003.

to the editor: Although the SAFE Study supports

my bias about the lack of superiority of albumin over crystalloid, I have one concern. Were the patients really hypovolemic? Baseline central venous pressures were about 9 mm Hg in both groups and increased to only 11 mm Hg (in the albumin group) and 10 mm Hg (in the saline group) during the four days of the study. Furthermore, the baseline heart rates and mean arterial pressures, as well as responses to the infusions, do not suggest se-

to the editor: The recent SAFE Study provides definitive evidence that the choice of albumin or crystalloid for fluid resuscitation does not affect overall mortality in adult patients in intensive care. Unfortunately, those who work with pediatric patients are left to extrapolate from data on adults once again. In theory, albumin may be more beneficial in pediatric patients, in whom volume management is crucial, yet this issue has not been well studied. Since 1992, there have been five randomized, controlled trials comparing albumin and crystalloid with respect to mortality in pediatric patients in intensive care. Four trials involved neonates, and mortality did not differ statistically.1-4 One pediatric trial involving patients with burns showed a

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higher mortality among those treated with albumin.5 All trials were relatively small, and not all compared albumin and crystalloid directly. The SAFE Study has shown that without corroborative results from a well-designed clinical trial, the conclusions drawn from a series of small trials may be incorrect. Until a similar trial is conducted with pediatric patients, intensivists will continue to practice on the basis of dogma and empiricism, rather than evidence-based medicine. Eric C. Walter, M.D. Richard Wendorf, M.D. Youngki Kim, M.D.
University of Minnesota Minneapolis, MN 55455 walte069@umn.edu
1. Kanarek KS, Williams PR, Blair C. Concurrent administration of

albumin with total parenteral nutrition in sick newborn infants. JPEN J Parenter Enteral Nutr 1992;16:49-53. 2. Greenough A, Emery EF, Hird MF, Gamsu HR. Randomised controlled trial of albumin infusion in ill preterm infants. Eur J Pediatr 1993;152:157-9. 3. So KW, Fok TF, Ng PC, Wong WW, Cheung KL. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child Fetal Neonatal Ed 1997;76:F43-F46. 4. Oca MJ, Nelson M, Donn SM. Randomized trial of normal saline versus 5% albumin for the treatment of neonatal hypotension. J Perinatol 2003;23:473-6. 5. Greenhalgh DG, Housinger TA, Kagan RJ, et al. Maintenance of serum albumin levels in pediatric burn patients: a prospective, randomized trial. J Trauma 1995;39:67-73.

the authors reply: Dr. Haynes and Mr. Berman

are concerned that the SAFE Study may spawn [the] misconception . . . that albumin and saline are equivalent for resuscitating a heterogeneous mix of patients in intensive care units. Far from being a misconception, we believe this is the key message of the SAFE Study. Whether one or the other is beneficial in particular subgroups still requires further study. Haynes and Berman may have misinterpreted the results of our subgroup analyses. For patients without trauma, 22.6 percent of those assigned to albumin died (641 of 2831) as Simon Finfer, M.B., B.S. compared with 23.5 percent of those assigned to Australian and New Zealand Intensive Care Society saline (666 of 2830) a difference of 0.9 percent Clinical Trials Group (relative risk, 0.96; 95 percent confidence interval, Carlton, VIC 3053, Australia 0.88 to 1.06; P=0.52). For patients with sepsis, 30.7 ctg@anzics.com.au percent of those assigned to albumin died (185 of Neil Boyce, M.B., B.S., Ph.D. 603) as compared with 35.3 percent of those as- Australian Red Cross Blood Service signed to saline (217 of 615); the difference in mor- Melbourne, VIC 3053, Australia tality was 4.6 percent (relative risk, 0.87; 95 percent Robyn Norton, Ph.D., M.P.H. confidence interval, 0.74 to 1.02; P=0.09). The re- George Institute for International Health sults do not indicate that albumin reduces mortal- Sydney, NSW 2050, Australia

ity in patients without trauma or in patients with severe sepsis. We agree with Dr. Cook that the subgroup with severe sepsis requires further study. Dr. Neff and colleagues comment on patients with trauma and brain injury. Our study does not provide definitive evidence that the administration of albumin increased mortality among patients with trauma who had brain injury, and thus it would be unwise to extrapolate our results to their findings in patients who received albumin in addition to other fluids. Appropriately designed randomized, controlled trials are required to determine the safety of albumin and other resuscitation fluids in patients with brain injury. We are not surprised that, as noted by Dr. Barone, baseline hemodynamic variables do not suggest severe hypovolemia. The current practice is to administer fluid as soon as intravascular volume depletion becomes apparent, rather than awaiting severe hypovolemia. We believe patients received a sufficient volume of the study fluid to address the issue of albumins safety, as had been raised by the Cochrane reviewers.1 Although albumin costs more than saline, direct costs of treatment are only one factor in the economic evaluation of new or established therapies.2 We were unable to secure resources for a formal cost-effectiveness assessment in the SAFE Study, and at present the overall cost implications of treatment with albumin or saline remain unknown. In reply to Dr. Walter and colleagues: we explored the idea of including children in the study, but the blinded administration sets were unsuitable for use in small children, and the lower mortality rate for children in intensive care units would have required studying thousands of additional patients. We hope that the SAFE Study will encourage others to conduct large randomized trials involving patients in intensive care units and in subgroups of these patients, including children.

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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. Coughlin MT, Angus DC. Economic evaluation of new therapies in critical illness. Crit Care Med 2003;31:Suppl:S7-S16.

the editorialist replies: Drs. Primack and Estes cite wholesale costs for 5 percent albumin and for normal saline, suggesting that intensivists should be aware of this difference. Although few may be able to cite institution-specific prices, I hope that all intensivists are familiar with this cost differential. An economic analysis requires quantitatively comparing two or more interventions with respect to both resource use and clinical end points. Accordingly, some intensivists will point to equivalent outcomes in the SAFE Study, including the lack of harm overall, and use albumin selectively based on a pathophysiological rationale. As I stated in my ed-

itorial, Others will conclude that without proof of benefit, routine use of albumin is hard to justify; for similar clinical outcomes at a lower cost, crystalloids may suffice in most circumstances. Primack and Estes highlight the fact that the costs of albumin may not be reimbursed by insurers. In countries with universal health care, insurance policies do not influence fluid choices, although rationing may occur for interventions without promise of a health advantage. As I noted, the rate of use of albumin will thus reflect interpretation of the SAFE Studys point estimate and confidence limits, as well as patient-specific conditions, clinicians preferences, perceptions regarding the safety of biologic fluids, availability, and cost. Deborah Cook, M.D.
McMaster University Hamilton, ON L8N 3Z5, Canada

Doxorubicin-Induced Myocardial Injury

to the editor: Lipshultz et al. (July 8 issue)1 show the authors reply: Induction failure due to per-

that dexrazoxane reduces the cardiac toxicity of doxorubicin without compromising the antileukemic effects. Although dexrazoxane is a promising cardioprotective agent, physicians might suspect that it reduces both the adverse and the beneficial effects of doxorubicin. Since the rate of complete remission is affected by the characteristics of the patient, monitoring of event-free survival is not sufficient to show that dexrazoxane does not reduce the antileukemic effects of doxorubicin. To show that dexrazoxane specifically affects the myocardium, the rates of noncardiac adverse events, such as myelosuppression and mucositis, would be helpful. George Fujisaki, M.D. Chiho Inokuchi, M.D. Naoko Murashige, M.D.
National Cancer Center Hospital Tokyo 104-0045, Japan nmurashi@ncc.go.jp
1. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazox-

ane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004;351:145-53.

sistent leukemia was observed in 4 percent of patients randomly assigned to doxorubicin alone and 2.9 percent of patients randomly assigned to doxorubicin and dexrazoxane. The rate of complete remission for patients who were randomly assigned to receive doxorubicin alone was 95 percent, as compared with 96 percent for those randomly assigned to receive doxorubicin and dexrazoxane. These data, along with similar data on event-free survival that appeared in our article (83 percent in both groups; P=0.87 by the log-rank test), suggest that dexrazoxane did not interfere with the antileukemic efficacy of doxorubicin. In terms of toxicity, the patients in both treatment groups had similar and low rates of lethal toxic effects: during induction, deaths occurred in 1 percent of the patients receiving doxorubicin alone and in 1 percent of the patients receiving both drugs, and deaths during remission in 2 percent of patients receiving doxorubicin alone and in 1 percent of the patients receiving both drugs. Mucositis and myelosuppression were not measured prospectively; clinically, however, the incidence and mag-

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