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Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.
N Engl J Med. 2012 Jul 12; 367(2):124-34
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11 Jul 2012
Herwig Gerlach
F1000 Critical Care & Emergency Medicine
Vivantes - Klinikum Neukoelln,
Berlin, Germany.
F1000 Critical Care & Emergency Medicine
Vivantes - Klinikum Neukoelln,
Berlin, Germany.
Clinical Trial, Confirmation, Good for Teaching
DOI: 10.3410/f.717648052.793202803
Changes clinical practice - Patients in the intensive care unit suffering from severe sepsis or septic shock should no longer receive hydroxyethyl starch (HES) fluid resuscitation therapy.
This important trial answers a key question on the choice of volume expander for early resuscitation in severe sepsis and septic shock. For years, discussions on the pros and cons of using hydroxyethyl starch (HES) have occupied clinicians, since many aspects are presented with considerable emotion. Now...Continue reading
This important trial answers a key question on the choice of volume expander for early resuscitation in severe sepsis and septic shock. For years, discussions on the pros and cons of using hydroxyethyl starch (HES) have occupied clinicians, since many aspects are presented with considerable emotion. Now we have the data! Following the volume substitution and insulin therapy in severe sepsis (VISEP) trial, which demonstrated a harmful effect of HES 200kDa {1}, we have now received the confirmation for HES 130kDa, again providing evidence that volume therapy with this type of colloid results in a higher mortality and increased rate of acute renal failure in septic patients. Trial registration: NCT00962156
References
1.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med. 2008 Jan 10; 358(2): 125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
Disclosures
None declared
Add Comment
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Gerlach H: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 11 Jul 2012; DOI: 10.3410/f.717648052.793202803. F1000Prime.com/717648052#eval793202803
17 Jul 2012
Michael O'Connor
F1000 Anesthesiology & Pain Management
University of Chicago,
Chicago, Illinois, USA.
F1000 Anesthesiology & Pain Management
University of Chicago,
Chicago, Illinois, USA.
Clinical Trial, Confirmation
DOI: 10.3410/f.717648052.793352835
Changes clinical practice - The use of starch-based fluids for resuscitation in sepsis should be abandoned.
This article affirms the finding of the volume substitution and insulin therapy in severe sepsis (VISEP) trial that the use of starch-based colloids is associated with worse outcomes in sepsis. The specific outcomes made worse from the use of a starch-based colloid were the requirement for renal replacement...Continue reading
This article affirms the finding of the volume substitution and insulin therapy in severe sepsis (VISEP) trial that the use of starch-based colloids is associated with worse outcomes in sepsis. The specific outcomes made worse from the use of a starch-based colloid were the requirement for renal replacement therapy and the risk of death at 90 days. Resuscitation in sepsis should be accomplished with either albumin or a crystalloid.
References
1.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med. 2008 Jan 10; 358(2): 125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
O'Connor M: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 17 Jul 2012; DOI: 10.3410/f.717648052.793352835. F1000Prime.com/717648052#eval793352835
19 Jul 2012
Peter Nagele
F1000 Anesthesiology & Pain Management
Washington University in St Louis,
St Louis, MO, USA.
F1000 Anesthesiology & Pain Management
Washington University in St Louis,
St Louis, MO, USA.
Clinical Trial, New Finding
DOI: 10.3410/f.717648052.793453513
Changes clinical practice - Given the clear evidence from this trial, clinicians should refrain from using hydroxyethyl starch 130/0.4 in patients with severe sepsis.
Filling a critical knowledge gap in evidence-based fluid therapy, this randomized controlled trial showed that the use of hydroxyethyl starch 130/0.4 in severe sepsis increases the risk of death. For further reading, see {1}.
References
1.
Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study.
Lancet. 2001 Mar 24; 357(9260): 911-6
PMID: 11289347
DOI: 10.1016/S0140-6736(00)04211-2
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Nagele P: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 19 Jul 2012; DOI: 10.3410/f.717648052.793453513. F1000Prime.com/717648052#eval793453513
20 Jul 2012
Clinical Trial, Controversial, Good for Teaching
DOI: 10.3410/f.717648052.793454100
Sepsis-related mortality is a leading cause of death worldwide, and aggressive intravenous fluid resuscitation is a critical component of early goal-directed therapy. While there is ample evidence accumulating that colloids offer no advantage over crystalloids as the initial choice of fluid resuscit an...Continue reading
Sepsis-related mortality is a leading cause of death worldwide, and aggressive intravenous fluid resuscitation is a critical component of early goal-directed therapy. While there is ample evidence accumulating that colloids offer no advantage over crystalloids as the initial choice of fluid resuscitation, an interesting global study by Finfer et al. {1} showed widespread use of colloids based on geographic areas, despite being more expensive. In this interesting trial, Perner et al. studied 798 patients and found an increased 90-day mortality and the need for renal replacement therapy in the hydroxyethyl starch (HES) group.
One of the major concerns with the use of HES as a resuscitation fluid has been the adverse effect leading to increased requirement of renal replacement therapy; this effect was overcome by the use of a lower molecular weight HES (130kD; 6%). A recent trial ('Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis' [CRYSTMAS]) compared HES (130kD; 6%) with 0.9% normal saline and showed no difference in renal dysfunction between the two groups (assessed using Acute Kidney Injury Network [AKIN] and risk, injury, failure, loss of function, and end-stage renal disease [RIFLE] criteria) and no difference in mortality up to 90 days after treatment initiation. However, significantly less volume was required to achieve hemodynamic stability for HES vs. NaCl in the initial phase of fluid resuscitation. This may have been an important finding in the context of the patients with critical valvular abnormalities, heart failure and pre-existing renal dysfunction {2}. This study had a small sample size and was not powered for assessing mortality. A large trial is currently underway (Crystalloid Versus Hydroxyethyl Starch Trials [CHEST]; crystalloids vs. HES trial) including around 7000 patients assessing 90-day mortality. What was extremely interesting was that the investigators did not find a significant difference in the trial fluid volumes.
Does this mean that the verdict is clear? The answer is no. In contrast to HES fluid, evidence suggests that albumin in sepsis may reduce death {3}. Analysis of 1218 patients with severe sepsis randomized to 4% albumin vs. normal saline in the 'Saline versus Albumin Fluid Evaluation' (SAFE) trial suggested a non-statistically significant reduction in 28-day mortality in the albumin group (30.7% vs. 35.3%, P=0.09).
A Canadian trial is currently underway, a pragmatic early septic shock fluid resuscitation trial that will compare the effectiveness of 5% albumin vs. normal saline on 90-day mortality (PRECISE). Results of this trial will be interesting. Until we have more results available, it is only prudent to say that crystalloids appear to be the resuscitation fluid of choice.
One of the major concerns with the use of HES as a resuscitation fluid has been the adverse effect leading to increased requirement of renal replacement therapy; this effect was overcome by the use of a lower molecular weight HES (130kD; 6%). A recent trial ('Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis' [CRYSTMAS]) compared HES (130kD; 6%) with 0.9% normal saline and showed no difference in renal dysfunction between the two groups (assessed using Acute Kidney Injury Network [AKIN] and risk, injury, failure, loss of function, and end-stage renal disease [RIFLE] criteria) and no difference in mortality up to 90 days after treatment initiation. However, significantly less volume was required to achieve hemodynamic stability for HES vs. NaCl in the initial phase of fluid resuscitation. This may have been an important finding in the context of the patients with critical valvular abnormalities, heart failure and pre-existing renal dysfunction {2}. This study had a small sample size and was not powered for assessing mortality. A large trial is currently underway (Crystalloid Versus Hydroxyethyl Starch Trials [CHEST]; crystalloids vs. HES trial) including around 7000 patients assessing 90-day mortality. What was extremely interesting was that the investigators did not find a significant difference in the trial fluid volumes.
Does this mean that the verdict is clear? The answer is no. In contrast to HES fluid, evidence suggests that albumin in sepsis may reduce death {3}. Analysis of 1218 patients with severe sepsis randomized to 4% albumin vs. normal saline in the 'Saline versus Albumin Fluid Evaluation' (SAFE) trial suggested a non-statistically significant reduction in 28-day mortality in the albumin group (30.7% vs. 35.3%, P=0.09).
A Canadian trial is currently underway, a pragmatic early septic shock fluid resuscitation trial that will compare the effectiveness of 5% albumin vs. normal saline on 90-day mortality (PRECISE). Results of this trial will be interesting. Until we have more results available, it is only prudent to say that crystalloids appear to be the resuscitation fluid of choice.
References
1.
Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units.
Crit Care. 2010; 14(5): R185
PMID: 20950434
DOI: 10.1186/cc9293
2.
Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study.
Crit Care. 2012 May 24; 16(3): R94
PMID: 22624531
DOI: 10.1186/cc11358
3.
A comparison of albumin and saline for fluid resuscitation in the intensive care unit.
N Engl J Med. 2004 May 27; 350(22): 2247-56
PMID: 15163774
DOI: 10.1056/NEJMoa040232
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Arora S: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 20 Jul 2012; DOI: 10.3410/f.717648052.793454100. F1000Prime.com/717648052#eval793454100
23 Jul 2012
Tom Woodcock
F1000 Critical Care & Emergency Medicine
Southampton General Hospital,
Southampton, Hants, UK.
F1000 Critical Care & Emergency Medicine
Southampton General Hospital,
Southampton, Hants, UK.
Clinical Trial, Confirmation, Good for Teaching
DOI: 10.3410/f.717648052.793153309
This is a long-awaited result which confirms the lethality of hydroxy-ethyl starch in patients with systemic sepsis. The number needed to kill was 13; that is, the addition of starch molecules to Ringer's solution used for intravenous resuscitation kills one patient with sepsis in 13. It is estimated...Continue reading
This is a long-awaited result which confirms the lethality of hydroxy-ethyl starch in patients with systemic sepsis. The number needed to kill was 13; that is, the addition of starch molecules to Ringer's solution used for intravenous resuscitation kills one patient with sepsis in 13. It is estimated that 30,000 patients a year suffer from severe sepsis in the United Kingdom, of whom around 10,000 die. If just half of the 30,000 received starch solutions in the intensive care unit (ICU), more than 1000 avoidable deaths will have been caused in the UK every year.
A European Society of Intensive Care Medicine (ESICM) Task Force have 'advised' against the use of colloid volume therapy in critically ill patients earlier this year {1}. In 2011, a Cochrane Review advised against the use of colloids in patients with trauma, burns or after surgery {2}. The widely held belief that resuscitation can be achieved with colloids at a fraction of the volume dose needed when colloid-free solutions are used has been disproven and discredited (see {3}, on which I am an author). There remains no indication as far as I can see for plasma substitutes, yet there are clinicians who will continue to prescribe them and continue to put their patients' lives at risk. My advice – medical directors responsible for patient safety in their hospitals should order the removal of plasma substitutes from their hospital's available drugs. Trial registration: NCT00962156
A European Society of Intensive Care Medicine (ESICM) Task Force have 'advised' against the use of colloid volume therapy in critically ill patients earlier this year {1}. In 2011, a Cochrane Review advised against the use of colloids in patients with trauma, burns or after surgery {2}. The widely held belief that resuscitation can be achieved with colloids at a fraction of the volume dose needed when colloid-free solutions are used has been disproven and discredited (see {3}, on which I am an author). There remains no indication as far as I can see for plasma substitutes, yet there are clinicians who will continue to prescribe them and continue to put their patients' lives at risk. My advice – medical directors responsible for patient safety in their hospitals should order the removal of plasma substitutes from their hospital's available drugs. Trial registration: NCT00962156
References
1.
Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients.
Intensive Care Med. 2012 Mar; 38(3): 368-83
PMID: 22323076
DOI: 10.1007/s00134-012-2472-9
2.
Colloids versus crystalloids for fluid resuscitation in critically ill patients.
Cochrane Database Syst Rev. 2012; 6: CD000567
PMID: 22696320
DOI: 10.1002/14651858.CD000567.pub5
3.
Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy.
Br J Anaesth. 2012 Mar; 108(3): 384-94
PMID: 22290457
DOI: 10.1093/bja/aer515
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Woodcock T: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 23 Jul 2012; DOI: 10.3410/f.717648052.793153309. F1000Prime.com/717648052#eval793153309
23 Jul 2012
Matthieu Legrand
F1000 Critical Care & Emergency Medicine
Lariboisière Hospital, Paris,
Paris, France.
F1000 Critical Care & Emergency Medicine
Lariboisière Hospital, Paris,
Paris, France.
Clinical Trial, Confirmation
DOI: 10.3410/f.717648052.793454708
Changes clinical practice - The present trial should cause physicians to totally abandon the use of hydroxyethyl starch (HES) in septic patients.
In this large randomized controlled trial, the new generation of hydroxyethyl starches (HESs, specifically HES 130/0.4) was compared to Ringer's acetate for fluid resuscitation in septic patients. HES infusion was limited to 33 milliliters per kilogram of ideal body weight per day, and only two patients...Continue reading
In this large randomized controlled trial, the new generation of hydroxyethyl starches (HESs, specifically HES 130/0.4) was compared to Ringer's acetate for fluid resuscitation in septic patients. HES infusion was limited to 33 milliliters per kilogram of ideal body weight per day, and only two patients received HES 130/0.4 at a dose higher than the maximum daily dose recommended by the manufacturer. The authors observed significantly more deaths in the HES group at day 90 and higher need of transfusion and renal replacement therapy.
Although more data reporting on hemodynamics and resuscitation endpoints would have been of interest, this well-performed study confirmed that HESs are associated with negative outcome in septic patients. Moreover, patients in the HES group received as much fluid as patients in the Ringer's acetate group, arguing against under-volume resuscitation in the HES group. Finally, the influence of blood transfusion in the HES group on outcome must be questioned.
In light of the previous randomized controlled trials comparing HES to gelatins or crystalloids {1,2}, the present trial should cause physicians to totally abandon the use of HES in septic patients. The use of HES should also probably be reconsidered in all conditions associated with systemic inflammatory response (burns patients, cardiopulmonary bypass, post-cardiac arrest syndrome etc.). Trial registration: NCT00962156
Although more data reporting on hemodynamics and resuscitation endpoints would have been of interest, this well-performed study confirmed that HESs are associated with negative outcome in septic patients. Moreover, patients in the HES group received as much fluid as patients in the Ringer's acetate group, arguing against under-volume resuscitation in the HES group. Finally, the influence of blood transfusion in the HES group on outcome must be questioned.
In light of the previous randomized controlled trials comparing HES to gelatins or crystalloids {1,2}, the present trial should cause physicians to totally abandon the use of HES in septic patients. The use of HES should also probably be reconsidered in all conditions associated with systemic inflammatory response (burns patients, cardiopulmonary bypass, post-cardiac arrest syndrome etc.). Trial registration: NCT00962156
References
1.
Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study.
Lancet 2001 Mar 24; 357(9260): 911-6
PMID: 11289347 DOI: 10.1016/S0140-6736(00)04211-2
2.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med 2008 Jan 10; 358(2): 125-39
PMID: 18184958 DOI: 10.1056/NEJMoa070716
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Legrand M: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 23 Jul 2012; DOI: 10.3410/f.717648052.793454708. F1000Prime.com/717648052#eval793454708
31 Jul 2012
Clinical Trial
DOI: 10.3410/f.717648052.793455362
This is a well-designed, -performed and -described large multicenter, randomized, blinded clinical trial in critically ill patients with severe sepsis comparing fluid resuscitation with a low molecular weight fourth-generation 6% hydroxyethylstarch (HES) (130/0.4) in Ringer's acetate (maximum daily dose 33ml/kg)...Continue reading
This is a well-designed, -performed and -described large multicenter, randomized, blinded clinical trial in critically ill patients with severe sepsis comparing fluid resuscitation with a low molecular weight fourth-generation 6% hydroxyethylstarch (HES) (130/0.4) in Ringer's acetate (maximum daily dose 33ml/kg) solution with Ringer's acetate alone regarding 90-day mortality or dialysis dependence. The trial enrolled 804 patients and is the largest performed to date evaluating HES in severe sepsis. The key finding from this trial was that those allocated to 6% HES had a significantly higher risk of death at 90 days compared to those resuscitated with balanced crystalloid alone (51% for HES vs. 43% for crystalloid, absolute risk reduction [ARR] 8%; relative risk [RR] 1.17; p=0.03), corresponding to a number need to harm (NNH) of 13. Moreover, those allocated to 6% HES were more likely to receive renal replacement therapy (RRT) (22% for HES vs. 16% for crystalloid, RR 1.35; p=0.04). Of interest, there were no differences between groups in terms of major bleeding events or cumulative volume of resuscitation fluid received.
This 6S trial would appear to confirm and extend the findings of prior randomized trials, including the VISEP trial, evaluating HES in critically ill septic patients, implying that resuscitation with HES portends an increased risk for acute kidney injury (AKI), need for RRT and death. Importantly, data from the 6S show the hazard of death is delayed, occurring approximately 20 days after enrollment, when patients have likely been discharged from the intensive care unit (ICU), suggesting impaired longer-term metabolism and clearance of HES from the body. In summary, considering there were no differences in the volumes of resuscitation fluid received between groups, that HES is far more expensive than crystalloid solutions and that there is considerable evidence of less favourable outcomes and harm with use of HES, it should not be used in critically ill septic patients. This would be consistent with the recommendations recently published by the ESICM Task Force on colloid volume therapy {1}. Trial registration: NCT00962156
This 6S trial would appear to confirm and extend the findings of prior randomized trials, including the VISEP trial, evaluating HES in critically ill septic patients, implying that resuscitation with HES portends an increased risk for acute kidney injury (AKI), need for RRT and death. Importantly, data from the 6S show the hazard of death is delayed, occurring approximately 20 days after enrollment, when patients have likely been discharged from the intensive care unit (ICU), suggesting impaired longer-term metabolism and clearance of HES from the body. In summary, considering there were no differences in the volumes of resuscitation fluid received between groups, that HES is far more expensive than crystalloid solutions and that there is considerable evidence of less favourable outcomes and harm with use of HES, it should not be used in critically ill septic patients. This would be consistent with the recommendations recently published by the ESICM Task Force on colloid volume therapy {1}. Trial registration: NCT00962156
References
1.
Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients.
Intensive Care Med. 2012 Mar; 38(3): 368-83
PMID: 22323076
DOI: 10.1007/s00134-012-2472-9
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Bagshaw S: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 31 Jul 2012; DOI: 10.3410/f.717648052.793455362. F1000Prime.com/717648052#eval793455362
31 Jul 2012
Clinical Trial
DOI: 10.3410/f.717648052.793456025
In this multicenter, parallel-group, blinded trial, the authors assigned patients with severe sepsis to either 6% hydroxyethyl starch (HES) 130/0.4 or Ringer's acetate at a dose up to 33ml per kilogram of ideal body weight per day. Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.4...Continue reading
In this multicenter, parallel-group, blinded trial, the authors assigned patients with severe sepsis to either 6% hydroxyethyl starch (HES) 130/0.4 or Ringer's acetate at a dose up to 33ml per kilogram of ideal body weight per day. Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.4 had an increased risk of death at day 90 and were more likely to require renal replacement therapy, as compared with those receiving Ringer's acetate. This very important study on the safety of using the low molecular weight HES is in agreement with the consensus statement of the ESICM task force on colloids {1} and confirms the results of previous studies like VISEP, which had showed almost the same results with use of pentastarch {2}.
The results of those studies can be very easy to explain if we understand the new concepts of tissue perfusion and the functions of endothelial surface layer. The synthetic colloids have been manufactured on the principle that high colloid oncotic pressure is the main factor in determining the intravascular volume and tissue perfusion. However, since the discovery of the glycocalyx and its function to maintain the integrity of the endothelial surface layer, the colloid oncotic pressure of the fluid is no longer the key factor. The albumin molecule has negative and positive charges on its surface that enable it to attach to the negative charges on the glycocalyx layer, therefore maintaining the integrity of endothelial surface layer. The synthetic colloids have only negative charges and therefore they do not maintain the integrity of endothelial surface layer. The endothelial surface layer plays very important roles in maintaining normal functions of the immune and coagulation systems of the body. Therefore, the use of synthetic colloids in septic patients had resulted in adverse outcomes in septic patients. Trial registration: NCT00962156
The results of those studies can be very easy to explain if we understand the new concepts of tissue perfusion and the functions of endothelial surface layer. The synthetic colloids have been manufactured on the principle that high colloid oncotic pressure is the main factor in determining the intravascular volume and tissue perfusion. However, since the discovery of the glycocalyx and its function to maintain the integrity of the endothelial surface layer, the colloid oncotic pressure of the fluid is no longer the key factor. The albumin molecule has negative and positive charges on its surface that enable it to attach to the negative charges on the glycocalyx layer, therefore maintaining the integrity of endothelial surface layer. The synthetic colloids have only negative charges and therefore they do not maintain the integrity of endothelial surface layer. The endothelial surface layer plays very important roles in maintaining normal functions of the immune and coagulation systems of the body. Therefore, the use of synthetic colloids in septic patients had resulted in adverse outcomes in septic patients. Trial registration: NCT00962156
References
1.
Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients.
Intensive Care Med. 2012 Mar; 38(3): 368-83
PMID: 22323076
DOI: 10.1007/s00134-012-2472-9
2.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med. 2008 Jan 10; 358(2): 125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Farag E: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 31 Jul 2012; DOI: 10.3410/f.717648052.793456025. F1000Prime.com/717648052#eval793456025
31 Jul 2012
Jean-Charles Preiser
F1000 Critical Care & Emergency Medicine
Erasme University Hospital,
Brussels, Belgium.
F1000 Critical Care & Emergency Medicine
Erasme University Hospital,
Brussels, Belgium.
Clinical Trial
DOI: 10.3410/f.717648052.793455985
This is an important, well-designed, and well-conducted prospective randomized controlled trial of colloid (hydroxyethyl starch) versus crystalloid (Ringer's acetate) solution for volume resuscitation during the early phase of severe sepsis. The primary end-point (90-day mortality or dependence on dialysis)...Continue reading
This is an important, well-designed, and well-conducted prospective randomized controlled trial of colloid (hydroxyethyl starch) versus crystalloid (Ringer's acetate) solution for volume resuscitation during the early phase of severe sepsis. The primary end-point (90-day mortality or dependence on dialysis) was higher in patients randomized to colloids than in those randomized to crystalloids, even after adjustment for potential confounders. The use of 130/0.4 hydroxyethyl starches should be avoided in patients with severe sepsis. Trial registration: NCT00962156
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Preiser J: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 31 Jul 2012; DOI: 10.3410/f.717648052.793455985. F1000Prime.com/717648052#eval793455985
07 Aug 2012
David Gaieski
F1000 Critical Care & Emergency Medicine
Hospital of the University of Pennsylvania,
Philadelphia, PA, USA.
F1000 Critical Care & Emergency Medicine
Hospital of the University of Pennsylvania,
Philadelphia, PA, USA.
Clinical Trial
DOI: 10.3410/f.717648052.793456623
Changes clinical practice - Synthetic colloids should not be used in the resuscitation of severe sepsis patients.
This is a well-designed and performed multicenter, international, blinded trial randomly assigning patients with severe sepsis to resuscitation with either a synthetic colloid (6% hydroxyethyl starch [HES] 130/0.4) vs. Ringer's acetate. A total of 798 were included in the intention-to-treat population....Continue reading
This is a well-designed and performed multicenter, international, blinded trial randomly assigning patients with severe sepsis to resuscitation with either a synthetic colloid (6% hydroxyethyl starch [HES] 130/0.4) vs. Ringer's acetate. A total of 798 were included in the intention-to-treat population. The two groups were well-balanced with regard to baseline characteristics. Mortality at 90 days was statistically significantly higher (p=0.03) in the HES 130/0.4 group (51%; 201/398) vs. the Ringer's acetate group (43%; 172/400). The deaths occurred late in the course of care (with separation of survival curves starting around day 20). When combined with similar results from the Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial {1}, the results of this trial should end the debate about the role of synthetic colloids in the management of severe sepsis. They should not be administered.
References
1.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med. 2008 Jan 10; 358(2): 125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
Disclosures
None declared
Addendum (18 Sep 2012)
Since this article has been published, a correction has been issued by the journal (for more details, please see http://www.nejm.org/doi/pdf/10.1056/NEJMx120048). The correction was published on July 12th, 2012 and specifies that throughout the article (with exceptions noted at http://www.nejm.org/doi/pdf/10.1056/NEJMx120048), 130/0.4 should have been 130/0.42. This correction also applies to F1000 recommendations that were published on this article.
Gaieski D: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 07 Aug 2012; DOI: 10.3410/f.717648052.793456623. F1000Prime.com/717648052#eval793456623
08 Aug 2012
Daniel De Backer
F1000 Critical Care & Emergency Medicine
Erasme University Hospital,
Brussels, Belgium.
F1000 Critical Care & Emergency Medicine
Erasme University Hospital,
Brussels, Belgium.
Clinical Trial, Confirmation
DOI: 10.3410/f.717648052.793456935
The choice of the ideal plasma expander is still a topic of intense debate. Hydroxyethyl starches (HESs) may provide beneficial short-term effects, but concerns have been raised about long-term safety {1-3}. This multicenter randomized trial conducted by the Scandinavian Critical Care Trial Group evaluated...Continue reading
The choice of the ideal plasma expander is still a topic of intense debate. Hydroxyethyl starches (HESs) may provide beneficial short-term effects, but concerns have been raised about long-term safety {1-3}. This multicenter randomized trial conducted by the Scandinavian Critical Care Trial Group evaluated the effects of HES 130/0.42 compared with Ringer's acetate on the composite outcome of mortality or end-stage kidney failure in 800 patients with severe sepsis. Trial fluid (6% HES 130/0.42 in Ringer's acetate, or Ringer's acetate), delivered in identical bags, was used when clinicians judged volume expansion to be needed in the intensive care unit (ICU) for a maximum of 90 days. Both groups were well balanced. Median cumulative trial fluid volumes were 44ml/kg and 47ml/kg of ideal body weight in the HES and Ringer's acetate groups (P=0.18), respectively. Occurrence of primary outcome of death or dialysis dependency at 90 days was higher in the HES than the Ringer's acetate group: 202 patients (51%) versus 173 patients (43%); relative risk, 1.17; 95% confidence interval (CI), 1.01 to 1.36; P=0.03. This difference was due to increased risk of death in the HES group, as only one patient in each group was dialysis-dependent at day 90.
This study's finding with a 'modern' HES is in line with other trials using older HESs showing detrimental effects of HES, especially in large amounts, in patients with severe sepsis {1-3}. Great caution should be used before administering HES in patients with severe sepsis and septic shock. Trial registration: NCT00962156
This study's finding with a 'modern' HES is in line with other trials using older HESs showing detrimental effects of HES, especially in large amounts, in patients with severe sepsis {1-3}. Great caution should be used before administering HES in patients with severe sepsis and septic shock. Trial registration: NCT00962156
References
1.
Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients.
Intensive Care Med. 2012 Mar; 38(3): 368-83
PMID: 22323076
DOI: 10.1007/s00134-012-2472-9
2.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med. 2008 Jan 10; 358(2): 125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
3.
Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study.
Lancet. 2001 Mar 24; 357(9260): 911-6
PMID: 11289347
DOI: 10.1016/S0140-6736(00)04211-2
Disclosures
Daniel De Backer was the Chair of the Data Safety Monitoring Board for this trial; however, he was not involved in the data analysis or write up of this study.
De Backer D: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 08 Aug 2012; DOI: 10.3410/f.717648052.793456935. F1000Prime.com/717648052#eval793456935
24 Sep 2012
Thomas Luecke
F1000 Anesthesiology & Pain Management
Faculty of Medicine, University of Heidelberg,
Mannheim, Germany.
F1000 Anesthesiology & Pain Management
Faculty of Medicine, University of Heidelberg,
Mannheim, Germany.
New Finding
DOI: 10.3410/f.717648052.793460794
Changes clinical practice - Fluid resuscitation in septic shock should no longer be performed using hydroxyethyl starch (HES) as first line.
This is an extremely important study re-examining the question of the efficacy and safety of hydroxyethyl starch (HES) compared to crystalloid for fluid resuscitation in patients with severe sepsis and septic shock. Enrolling 804 patients, the study clearly shows that patients assigned to fluid resuscitation...Continue reading
This is an extremely important study re-examining the question of the efficacy and safety of hydroxyethyl starch (HES) compared to crystalloid for fluid resuscitation in patients with severe sepsis and septic shock. Enrolling 804 patients, the study clearly shows that patients assigned to fluid resuscitation with HES 130/0.42 were more likely to require renal replacement therapy and had an increased risk of death at day 90 (with a number needed to harm as low as 13). In contrast to the VISEP trial {1}, this study strictly adheres to the dose recommendations for HES and uses a new-generation, low-molecular-weight HES preparation, but still shows the same strong signal towards harmful effects for the use of synthetic colloids, as emphasized by my Faculty colleagues in their respective evaluations.
In addition, however, I would like to stress two aspects that seem important to me when critically interpreting the study results:
First, this has been a pragmatic trial, so there was no protocol for targeting endpoints of resuscitation or to standardize other aspects of treatment. The only intervention was to use the study fluid at a dose up to 33ml per kilogram of ideal body weight (IBW) per day.
Second, when looking at the median cumulative volume of fluid received, the data show a median of 44ml per kilogram of IBW for the starch group and 47ml per kilogram of IBW for the crystalloid group. As study fluids (HES or crytalloid) were used at a dose up to 33ml per kilogram of IBW per day as mentioned above, this makes me wonder whether some patients in the HES group were almost completely resuscitated using colloids only. This would be different to the common approach to use a combined crystalloid and colloid approach in a 2:1 to 3:1 ratio. Unfortunately, the authors of the study do not comment on that issue.
Considering that limitation and the evidence presented, I would conclude that - based on this study - fluid resuscitation in septic shock using colloids as first line should not be used. Trial registration: NCT00962156
In addition, however, I would like to stress two aspects that seem important to me when critically interpreting the study results:
First, this has been a pragmatic trial, so there was no protocol for targeting endpoints of resuscitation or to standardize other aspects of treatment. The only intervention was to use the study fluid at a dose up to 33ml per kilogram of ideal body weight (IBW) per day.
Second, when looking at the median cumulative volume of fluid received, the data show a median of 44ml per kilogram of IBW for the starch group and 47ml per kilogram of IBW for the crystalloid group. As study fluids (HES or crytalloid) were used at a dose up to 33ml per kilogram of IBW per day as mentioned above, this makes me wonder whether some patients in the HES group were almost completely resuscitated using colloids only. This would be different to the common approach to use a combined crystalloid and colloid approach in a 2:1 to 3:1 ratio. Unfortunately, the authors of the study do not comment on that issue.
Considering that limitation and the evidence presented, I would conclude that - based on this study - fluid resuscitation in septic shock using colloids as first line should not be used. Trial registration: NCT00962156
References
1.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med 2008 Jan 10; 358(2):125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
Disclosures
None declared
Luecke T: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 24 Sep 2012; DOI: 10.3410/f.717648052.793460794. F1000Prime.com/717648052#eval793460794
02 Oct 2012
Emmanuel Burdmann
F1000 Nephrology
University of Sao Paulo Medical School,
Sao Paulo, Sao Paulo, Brazil.
F1000 Nephrology
University of Sao Paulo Medical School,
Sao Paulo, Sao Paulo, Brazil.
Clinical Trial
DOI: 10.3410/f.717648052.793461086
Changes clinical practice - Hydroxyethyl Starch 130/0.4 must not be used in the resuscitation of severe sepsis patients.
This study assesses an unmet clinical need, specifically what is the better kind of fluid for early resuscitation of severe sepsis patients. Colloids are considered more potent plasma volume expanders than crystalloids, and hydroxyethyl starch (HES) has been extensively used for this purpose. Previous...Continue reading
This study assesses an unmet clinical need, specifically what is the better kind of fluid for early resuscitation of severe sepsis patients. Colloids are considered more potent plasma volume expanders than crystalloids, and hydroxyethyl starch (HES) has been extensively used for this purpose. Previous studies suggested that HES solutions with a 200kD molecular weight and a substitution rate >0.4 are associated with acute kidney injury and death {1,2}. Here, Perner and colleagues evaluated the effects of HES 130/0.42 (lower molecular weight and substitution rate) on the composite outcome of death or need for renal replacement therapy (RRT) in patients with severe sepsis. The authors performed a randomized, controlled, blinded, parallel-group, multicenter trial, where 798 severe sepsis intensive care unit (ICU) patients were randomized to receive Ringer's acetate (400 patients) or 6% HES 130/0.42 (398 patients) as fluid resuscitation. HES was associated with a higher day 90 risk of death and higher use of RRT both by bi- and multivariate analysis. HES was also associated with coagulation impairment and higher need for red blood cell pack rescue.
This study has some limitations -- hemodynamic parameters and co-interventions were not assessed, there is the possibility that significant differences exist in the algorithms for severe sepsis treatment in the diverse centers included, and patients with AKI at randomization were included. The study has several strengths: it was blinded, is powered (80%), included university and non-university hospitals, included a large number of patients with shock and using mechanical ventilation, and the number of patients already with AKI at randomization was similar in both groups. The take-home message is that HES 130/0.42 use for fluid resuscitation in severe sepsis was clearly associated with higher mortality and RRT use, confirming previous results from studies assessing HES 200 use in the same kind of patients. Trial registration: NCT00962156
This study has some limitations -- hemodynamic parameters and co-interventions were not assessed, there is the possibility that significant differences exist in the algorithms for severe sepsis treatment in the diverse centers included, and patients with AKI at randomization were included. The study has several strengths: it was blinded, is powered (80%), included university and non-university hospitals, included a large number of patients with shock and using mechanical ventilation, and the number of patients already with AKI at randomization was similar in both groups. The take-home message is that HES 130/0.42 use for fluid resuscitation in severe sepsis was clearly associated with higher mortality and RRT use, confirming previous results from studies assessing HES 200 use in the same kind of patients. Trial registration: NCT00962156
References
1.
Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study.
Lancet 2001 Mar 24; 357(9260):911-6
PMID: 11289347
DOI: 10.1016/S0140-6736(00)04211-2
2.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med 2008 Jan 10; 358(2):125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
Disclosures
None declared
Burdmann E: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 02 Oct 2012; DOI: 10.3410/f.717648052.793461086. F1000Prime.com/717648052#eval793461086
08 Oct 2012
Confirmation, Controversial
DOI: 10.3410/f.717648052.793462218
Changes clinical practice - Hydroxyethyl starches should not be used for fluid resuscitation in adult patients who have severe sepsis.
The authors of this paper should be congratulated for two reasons. One, they have provided further high-quality evidence to support the hypothesis that hydroxyethyl starches, when used for fluid resuscitation in adult patients who have severe sepsis, lead to higher mortality rates; the size of this...Continue reading
The authors of this paper should be congratulated for two reasons. One, they have provided further high-quality evidence to support the hypothesis that hydroxyethyl starches, when used for fluid resuscitation in adult patients who have severe sepsis, lead to higher mortality rates; the size of this multi-centre trial and its pragmatic nature provide good external validity to the results. Secondly, it is a well-conducted trial that has provided excellent supplementary data. This provides us with a very clear picture of the patients, their management and how the analysis has been carried out. Trial registration: NCT00962156
Disclosures
None declared
Gordon A: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 08 Oct 2012; DOI: 10.3410/f.717648052.793462218. F1000Prime.com/717648052#eval793462218
19 Oct 2012
Confirmation, Controversial, Good for Teaching
DOI: 10.3410/f.717648052.793462878
Changes clinical practice - The use of hydroxyethyl starches for fluid resuscitation in patients with severe septic shock should be restricted to high-quality clinical trials.
This article is a landmark study that confirms prior suggestions that synthetic starch-based colloids cause acute kidney injury and increase the risk of death for patients with septic shock.
An early study in this field identified starch products as potentially causing acute kidney injury in seps but...Continue reading
An early study in this field identified starch products as potentially causing acute kidney injury in seps but...Continue reading
This article is a landmark study that confirms prior suggestions that synthetic starch-based colloids cause acute kidney injury and increase the risk of death for patients with septic shock.
An early study in this field identified starch products as potentially causing acute kidney injury in sepsis, but the comparison to gelatin limited trial interpretation {1}. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study subsequently demonstrated that 10% hydroxyethyl starch (HES) caused increased rates of kidney injury, with a dose-dependent increase in mortality {2}. With the findings of this trial, it seems that the effect of starches on kidney injury is a class effect. With this current state of knowledge regarding synthetic colloids, starch solutions should be avoided in patients with septic shock. Additional studies are required to demonstrate their safety in many populations, and whether newer generation starches may be safely used in critically ill patients remains to be seen. At present, these results are only applicable to starch solutions and do not apply to other synthetic or natural colloids, which have been associated with either safety or even improved outcomes in septic shock {3}.
An early study in this field identified starch products as potentially causing acute kidney injury in sepsis, but the comparison to gelatin limited trial interpretation {1}. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study subsequently demonstrated that 10% hydroxyethyl starch (HES) caused increased rates of kidney injury, with a dose-dependent increase in mortality {2}. With the findings of this trial, it seems that the effect of starches on kidney injury is a class effect. With this current state of knowledge regarding synthetic colloids, starch solutions should be avoided in patients with septic shock. Additional studies are required to demonstrate their safety in many populations, and whether newer generation starches may be safely used in critically ill patients remains to be seen. At present, these results are only applicable to starch solutions and do not apply to other synthetic or natural colloids, which have been associated with either safety or even improved outcomes in septic shock {3}.
References
1.
Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study.
Lancet 2001 Mar 24; 357(9260):911-6
PMID: 11289347
DOI: 10.1016/S0140-6736(00)04211-2
2.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med 2008 Jan 10; 358(2):125-39
PMID: 18184958
DOI: 10.1056/NEJMoa070716
3.
Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis.
Intensive Care Med 2011 Jan; 37(1):86-96
PMID: 20924555
DOI: 10.1007/s00134-010-2039-6
Disclosures
None declared
Martin G: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 19 Oct 2012; DOI: 10.3410/f.717648052.793462878. F1000Prime.com/717648052#eval793462878
02 May 2013
Clinical Trial
DOI: 10.3410/f.717648052.793475160
This important study showed that hydroxyethyl starch (HES) 130/0.42 should not be used for fluid resuscitation in critically ill patients with severe sepsis because fluid resuscitation with HES 130/0.42 increases the risk of acute kidney injury (AKI) requiring renal replacement therapy and mortality in...Continue reading
This important study showed that hydroxyethyl starch (HES) 130/0.42 should not be used for fluid resuscitation in critically ill patients with severe sepsis because fluid resuscitation with HES 130/0.42 increases the risk of acute kidney injury (AKI) requiring renal replacement therapy and mortality in patients with severe sepsis.
Disclosures
None declared
Imai E: F1000Prime Recommendation of [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 02 May 2013; DOI: 10.3410/f.717648052.793475160. F1000Prime.com/717648052#eval793475160
F1000Prime Recommendations, Dissents and Comments for [Perner A et al., N Engl J Med 2012, 367(2):124-34]. In F1000Prime, 18 May 2013; F1000Prime.com/717648052
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BACKGROUND: Hydroxyethyl starch (HES) 130/0.42 is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.
METHODS: In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.
RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.
CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.).
PMID: 22738085
