2012 SCCM Consensus in HES usage in Severe Sepsis
Based on the results of several small trials, the safety of colloid solutions containing high-molecular-weight hydroxyethyl starch (HES) has been questioned in patients with severe sepsis. In the July 12 issue of The New England Journal of Medicine, Perner and investigators from the 6S Trial Group and the Scandinavian Critical Care Trials Group reported the results from a multicenter, blinded, stratified, parallel-group randomized trial conducted in 26 Scandinavian intensive care units from 2009 to 2011. The effects of HES (130/0.42) were compared to those of Ringer’s acetate on the composite outcomes of death or end-stage renal failure in patients with severe sepsis.
Computerized allocation was used to blindly randomize 804 patients. Treatment assignments were concealed from investigators, clinicians and patients. Adults older than 18 and fulfilling criteria for severe sepsis were enrolled. The primary outcome was death or dependence on dialysis 90 days after randomization. The study was appropriately powered to detect an absolute difference in the primary outcome, with multivariate analyses used to adjust for differences in baseline variables.
The study followed 398 patients in the HES group and 400 in the Ringer’s group (N=798 total) for at least 90 days. Baseline characteristics were similar in the two groups, with each having an incidence of acute kidney injury over 35%. The median cumulative volume of fluid received was not statistically significantly different between the two groups. More patients in the HES group received blood products and required renal replacement therapy. The primary outcome of death was higher in the HES group (relative risk [RR], 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 53% of patients in the HES group died compared to 43% in the Ringer’s group. The authors hypothesized that one explanation for the findings may be that HES is deposited in tissues, and may act as a toxic foreign body.
This well-conducted study conformed to a modified intention-to-treat protocol. Although a high number of patients with acute kidney injury were included, this comorbidity was evenly balanced with the randomized design. Patients received strikingly similar amounts of fluids, though the trial did not employ advanced hemodynamic monitoring or protocols for titrating fluids.
HES was associated with an increase in absolute risk of death (number needed to harm=13). Based on the results of this trial and previous work in this area, the use of HES should be critically examined as an option for colloid resuscitation in patients with severe sepsis. Patients with severe sepsis who received HES were at increased risk of death at 90 days, more likely to receive renal-replacement therapy, and were alive for fewer days once discharged from the hospital.
※ 敗血症は全身性炎症の代表的病態です。このような検証が行われるまでもなく，重症敗血症や敗血症性ショックにHESを使うことはないと思いますがが，これは敗血症にのみ有害なわけではありません。理論的には炎症性手術においてHESを用いれば臓器不全が進行する可能性があり，既に一臓器以上の臓器不全を持っている場合には，90日死亡率にも影響が出る可能性があるということです。特に，術後に腎機能を低下させる可能性については，炎症性サイトカインの増加する手術において，極めてリスクが高いと評価されます。
Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis
N Engl J Med 2012; 367:124-134
Anders Perner, M.D., Ph.D., Nicolai Haase, M.D., Anne B. Guttormsen, M.D., Ph.D., Jyrki Tenhunen, M.D., Ph.D., Gudmundur Klemenzson, M.D., Anders Åneman, M.D., Ph.D., Kristian R. Madsen, M.D., Morten H. Møller, M.D., Ph.D., Jeanie M. Elkjær, M.D., Lone M. Poulsen, M.D., Asger Bendtsen, M.D., M.P.H., Robert Winding, M.D., Morten Steensen, M.D., Pawel Berezowicz, M.D., Ph.D., Peter Søe-Jensen, M.D., Morten Bestle, M.D., Ph.D., Kristian Strand, M.D., Ph.D., Jørgen Wiis, M.D., Jonathan O. White, M.D., Klaus J. Thornberg, M.D., Lars Quist, M.D., Jonas Nielsen, M.D., Ph.D., Lasse H. Andersen, M.D., Lars B. Holst, M.D., Katrin Thormar, M.D., Anne-Lene Kjældgaard, M.D., Maria L. Fabritius, M.D., Frederik Mondrup, M.D., Frank C. Pott, M.D., D.M.Sci., Thea P. Møller, M.D., Per Winkel, M.D., D.M.Sci., and Jørn Wetterslev, M.D., Ph.D. for the 6S Trial Group and the Scandinavian Critical Care Trials Group
BACKGROUND
Hydroxyethyl starch (HES) 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.)
Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function.
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007594.
Dart AB, Mutter TC, Ruth CA, Taback SP.
Source
Department of Pediatrics and Child Health, University of Manitoba, FE-009 840 Sherbrook St, Winnipeg, Manitoba, Canada, R3A 1S1.
Abstract
BACKGROUND:
Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation, yet controversy exists about their impact on kidney function.
OBJECTIVES:
To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations.
SEARCH STRATEGY:
We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles.
SELECTION CRITERIA:
Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes included serum creatinine and creatinine clearance.
DATA COLLECTION AND ANALYSIS:
Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random effects model.
MAIN RESULTS:
The review included 34 studies (2607 patients). Overall, the RR of author-defined kidney failure was 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients. Non-septic patient studies were smaller and had lower event rates, so subgroup differences may have been due to lack of statistical power in these studies. Only limited data was obtained for analysis of kidney outcomes by the RIFLE criteria. Overall, methodological quality of studies was good but subjective outcomes were potentially biased because most studies were unblinded.
AUTHORS' CONCLUSIONS:
Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HES products in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function in future studies of HES and, where data is available, to re-analyse those studies already published. There is inadequate clinical data to address the claim that safety differences exist between different HES products.
循環血液量増加に関してはアルブミンもHESも有効 by びんちゃん
Su F, Wang Z, Cai Y, Rogiers P, Vincent JL.
Shock. 2007 May;27(5):520-6.
Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or ringer's lactate-does it really make a difference?
Abstract
The aim of this study was to investigate whether the type of i.v. fluid administered has an impact on outcome in an animal model of septic shock. The study included 28 anesthetized, invasively monitored, mechanically ventilated female sheep (29.5 +/- 4.0 kg), which received 0.5 g/kg body weight of feces into the abdominal cavity to induce peritonitis. During the surgical operation and 4 h after feces spillage, only Ringer's lactate (RL) was administered in all animals. Thereafter, animals were randomized to receive continuous infusions of RL (n = 7) alone or combined with either 20% albumin (n = 7, volume ratio to RL 1:10) or 6% hydroxyethyl starch (HES) (n = 7, volume ratio to RL 1:1), or gelatin alone (n= 7, no volume limitation). Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline levels throughout the experiment. No antibiotics or vasoactive drugs were administered, and animals were monitored until their spontaneous death. Hemodynamic variables were better with HES and albumin than with the other fluids, as reflected by higher stroke volume, cardiac index, and oxygen delivery (all P < 0.05). Hydroxyethyl-starch-treated animals also had lower arterial lactate concentrations (P < 0.01). However, times to develop hypotension and oliguria were similar in all groups. Blood interleukin (IL) 6 concentrations were significantly increased in all groups. The mean survival time was similar in all groups. In this clinically relevant model of prolonged septic shock, albumin and HES solution resulted in higher cardiac output, oxygen delivery, and lower blood lactate levels than gelatin and RL; however, the choice of i.v. fluid did not affect outcome.
Based on the results of several small trials, the safety of colloid solutions containing high-molecular-weight hydroxyethyl starch (HES) has been questioned in patients with severe sepsis. In the July 12 issue of The New England Journal of Medicine, Perner and investigators from the 6S Trial Group and the Scandinavian Critical Care Trials Group reported the results from a multicenter, blinded, stratified, parallel-group randomized trial conducted in 26 Scandinavian intensive care units from 2009 to 2011. The effects of HES (130/0.42) were compared to those of Ringer’s acetate on the composite outcomes of death or end-stage renal failure in patients with severe sepsis.
Computerized allocation was used to blindly randomize 804 patients. Treatment assignments were concealed from investigators, clinicians and patients. Adults older than 18 and fulfilling criteria for severe sepsis were enrolled. The primary outcome was death or dependence on dialysis 90 days after randomization. The study was appropriately powered to detect an absolute difference in the primary outcome, with multivariate analyses used to adjust for differences in baseline variables.
The study followed 398 patients in the HES group and 400 in the Ringer’s group (N=798 total) for at least 90 days. Baseline characteristics were similar in the two groups, with each having an incidence of acute kidney injury over 35%. The median cumulative volume of fluid received was not statistically significantly different between the two groups. More patients in the HES group received blood products and required renal replacement therapy. The primary outcome of death was higher in the HES group (relative risk [RR], 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 53% of patients in the HES group died compared to 43% in the Ringer’s group. The authors hypothesized that one explanation for the findings may be that HES is deposited in tissues, and may act as a toxic foreign body.
This well-conducted study conformed to a modified intention-to-treat protocol. Although a high number of patients with acute kidney injury were included, this comorbidity was evenly balanced with the randomized design. Patients received strikingly similar amounts of fluids, though the trial did not employ advanced hemodynamic monitoring or protocols for titrating fluids.
HES was associated with an increase in absolute risk of death (number needed to harm=13). Based on the results of this trial and previous work in this area, the use of HES should be critically examined as an option for colloid resuscitation in patients with severe sepsis. Patients with severe sepsis who received HES were at increased risk of death at 90 days, more likely to receive renal-replacement therapy, and were alive for fewer days once discharged from the hospital.
※ 敗血症は全身性炎症の代表的病態です。このような検証が行われるまでもなく，重症敗血症や敗血症性ショックにHESを使うことはないと思いますがが，これは敗血症にのみ有害なわけではありません。理論的には炎症性手術においてHESを用いれば臓器不全が進行する可能性があり，既に一臓器以上の臓器不全を持っている場合には，90日死亡率にも影響が出る可能性があるということです。特に，術後に腎機能を低下させる可能性については，炎症性サイトカインの増加する手術において，極めてリスクが高いと評価されます。
Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis
N Engl J Med 2012; 367:124-134
Anders Perner, M.D., Ph.D., Nicolai Haase, M.D., Anne B. Guttormsen, M.D., Ph.D., Jyrki Tenhunen, M.D., Ph.D., Gudmundur Klemenzson, M.D., Anders Åneman, M.D., Ph.D., Kristian R. Madsen, M.D., Morten H. Møller, M.D., Ph.D., Jeanie M. Elkjær, M.D., Lone M. Poulsen, M.D., Asger Bendtsen, M.D., M.P.H., Robert Winding, M.D., Morten Steensen, M.D., Pawel Berezowicz, M.D., Ph.D., Peter Søe-Jensen, M.D., Morten Bestle, M.D., Ph.D., Kristian Strand, M.D., Ph.D., Jørgen Wiis, M.D., Jonathan O. White, M.D., Klaus J. Thornberg, M.D., Lars Quist, M.D., Jonas Nielsen, M.D., Ph.D., Lasse H. Andersen, M.D., Lars B. Holst, M.D., Katrin Thormar, M.D., Anne-Lene Kjældgaard, M.D., Maria L. Fabritius, M.D., Frederik Mondrup, M.D., Frank C. Pott, M.D., D.M.Sci., Thea P. Møller, M.D., Per Winkel, M.D., D.M.Sci., and Jørn Wetterslev, M.D., Ph.D. for the 6S Trial Group and the Scandinavian Critical Care Trials Group
BACKGROUND
Hydroxyethyl starch (HES) 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.)
Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function.
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007594.
Dart AB, Mutter TC, Ruth CA, Taback SP.
Source
Department of Pediatrics and Child Health, University of Manitoba, FE-009 840 Sherbrook St, Winnipeg, Manitoba, Canada, R3A 1S1.
Abstract
BACKGROUND:
Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation, yet controversy exists about their impact on kidney function.
OBJECTIVES:
To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations.
SEARCH STRATEGY:
We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles.
SELECTION CRITERIA:
Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes included serum creatinine and creatinine clearance.
DATA COLLECTION AND ANALYSIS:
Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random effects model.
MAIN RESULTS:
The review included 34 studies (2607 patients). Overall, the RR of author-defined kidney failure was 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients. Non-septic patient studies were smaller and had lower event rates, so subgroup differences may have been due to lack of statistical power in these studies. Only limited data was obtained for analysis of kidney outcomes by the RIFLE criteria. Overall, methodological quality of studies was good but subjective outcomes were potentially biased because most studies were unblinded.
AUTHORS' CONCLUSIONS:
Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HES products in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function in future studies of HES and, where data is available, to re-analyse those studies already published. There is inadequate clinical data to address the claim that safety differences exist between different HES products.
循環血液量増加に関してはアルブミンもHESも有効 by びんちゃん
Su F, Wang Z, Cai Y, Rogiers P, Vincent JL.
Shock. 2007 May;27(5):520-6.
Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or ringer's lactate-does it really make a difference?
Abstract
The aim of this study was to investigate whether the type of i.v. fluid administered has an impact on outcome in an animal model of septic shock. The study included 28 anesthetized, invasively monitored, mechanically ventilated female sheep (29.5 +/- 4.0 kg), which received 0.5 g/kg body weight of feces into the abdominal cavity to induce peritonitis. During the surgical operation and 4 h after feces spillage, only Ringer's lactate (RL) was administered in all animals. Thereafter, animals were randomized to receive continuous infusions of RL (n = 7) alone or combined with either 20% albumin (n = 7, volume ratio to RL 1:10) or 6% hydroxyethyl starch (HES) (n = 7, volume ratio to RL 1:1), or gelatin alone (n= 7, no volume limitation). Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline levels throughout the experiment. No antibiotics or vasoactive drugs were administered, and animals were monitored until their spontaneous death. Hemodynamic variables were better with HES and albumin than with the other fluids, as reflected by higher stroke volume, cardiac index, and oxygen delivery (all P < 0.05). Hydroxyethyl-starch-treated animals also had lower arterial lactate concentrations (P < 0.01). However, times to develop hypotension and oliguria were similar in all groups. Blood interleukin (IL) 6 concentrations were significantly increased in all groups. The mean survival time was similar in all groups. In this clinically relevant model of prolonged septic shock, albumin and HES solution resulted in higher cardiac output, oxygen delivery, and lower blood lactate levels than gelatin and RL; however, the choice of i.v. fluid did not affect outcome.
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