7/30/2019 Fluid Resuscitation in Acute Illness Time to Reappraise the Basics

1/2

10.1056/nejme1105490 nejm.org 1

editorial

T h e n e w e n g l a n d j o u r n a l o f medicine

Fluid Resuscitation in Acute Illness Time to Reappraisethe Basics

John A. Myburgh, M.B., B.Ch., Ph.D.

Fluid resuscitation is a fundamental interventionin the treatment of critically ill patients. However,there is little conclusive evidence to guide clini-cians about the best type of resuscitation fluid;the appropriate timing, volume, and rate of fluid

administration; and the optimal way to adequate-ly monitor the eff icacy and safety of f luid resusci-tation in various clinical conditions.1

Although the complications associated withexcessive volume of resuscitation fluid such aspulmonary and interstitial edema are well rec-ognized, an emerging body of evidence suggeststhat the type of resuscitation fluid may adverselyaffect the outcomes in specific clinical condi-tions; for example, albumin is associated with in-creased mortality in patients with traumatic braininjury,2 and high-molecular-weight preparations ofhydroxyethyl starch are associated with acute kid-ney injury in patients with severe sepsis.3

Conversely, improved outcomes associatedwith the use of albumin for resuscitation havebeen shown in children with severe malaria4 andin a subgroup of adults with severe sepsis in theSaline versus Albumin Fluid Evaluation study(SAFE; Current Controlled Trials number, IS-RCTN76588266).5,6 However, these reports werenot sufficiently conclusive to justify the adoptionof strong clinical recommendations.

The results of the Fluid Expansion as Sup-portive Therapy (FEAST) trial,7 reported in thisissue of the Journal, are an important contribu-tion to the literature. This remarkable, pragmat-ic, randomized, controlled trial, conducted insix hospitals in Kenya, Tanzania, and Uganda,assessed the effects of bolus-fluid resuscitationwith albumin or saline as compared with no bo-lus fluid in children with febrile medical illnessand impaired perfusion. Children with severehypotension, or decompensated shock, received

boluses of either albumin or saline for resusci-tation. The trial centers had no access to inten-sive care units, and the trial included a compre-hensive education program aimed at optimizingearly case recognition and by training in emer-

gency pediatric life support. The primary outcomewas 48-hour mortality a relevant patient-cen-tered outcome in regions in which the high prev-alence of severe sepsis in children, often due tomalaria, is associated with high early mortality.8

The trial was powered to determine a plausi-ble absolute risk reduction in 48-hour mortality(as derived from power calculations described inthe Methods section in the article) of 5 percent-age points and was conducted with high stan-dards of internal validity excellent random-ization procedures, a high rate of adherence to theprotocol, concealment of the treatment assign-ments, a minimal loss to follow-up, the use of theintention-to-treat principle for the analyses, andperformance of analyses according to prespeci-fied subgroups. The sample size was appropriatelyincreased from 2800 patients to 3600 patientsafter an interim analysis showed that the rate ofdeath was lower than predicted in the interven-tion groups. However, the trial was stopped af-ter the recruitment of 3141 patients when bolus-fluid resuscitation with albumin or saline was

shown to increase the absolute risk of death at48 hours by 3.3 percentage points and the riskof death, neurologic sequelae, or both at 4 weeksby 4 percentage points. No difference in mortalitywas observed in patients with decompensatedshock, although these patients were few in num-ber and had significantly higher mortality. Theexcess mortality associated with bolus-fluid re-suscitation was consistent across all prespecifiedsubgroups, which included subgroups accordingto age, lactate level, base deficit, presence or ab-

The New England Journal of Medicine

Downloaded from nejm.org on May 26, 2011. For personal use only. No other uses without permission.

Copyright 2011 Massachusetts Medical Society. All rights reserved.

7/30/2019 Fluid Resuscitation in Acute Illness Time to Reappraise the Basics

2/2

editorial

10.1056/nejme1105490 nejm.org2

sence of severe anemia, and status with respectto coma and malaria.

These results will have an immediate effecton the way children presenting with febrile ill-ness due to medical causes and with associatedhypotension are treated in resource-poor settings.In conjunction with a program of education and

training, discontinuation of the practice of bo-lus-fluid resuscitation in patients with febrileillness due to medical causes and impaired per-fusion or compensated shock must be recom-mended. Given that 2 million children die fromthis condition each year in sub-Saharan Africa,the potential impact is enormous. Extrapolatingthese results to children with other hypotensiveconditions, such as severe dehydration from gas-troenteritis and malnutrition, burns, and surgery,is not justified on the basis of these data; furtherresearch would be required.

The results of the FEAST trial, as with those ofother trials that generated results contrary to clin-ical opinion and practice,9,10 make it imperativethat we reappraise the fundamentals. Early iden-tification of shock, basic life support, and earlyantimicrobial therapy remain at the forefront ofthe clinical care of young patients with severe in-fection and shock. It is highly probable that ed-ucation, training, and participation in a high-quality, randomized, controlled trial itself had asubstantive positive effect on the overall rate ofdeath, although these factors were not directly as-sessed in this trial. However, the entrenched prac-tice of f luid-bolus resuscitation in patients withcompensated shock remains highly questionable.

We can only speculate about the mechanismsby which bolus-fluid resuscitation had adversebiologic effects in these patients. Potential mech-anisms may include the interruption of geneticallydetermined catecholamine-mediated host defenseresponses by the rapid increase in plasma volume,which might result in a reperfusion injury. Simi-larly, transient hypervolemia or hyperosmolality

might exacerbate capillary leak in patients whoare susceptible to intracranial hypertension2 orpulmonary edema, with fatal consequences.

How should clinicians who work under cir-cumstances different from those in this trial that is, in high-income countries with access tointensive care units or clinicians who carefor adult patients interpret the results of thisimportant trial? It seems clear that the results ofthis trial indicate that bolus-fluid resuscitationwith either crystalloids or colloids in patients

with compensated shock who do not have aclinical fluid deficit must be practiced withmuch greater caution than is now the case andwith increased vigilance.

Fluid resuscitation is such a fundamental in-tervention in acute medicine that these resultsindicate that further high-quality research is ur-

gently required to define appropriate practice forfluid resuscitation, including a study of the tim-ing and rates of fluid administration and ways tomonitor its effects. Similarly, a careful assess-ment of the safety, efficacy, and cost-effectivenessof various resuscitation fluids is mandatory be-fore their incorporation into clinical practice.

The courage and dedication of the FEAST in-vestigators and attending clinicians must be ac-knowledged, not only because of the quality ofthe research they conducted in this vitally impor-tant area of acute medicine, but also because they

conducted a landmark trial in such challengingeconomic conditions in sub-Saharan Africa.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

From the George Institute for Global Health and University ofNew South Wales, Sydney.

This article (10.1056/NEJMe1105490) was published on May 26,2011, at NEJM.org.

1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving SepsisCampaign: international guidelines for management of severesepsis and septic shock: 2008. Crit Care Med 2008;36:296-327.

2. The SAFE Study Investigators. Saline or albumin for fluidresuscitation in patients with traumatic brain injury. N Engl JMed 2007;357:874-84.3. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulintherapy and pentastarch resuscitation in severe sepsis. N Engl JMed 2008;358:125-39.4. Maitland K, Pamba A, English M, et al. Randomized tria l ofvolume expansion with albumin or saline in children with severemalaria: preliminary evidence of albumin benefit. Clin InfectDis 2005;40:538-45.5. The SAFE Study Investigators. A comparison of albumin andsaline for fluid resuscitation in the intensive care unit. N Engl JMed 2004;350:2247-56.6. Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, Nor-ton R. Impact of albumin compared to saline on organ functionand mortalit y of patients with severe sepsis. Intensive Care Med

2011;37:86-96.7. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluidbolus in African children with severe infection. N Engl J Med2011. DOI: 10.1056/NEJMoa1101549.8. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among chil-dren admitted to a rural hospital in Kenya. N Engl J Med 2005;352:39-47.9. The NICE-SUGAR Study Invest igators. Intensive versus con-ventional glucose control in critically ill pat ients. N Engl J Med2009;360:1283-97.10. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive cra-niectomy in diffuse traumatic brain injury. N Engl J Med 2011;364:1493-502.Copyright 2011 Massachusetts Medical Society.

The New England Journal of Medicine

Downloaded from nejm.org on May 26, 2011. For personal use only. No other uses without permission.

Copyright 2011 Massachusetts Medical Society. All rights reserved.