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1.  Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality 
Objective To assess the efficacy and safety of pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of baseline hypoalbuminaemia) in critically unwell adults with sepsis of any severity.
Design Systematic review and meta-analysis of randomised clinical trials, with trial sequential analysis, subgroup, and meta-regression analyses.
Data sources PubMed, PubMed Central, Web of Science (includes Medline, Conference Proceedings Citation Index, Data Citation Index, Chinese Science Citation Database, CAB abstracts, Derwent Innovations Index), OvidSP (includes Embase, Ovid Medline, HMIC, PsycINFO, Maternity and Infant Care, Transport Database), Cochrane Library, clinicaltrials.gov, controlled-trials.com, online material, relevant conference proceedings, hand searching of reference lists, and contact with authors as necessary.
Eligibility criteria Prospective randomised clinical trials of adults with sepsis of any severity (with or without baseline hypoalbuminaemia) in critical or intensive care who received pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of hypoalbuminaemia) compared with those who received control fluids (crystalloid or colloid), were included if all-cause mortality outcome data were available. No restriction of language, date, publication status, or primary study endpoint was applied.
Data extraction Two reviewers independently assessed articles for inclusion, extracted data to assess risk of bias, trial methods, patients, interventions, comparisons, and outcome. The relative risk of all-cause mortality was calculated using a random effects model accounting for clinical heterogeneity.
Primary outcome measure All-cause mortality at final follow-up.
Results Eighteen articles reporting on 16 primary clinical trials that included 4190 adults in critical or intensive care with sepsis, severe sepsis, or septic shock. A median of 70.0 g daily of pooled human albumin was received over a median of 3 days by adults with a median age of 60.8 years as part of fluid volume expansion and resuscitation, with or without correction of hypoalbuminaemia. The relative risk of death was similar between albumin groups (that received a median of 175 g in total) and control fluid groups (relative risk 0.94; 95% confidence interval 0.87 to 1.01; P=0.11; I2=0%). Trial sequential analysis corrected the 95% confidence interval for random error (0.85 to 1.02; D2=0%). Eighty eight per cent of the required information size (meta-analysis sample size) of 4894 patients was achieved, and the cumulative effect size measure (z score) entered the futility area, supporting the notion of no relative benefit of albumin (GRADE quality of evidence was moderate). Evidence of no difference was also found when albumin was compared with crystalloid fluid (relative risk 0.93; 0.86 to 1.01; P=0.07; I2=0%) in 3878 patents (GRADE quality of evidence was high; 79.9% of required information size) or colloid fluids in 299 patients (relative risk 1.04; 0.79 to 1.38; P=0.76; I2=0%) (GRADE quality of evidence was very low; 5.8% of required information size). When studies at high risk of bias were excluded in a predefined subgroup analysis, the finding of no mortality benefit remained, and the cumulative z score was just outside the boundary of futility. Overall, the meta-analysis was robust to sensitivity, subgroup, meta-regression, and trial sequential analyses.
Conclusions In this analysis, human albumin solutions as part of fluid volume expansion and resuscitation for critically unwell adults with sepsis of any severity (with or without baseline hypoalbuminaemia) were not robustly effective at reducing all-cause mortality. Albumin seems to be safe in this setting, as a signal towards harm was not detected, but this analysis does not support a recommendation for use.
doi:10.1136/bmj.g4561
PMCID: PMC4106199  PMID: 25099709
2.  Volume Expansion with Albumin Compared to Gelofusine in Children with Severe Malaria: Results of a Controlled Trial  
PLoS Clinical Trials  2006;1(5):e21.
Objectives:
Previous studies have shown that in children with severe malaria, resuscitation with albumin infusion results in a lower mortality than resuscitation with saline infusion. Whether the apparent benefit of albumin is due solely to its colloidal properties, and thus might also be achieved with other synthetic colloids, or due to the many other unique physiological properties of albumin is unknown. As albumin is costly and not readily available in Africa, examination of more affordable colloids is warranted. In order to inform the design of definitive phase III trials we compared volume expansion with Gelofusine (succinylated modified fluid gelatin 4% intravenous infusion) with albumin.
Design:
This study was a phase II safety and efficacy study.
Setting:
The study was conducted at Kilifi District Hospital, Kenya.
Participants:
The participants were children admitted with severe falciparum malaria (impaired consciousness or deep breathing), metabolic acidosis (base deficit > 8 mmol/l), and clinical features of shock.
Interventions:
The interventions were volume resuscitation with either 4.5% human albumin solution or Gelofusine.
Outcome Measures:
Primary endpoints were the resolution of shock and acidosis; secondary endpoints were in-hospital mortality and adverse events including neurological sequelae.
Results:
A total of 88 children were enrolled: 44 received Gelofusine and 44 received albumin. There was no significant difference in the resolution of shock or acidosis between the groups. Whilst no participant developed pulmonary oedema or fluid overload, fatal neurological events were more common in the group receiving gelatin-based intervention fluids. Mortality was lower in patients receiving albumin (1/44; 2.3%) than in those treated with Gelofusine (7/44; 16%) by intention to treat (Fisher's exact test, p = 0.06), or 1/40 (2.5%) and 4/40 (10%), respectively, for those treated per protocol (p = 0.36). Meta-analysis of published trials to provide a summary estimate of the effect of albumin on mortality showed a pooled relative risk of death with albumin administration of 0.19 (95% confidence interval 0.06–0.59; p = 0.004 compared to other fluid boluses).
Conclusions:
In children with severe malaria, we have shown a consistent survival benefit of receiving albumin infusion compared to other resuscitation fluids, despite comparable effects on the resolution of acidosis and shock. The lack of similar mortality benefit from Gelofusine suggests that the mechanism may involve a specific neuroprotective effect of albumin, rather than solely the effect of the administered colloid. Further exploration of the benefits of albumin is warranted in larger clinical trials.
Editorial Commentary
Background: In Africa, children admitted to hospital with severe malaria are at high risk of death even though effective malaria treatment is available. Death typically occurs during a narrow time window after admission and before antimalarial treatments can start working. Acidosis (excessive acidity of the blood) is thought to predict death, but it is not clear how acidosis arises. One possibility is that hypovolemia (lowered blood fluid volume) is important, which would normally require urgent resuscitation with fluids. However, there is little evidence on what type of fluid should be given. In the trial reported here, carried out in Kenya's Kilifi District Hospital between 2004 and 2006, 88 children admitted with severe malaria were assigned to receive either albumin solution (a colloid solution made from blood protein) or Gelofusine (a synthetic colloid). The primary outcomes that the researchers were interested in were correction of shock and acidosis in the blood after 8 h. However, the researchers also looked at death rate in hospital and adverse events after treatment.
What this trial shows: The investigators found no significant differences in the primary outcomes (correction of shock and acidosis in the blood 8 h after fluids were started) between children given Gelofusine and those given albumin. However, they did see a difference in death rates between children given Gelofusine and those given albumin. Death rates in hospital were lower in the group given albumin, and this was statistically significant. The researchers then combined the data on death rates from this trial with data from two other trials with an albumin arm. This combined analysis also supported the suggestion that death rates with albumin were lower than with other fluids, either Gelofusine or salt solution.
Strengths and limitations: There is currently very little evidence from trials to guide the initial management of fluids in children with severe malaria. The results from this trial indicate that further research is a priority. However, the actual findings from this trial must be tested in larger trials that recruit enough children to establish reliably whether there is a difference in death rate between albumin treatment and treatment with other fluids. This trial was not originally planned to find a clinically relevant difference in death rate, and therefore does not definitively answer that question. Further trials would also need to use a random method to assign participants to the different treatments, rather than alternate blocks (as in this trial). A random method ensures greater comparability of the two groups in the trial, and reduces the chance of selection bias (where assignment of patients to different treatments can be distorted during the enrollment process).
Contribution to the evidence: This study adds data suggesting that fluid resuscitation with albumin solution, as compared to Gelofusine, may reduce the chance of death in children with severe malaria. However, this finding is not definitive and would need to be examined in further carefully controlled trials. If the finding is supported by further research, then a solution to the problems of high cost and limited availability of albumin will need to be found.
doi:10.1371/journal.pctr.0010021
PMCID: PMC1569382  PMID: 16998584
3.  Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials 
Critical Care  2014;18(6):702.
Introduction
The aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis.
Methods
We searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software.
Results
A total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I2 = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09).
Conclusions
In this meta-analysis, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0702-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0702-y
PMCID: PMC4284920  PMID: 25499187
4.  Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study 
BMJ : British Medical Journal  2006;333(7577):1044.
Objective To determine whether outcomes of resuscitation with albumin or saline in the intensive care unit depend on patients' baseline serum albumin concentration.
Design Analysis of data from a double blind, randomised controlled trial.
Setting Intensive care units of 16 hospitals in Australia and New Zealand.
Participants 6045 participants in the saline versus albumin fluid evaluation (SAFE) study.
Interventions Fluid resuscitation with 4% albumin or saline in patients with a baseline serum albumin concentration of 25 g/l or less or more than 25 g/l.
Main outcome measures Primary outcome was all cause mortality at 28 days. Secondary outcomes were length of stay in the intensive care unit, length of stay in hospital, duration of renal replacement therapy, and duration of mechanical ventilation.
Main results The odds ratios for death for albumin compared with saline for patients with a baseline serum albumin concentration of 25 g/l or less and more than 25 g/l were 0.87 and 1.09, respectively (ratio of odds ratios 0.80, 95% confidence interval 0.63 to 1.02); P=0.08 for heterogeneity. No significant interaction was found between baseline serum albumin concentration as a continuous variable and the effect of albumin and saline on mortality. No consistent interaction was found between baseline serum albumin concentration and treatment effects on length of stay in the intensive care unit, length of hospital stay, duration of renal replacement therapy, or duration of mechanical ventilation.
Conclusion The outcomes of resuscitation with albumin and saline are similar irrespective of patients' baseline serum albumin concentration.
Trial registration ISRCTN76588266.
doi:10.1136/bmj.38985.398704.7C
PMCID: PMC1647335  PMID: 17040925
5.  Hydroxyethyl starch - the importance of being earnest 
Despite ongoing controversial expert discussions the European Medicines Agency (EMA) recently recommended to suspend marketing authorisations for hydroxyethyl starch. This comment critically evaluates the line of arguments. Basically, the only indication for a colloid is intravascular hypovolemia. Crystalloid use appears reasonable to compensate ongoing extracellular losses beyond. In the hemodynamically instable patient this leads to the distinction between an initial resuscitation phase where colloids might be indicated and a crystalloidal maintenance phase thereafter. It is important to bear this in mind when reevaluating the studies the EMA referred to in the context of its recent decision: i) VISEP compared ringer’s lactate to 10% HES 200/0.5 in septic patients and found an increased incidence of renal failure in HES receivers. Unfortunately, study treatment was started only after initial stabilization with HES, randomizing hemodynamically stable patients into a rational (crystalloids) and an irrational (high dose starch until ICU discharge) maintenance treatment. ii) 6S compared ringer’s acetate to 6% HES 130/0.42 for fluid resuscitation in septic patients and found an increased need of renal replacement therapy and a higher mortality in the HES group. However, patients of both groups were again randomized only after initial stabilization with colloids, the actual comparison was, therefore, again rational vs. irrational. Beyond that, the documentation is partly fragmentary, leaving many important questions around the fate of the patients unanswered. iii) CHEST randomized ICU patients to receive saline or 6% HES 130/0.4 for fluid resuscitation. Actually, despite partly discussed in a different way, this trial showed no relevant differences in outcome.
In all, two studies showed what happens to septic patients if starches are used in a way we do not observe in daily practice. The third one actually proves their safety. The benefit of perioperative goal-directed preload optimization using starches is unquestioned. Taking these informations into account, the recommendation of the EMA starches to be generally dangerous remains mysterious and incomprehensible. An authority being able to dictate behavior should stand clear from oppressively ending a worldwide expert discussion and step back into the role of the observer until science achieves an agreement.
doi:10.1186/1757-7241-21-61
PMCID: PMC3751873  PMID: 23926905
Colloids; Crystalloids; Fluid therapy; Hydroxyethyl starch; Sepsis
6.  Albumin and artificial colloids in fluid management: where does the clinical evidence of their utility stand? 
Critical Care  2000;4(Suppl 2):S16-S20.
Key questions remain unresolved regarding the advantages and limitations of colloids for fluid resuscitation despite extensive investigation. Elucidation of these questions has been slowed, in part, by uncertainty as to the optimal endpoints that should be monitored in assessing patient response to administered fluid. Colloids and crystalloids do not appear to differ notably in their effects on preload recruitable stroke volume or oxygen delivery. Limited evidence nevertheless suggests that colloids might promote greater oxygen consumption than crystalloids. It remains unclear, in any case, to what extent such physiological parameters might be related to clinically relevant outcomes such as morbidity and mortality. Recent randomized controlled trial results indicate that, at least in certain forms of fluid imbalance, albumin is effective in significantly reducing morbidity and mortality. Much further investigation is needed, however, to determine the effects of colloid administration on clinically relevant outcomes in a broad range of critically ill patients. The ability of administered colloids to increase colloid osmotic pressure (COP) constitutes one mechanism by which colloids might reduce interstitial oedema and promote favourable patient outcomes. However, the applicability of this mechanism may be limited, due to the operation of compensatory mechanisms such as increased lymphatic drainage. Attempts to increase COP might also be less useful in states of increased vascular permeability such as acute respiratory distress syndrome, although this issue has by no means been settled by empirical data. Colloids are clearly more efficient than crystalloids in attaining resuscitation endpoints as judged by the need for administration of far smaller fluid volumes. Among the colloids, albumin offers several advantages compared with artificial colloids, including less restrictive dose limitations, lower risk of impaired haemostasis, absence of tissue deposition leading to severe prolonged pruritus, reduced incidence of anaphylactoid reactions, and ease of monitoring to prevent fluid overload. The cost of albumin, nevertheless, limits its usage. Crystalloids currently serve as the first-line fluids in hypovolaemic patients. Colloids can be considered in patients with severe or acute shock or hypovolaemia resulting from sudden plasma loss. Colloids may be combined with crystalloids to obviate administration of large crystalloid volumes. Further clinical trials are needed to define the optimal role for colloids in critically ill patients.
doi:10.1186/cc965
PMCID: PMC3226170  PMID: 11255594
colloids; critical care; osmotic pressure; serum albumin; shock
7.  Relative Survival Benefit and Morbidity with Fluids in Severe Sepsis - A Network Meta-Analysis of Alternative Therapies 
Current Drug Safety  2013;8(4):236-245.
Background:
Fluid resuscitation is widely practiced in intensive care units for the treatment of sepsis. A comparison of the evidence base of different fluids may inform therapeutic choice.
Methods:
The risks of mortality and morbidity (the need for renal replacement therapies (RRT)) were assessed in patients with severe sepsis. A network meta-analysis compared trials for crystalloids, albumin and hydroxyethyl starch (HES). A literature search of human randomized clinical trials was conducted in databases, the bibliographies of other recent relevant systematic reviews and data reported at recent conferences. Mortality outcomes and RRT data with the longest follow up period were compared. A Bayesian network meta-analysis assessed the risk of mortality and a pair-wise meta-analysis assessed RRT using crystalloids as the reference treatment.
Results:
13 studies were identified. A fixed-effects meta-analysis of mortality data in the trials demonstrated an odds-ratio (OR) of 0.90 between crystalloids and albumin, 1.25 between crystalloids and HES and 1.40 between albumin and HES. The probability that albumin is associated with the highest survival was 96.4% followed by crystalloid at 3.6%, with a negligible probability for HES. Sub-group analyses demonstrated the robustness of this result to variations in fluid composition, study source and origin of septic shock. A random-effects pairwise comparison for the risk of RRT provided an OR of 1.52 favoring crystalloid over HES.
Conclusion:
Fluid therapy with albumin was associated with the highest survival benefit. The higher morbidity with HES may affect mortality and requires consideration by prescribers.
doi:10.2174/15748863113089990046
PMCID: PMC3856428  PMID: 23909705
Albumin; crystalloid; hydroxyethyl starch; meta-analysis; resuscitation; sepsis; septic shock; severe sepsis.
8.  Fluid balance and colloid osmotic pressure in acute respiratory failure: emerging clinical evidence 
Critical Care  2000;4(Suppl 2):S21-S25.
Available evidence suggests that both hydrostatic and osmotic forces are important in the development of acute respiratory distress syndrome (ARDS) or, more broadly, acute lung injury (ALI). More than 80% of ARDS patients in a large-scale randomized controlled trial (RCT) exhibited, at least intermittently, pulmonary artery wedge pressures (PAWP) above 18 mmHg. Retrospective analyses have shown that PAWP elevation is associated with increased mortality. Reduction in serum total protein (STP) has been shown, in a recent retrospective analysis of data from a sepsis patient population with a high frequency of ARDS, to be highly predictive of positive fluid balance, weight gain, development of ARDS, prolonged mechanical ventilation, and mortality. These findings suggest that therapy with diuretics and colloids might be of benefit in the prevention or treatment of ALI. A prospective RCT was designed and conducted to evaluate combination therapy with furosemide and albumin over a 5-day period in 37 ALI patients. Both mean serum albumin and mean STP increased promptly and substantially in furosemide + albumin recipients. The furosemide + albumin group also achieved a mean weight loss of 10 kg by the end of the treatment phase, and their weight loss exceeded that of placebo patients throughout. Hemodynamics improved in the treatment group during the 5-day protocol. Oxygenation, as assessed by the ratio between the fraction of inspired oxygen and the partial pressure of oxygen in arterial blood (PaO2/FiO2), was significantly higher within 24 h after commencement of treatment in the furosemide + albumin than the placebo group. No clinically important adverse effects of furosemide + albumin therapy were encountered. These results provide evidence that combined therapy with furosemide and albumin is effective in augmenting serum albumin and STP levels, promoting weight loss, and improving oxygenation and longer-term hemodynamic stability. Although mortality did not differ between groups, the RCT showed a trend toward reduced duration of mechanical ventilation and length of stay in the intensive care unit in patients receiving furosemide + albumin. The findings of the RCT further highlight the importance of both hydrostatic and osmotic forces in hypoxemic respiratory failure, a subject that requires further investigation.
doi:10.1186/cc966
PMCID: PMC3226171  PMID: 11255595
furosemide; hydrostatic pressure; osmotic pressure; respiratory distress syndrome (adult); serum albumin
9.  Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials 
BMJ : British Medical Journal  1998;316(7136):961-964.
Objective: To determine the effect on mortality of resuscitation with colloid solutions compared with resuscitation with crystalloids.
Design: Systematic review of randomised controlled trials of resuscitation with colloids compared with crystalloids for volume replacement of critically ill patients; analysis stratified according to patient type and quality of allocation concealment.
Subjects: 37 randomised controlled trials were eligible, of which 26 unconfounded trials compared colloids with crystalloids (n=1622). (The 10 trials that compared colloid in hypertonic crystalloid with isotonic crystalloid (n=1422) and one trial that compared colloid in isotonic crystalloid with hypertonic crystalloid (n=38) are described in the longer version on our website www.bmj.com).
Main outcome measures: Mortality from all causes at end of follow up for each trial.
Results: Resuscitation with colloids was associated with an increased absolute risk of mortality of 4% (95% confidence interval 0% to 8%), or four extra deaths for every 100 patients resuscitated. The summary effect measure shifted towards increased mortality with colloids when only trials with adequate concealment of allocation were included. There was no evidence for differences in effect among patients with different types of injury that required fluid resuscitation.
Conclusions: This systematic review does not support the continued use of colloids for volume replacement in critically ill patients.
Key messages For decades there has been controversy over the relative benefits of colloid and crystalloid solutions for fluid resuscitation of hypovolaemic patients Although more expensive than crystalloids, use of colloids far exceeds current recommendations In this systematic review of randomised controlled trials we found that, compared with crystalloids, use of colloids was associated with an increase in absolute risk of mortality of 4% There was no evidence for differences of effect among different types of injury necessitating fluid resuscitation
PMCID: PMC28497  PMID: 9550953
10.  Greater cardiac response of colloid than saline fluid loading in septic and non-septic critically ill patients with clinical hypovolaemia 
Intensive Care Medicine  2010;36(4):697-701.
Background and objective
The haemodynamics of crystalloid and colloid fluid loading may depend on underlying disease, i.e. sepsis versus non-sepsis.
Design and setting
A single-centre, single-blinded, randomized clinical trial was carried out on 24 critically ill sepsis and 24 non-sepsis patients with clinical hypovolaemia, assigned to loading with normal saline, gelatin 4%, hydroxyethyl starch 6% or albumin 5% in a 90-min (delta) central venous pressure (CVP)-guided fluid loading protocol. Transpulmonary thermodilution was done each 30 min, yielding, among others, global end-diastolic volume and cardiac indices (GEDVI, CI).
Results
Sepsis patients had hyperdynamic hypotension in spite of myocardial depression and dilatation, and greater inotropic/vasopressor requirements than non-sepsis patients. Independent of underlying disease, CVP and GEDVI increased more after colloid than saline loading (P < 0.018), so that CI increased by about 2% after saline and 12% after colloid loading (P = 0.029). The increase in preload-recruitable stroke work was also greater with colloids and did not differ among conditions.
Conclusion
Fluid loading with colloids results in a greater linear increase in cardiac filling, output and stroke work than does saline loading, in both septic and non-septic clinical hypovolaemia, in spite of myocardial depression and presumably increased vasopermeability potentially decreasing the effects of colloid fluid loading in the former.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-1776-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00134-010-1776-x
PMCID: PMC2837190  PMID: 20165941
Colloids; Crystalloids; Sepsis; Preload-recruitable stroke work; Hypovolaemia; Global end-diastolic volume; Fluid challenge
11.  Choice of Fluids in Severe Septic Patients - A Cost-effectiveness Analysis Informed by Recent Clinical Trials 
Fluid resuscitation with colloids is an established second line therapy for septic patients. Evidence of relative efficacy outcomes is tempered by considerations of the relative costs of the individual fluids. An assessment of recent large clinical trials was performed, resulting in a ranking in the efficacy of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) were derived and used to inform a decision analysis model comparing the effect of crystalloid, albumin and hydroxyethyl starch solutions in severe septic patients followed from hospital admission to 90 days in intensive care. The US payer perspective was used. Model inputs for costs and efficacy were derived from the peer-reviewed literature, assuming that that all fluid preparations are bio-equivalent within each class of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) data were synthesized using a Bayesian meta-analysis. Relative to crystalloid therapy, 0.21 life years were gained with albumin and 0.85 life years were lost with hydroxyethyl starch. One-way sensitivity analysis showed that the model’s outcomes were sensitive to the cost of RRT but not to the costs of the actual fluids or any other costs. We conclude that albumin may be the most cost-effective treatment in these patients when the total medical costs and iatrogenic morbidities involved in treating sepsis with fluids are considered. These results should assist and inform decision making in the choice of these drugs.
doi:10.2174/1574887108666131213120816
PMCID: PMC4112378
Clinical trials; colloids; costs; decision analysis; fluid therapies; sepsis.
12.  The impact of hydroxyethyl starches in cardiac surgery: a meta-analysis 
Critical Care  2014;18(6):656.
Introduction
Recent studies in septic patients showed that adverse effects of hydroxyethyl starches (HESs) possibly outweigh their benefits in severely impaired physiological haemostasis. It remains unclear whether this also applies to patient populations that are less vulnerable. In this meta-analysis, we evaluated the impact of various HES generations on safety and efficacy endpoints in patients undergoing cardiac surgery.
Methods
We searched the PubMed, Embase and Cochrane Central Register of Controlled Trials databases for randomised controlled trials (RCTs) in the English or German language comparing the use of HES to any other colloid or crystalloid during open heart surgery.
Results
Blood loss and transfusion requirements were higher for older starches with mean molecular weights more than 200 kDa compared to other volume substitutes. In contrast, this effect was not observed with latest-generation tetrastarches (130/0.4), which performed even better when compared to albumin (blood loss of tetrastarch versus albumin: standardised mean difference (SMD), −0.34; 95% CI, −0.63, −0.05; P = 0.02; versus gelatin: SMD, −0.06; 95% CI, −0.20, 0.08; P = 0.39; versus crystalloids: SMD, −0.05; 95% CI, −0.20, 0.10; P = 0.54). Similar results were found for transfusion needs. Lengths of stay in the intensive care unit or hospital were significantly shorter with tetrastarches compared to gelatin (intensive care unit: SMD, −0.10; 95% CI, −0.15, −0.05; P = 0.0002) and crystalloids (hospital: SMD, −0.52; 95% CI, −0.90, −0.14; P = 0.007).
Conclusions
In this meta-analysis of RCTs, we could not identify safety issues with tetrastarches compared with other colloid or crystalloid solutions in terms of blood loss, transfusion requirements or hospital length of stay in patients undergoing cardiac surgery. The safety data on coagulation with older starches raise some issues that need to be addressed in future trials.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0656-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0656-0
PMCID: PMC4301454  PMID: 25475406
13.  The evidence for small-volume resuscitation with hyperoncotic albumin in critical illness 
Critical Care  2008;12(2):143.
Small-volume resuscitation of critically ill patients with hyperoncotic albumin offers a number of theoretical advantages, such as increasing intravascular volume in excess of the volume of fluid administered and reducing interstitial edema. Whilst iso-oncotic albumin has been shown to be equi-effective to isotonic saline for the resuscitation of critically ill patients without associated traumatic brain injury, the efficacy of hyperoncotic albumin for resuscitation has not been evaluated in large-scale randomized-controlled trials. Overall, the evidence for resuscitation with hyper-oncotic albumin is limited by studies of poor methodological quality with heterogenous study populations and control regimens. There is marginal qualitative evidence of improvements in surrogate outcomes in disparate patient populations, but no evidence of any survival benefit associated with resuscitation with hyperoncotic albumin. Given the lack of evidence and clinical uncertainty about the efficacy of hyperoncotic albumin, a large-scale randomized-controlled trial is required to determine its role in the acute resuscitation of hypovolemic or hypoalbuminemic critically ill patients.
doi:10.1186/cc6882
PMCID: PMC2447614  PMID: 18492216
14.  Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis 
Critical Care  2014;18(1):R10.
Introduction
In patients with acute respiratory distress syndrome (ARDS) fluid therapy might be necessary. The aim of this systematic review and meta-analysis is to determine the effects of colloid therapy compared to crystalloids on mortality and oxygenation in adults with ARDS.
Methods
Randomized controlled trials (RCTs) were identified through a systematic literature search of MEDLINE, EMBASE, CENTRAL and LILACS. Articles published up to 15th February 2013 were independently screened, abstracted, and assessed (Cochrane Risk of Bias Tool) to provide evidence-based therapy recommendations. RCTs were eligible if they compared colloid versus crystalloid therapy on lung function, inflammation, damage or mortality in adults with ARDS. Primary outcome parameters were respiratory mechanics, gas exchange lung inflammation and damage as well as hospital mortality. Kidney function, need for renal replacement therapy, hemodynamic stabilization and intensive care unit (ICU) length of stay served as secondary outcomes.
Results
A total of 3 RCTs out of 4130 potential trials found in the databases were selected for qualitative and quantitative analysis totaling 206 patients who received either albumin or saline. Overall risk of bias was unclear to high in the identified trials. Calculated pooled risk of death was not statistically significant (albumin 34 of 100 (34.0%) versus 40 of 104 (38.5%), relative risk (RR) = 0.89, 95% confidence interval (CI) 0.62 to 1.28, P = 0.539). Weighted mean difference (WMD) in PaO2/FiO2 (mmHg) improved in the first 48 hours (WMD = 62, 95% CI 47 to 77, P <0.001, I2 = 0%) after therapy start and remained stable after 7 days (WMD = 20, 95% CI 4 to 36, P = 0.017, I2 = 0%).
Conclusions
There is a high need for RCTs investigating the effects of colloids in ARDS patients. Based on the findings of this review, colloid therapy with albumin improved oxygenation but did not affect mortality.
doi:10.1186/cc13187
PMCID: PMC4056106  PMID: 24405693
15.  Choices in fluid type and volume during resuscitation: impact on patient outcomes 
We summarize the emerging new literature regarding the pathophysiological principles underlying the beneficial and deleterious effects of fluid administration during resuscitation, as well as current recommendations and recent clinical evidence regarding specific colloids and crystalloids. This systematic review allows us to conclude that there is no clear benefit associated with the use of colloids compared to crystalloids and no evidence to support the unique benefit of albumin as a resuscitation fluid. Hydroxyethyl starch use has been associated with increased acute kidney injury (AKI) and use of renal replacement therapy. Other synthetic colloids (dextran and gelatins) though not well studied do not appear superior to crystalloids. Normal saline (NS) use is associated with hyperchloremic metabolic acidosis and increased risk of AKI. This risk is decreased when balanced salt solutions are used. Balanced crystalloid solutions have shown no harmful effects, and there is evidence for benefit over NS. Finally, fluid resuscitation should be applied in a goal-directed manner and targeted to physiologic needs of individual patients. The evidence supports use of fluids in volume-responsive patients whose end-organ perfusion parameters have not been met.
doi:10.1186/s13613-014-0038-4
PMCID: PMC4298675  PMID: 25625012
Colloids; Crystalloids; Osmolality; Glycocalyx; Intravascular volume replacement; Systematic review
16.  Albumin administration is associated with acute kidney injury in cardiac surgery: a propensity score analysis 
Critical Care  2014;18(6):602.
Introduction
The risk of acute kidney injury (AKI) with the use of albumin-containing fluids compared to starches in the surgical intensive care setting remains uncertain. We evaluated the adjusted risk of AKI associated with colloids following cardiac surgery.
Methods
We performed a retrospective cohort study of patients undergoing on-pump cardiac surgery in a tertiary care center from 2008 to 2010. We assessed crystalloid and colloid administration until 36 hours after surgery. AKI was defined by the RIFLE (risk, injury, failure, loss and end-stage kidney disease) risk and Acute Kidney Injury Network (AKIN) stage 1 serum creatinine criterion within 96 hours after surgery.
Results
Our cohort included 984 patients with a baseline glomerular filtration rate of 72 ± 19 ml/min/1.73 m2. Twenty-three percent had a reduced left ventricular ejection fraction (LVEF), thirty-one percent were diabetics and twenty-three percent underwent heart valve surgery. The incidence of AKI was 5.3% based on RIFLE risk and 12.0% based on the AKIN criterion. AKI was associated with a reduced LVEF, diuretic use, anemia, heart valve surgery, duration of extracorporeal circulation, hemodynamic instability and the use of albumin, pentastarch 10% and transfusions. There was an important dose-dependent AKI risk associated with the administration of albumin, which also paralleled a higher prevalence of concomitant risk factors for AKI. To address any indication bias, we derived a propensity score predicting the likelihood to receive albumin and matched 141 cases to 141 controls with a similar risk profile. In this analysis, albumin was associated with an increased AKI risk (RIFLE risk: 12% versus 5%, P = 0.03; AKIN stage 1: 28% versus 13%, P = 0.002). We repeated this methodology in patients without postoperative hemodynamic instability and still identified an association between the use of albumin and AKI.
Conclusions
Albumin administration was associated with a dose-dependent risk of AKI and remained significant using a propensity score methodology. Future studies should address the safety of albumin-containing fluids on kidney function in patients undergoing cardiac surgery.
doi:10.1186/s13054-014-0602-1
PMCID: PMC4256900  PMID: 25394836
17.  Crystalloids vs. colloids: KO at the twelfth round? 
Critical Care  2013;17(3):319.
Expanded abstract
Citation
Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012, 367:1901-1911.
Background
The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported.
Methods
We randomly assigned 7,000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kDa and a molar substitution ratio of 0.4 (130/0.4, Voluven; Fresenius Kabi AG, Bad Homburg vor der Höhe, Germany) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal replacement therapy.
Objective
We conducted a large-scale randomized controlled trial to evaluate the safety and efficacy of 6% HES (130/0.4) in 0.9% saline as compared with 0.9% saline alone for fluid resuscitation in a heterogeneous population of adult patients in the ICU.
Design
The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) was an investigator-initiated, multicenter, prospective, blinded, parallel-group, randomized controlled trial.
Setting
The study was set at 32 hospitals in Australia and New Zealand.
Subjects
The subjects were adult patients (>18 years) who were admitted to the ICU and who required intravenous fluid above maintenance requirements determined by the treating clinician and supported by at least one objective physiological criterion. Patients were excluded if they received more than 1 L of 6% HES within 24 hours of screening or had one of the following: dialysis-dependent or impending dialysis renal failure, computed tomography evidence of non-traumatic intracranial hemorrhage (ICH) or severe traumatic ICH, creatinine of more than 3.9 mg/dL or urine output of less than 10 mL/hour for 12 hours, sodium of more than 160 meq/L, or chloride of more than 130 meq/L. Also excluded were females of childbearing age (unless proven not to be pregnant) and patients who had post-cardiac surgery status, liver transplant, or burns and those whose death was judged to be imminent or whose underlying disease process indicated a life expectancy of less than 90 days.
Intervention
If fluid was deemed necessary by the treating clinician by the parameters described above, the patient received 'study' fluid with identical packaging and appearance. The fluid was either 6% HES (130/0.4) in saline (Voluven) or 0.9% saline.
Outcomes
The primary outcome was death within 90 days. Secondary outcomes were acute kidney injury (AKI) and failure and treatment with renal replacement therapy.
Results
A total of 597 (18.0%) of 3,315 patients in the HES group and 566 (17.0%) of 3,336 in the saline group died (relative risk (RR) in the HES group 1.06, 95% confidence interval (CI) 0.96 to 1.18; P = 0.26). There was no significant difference in mortality in six predefined subgroups. AKI - defined by RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria - occurred in few patients receiving HES (34.6%) compared with saline (38%) (RR 0.91, 95% CI 0.85 to 0.97). However, renal replacement therapy was used in 235 (7.0%) of 3,352 patients in the HES group and 196 (5.8%) of 3,375 in the saline group (RR 1.21, 95% CI 1.00 to 1.45; P = 0.04). HES was significantly associated with more adverse events (5.3% versus 2.8%; P <0.001).
Conclusions
In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with6% HES (130/0.4) or saline. However, despite a lower overall rate of AKI, more patients who received resuscitation with HES were given renal replacement therapy. (The study was supported by the National Health and Medical Research Council of Australia; the Ministry of Health, New South Wales Government, Australia; and Fresenius Kabi; and by a Practitioner Fellowship from the National Health and Medical Research Council of Australia (to Drs Myburgh and Bellomo), by a Principal Research Fellowship from the National Health and Medical Research Council of Australia (to Dr Cass), and by a Practitioner Fellowship from the Medical Research Foundation of the Royal Perth Hospital (to Dr Webb); CHEST ClinicalTrials.gov number NCT00935168.)
doi:10.1186/cc12708
PMCID: PMC3706790  PMID: 23731998
18.  Albumin versus Other Fluids for Fluid Resuscitation in Patients with Sepsis: A Meta-Analysis 
PLoS ONE  2014;9(12):e114666.
Background
Early fluid resuscitation is vital to patients with sepsis. However, the choice of fluid has been a hot topic of discussion. The objective of this study was to evaluate whether the use of albumin-containing fluids for resuscitation in patients with sepsis was associated with a decreased mortality rate.
Methods
We systematically searched PubMed, EMBASE and Cochrane library for eligible randomized controlled trials (RCTs) up to March 2014. The selection of eligible studies, assessment of methodological quality, and extraction of all relevant data were conducted by two authors independently.
Results
In total, 15 RCTs were eligible for analysis. After pooling the data, we found there was no significant effect of albumin-containing fluids on mortality in patients with sepsis of any severity (RR: 0.94, 95% CI: 0.87, 1.02 and RD: –0.01, 95% CI: –0.03, 0.01). The results were robust to subgroup analyses, sensitivity analyses and trial sequential analyses.
Conclusion
The present meta-analysis did not demonstrate significant advantage of using albumin-containing fluids for resuscitation in patients with sepsis of any severity. Given the cost-effectiveness of using albumin, crystalloids should be the first choice for fluid resuscitation in septic patients.
doi:10.1371/journal.pone.0114666
PMCID: PMC4256427  PMID: 25474401
19.  Furosemide and albumin for diuresis of edema (FADE): a study protocol for a randomized controlled trial 
Trials  2014;15:222.
Background
Fluid retention is a common complication of critical illness. It typically results from large-volume fluid infusions during acute resuscitation and is worsened by hypoalbuminemia. Recognized as edema, fluid retention is important for its association with delayed weaning and increased mortality. The standard treatment is the administration of diuretics, with or without albumin. We hypothesize that intravenous 25% albumin plus furosemide, by comparison with furosemide alone, improves diuresis, oxygenation, and hemodynamic stability in the deresuscitation of critically ill, hypoalbuminemic patients. We propose a pilot study to determine the feasibility of a trial to investigate this hypothesis.
Methods/Design
FADE is a single-center, parallel, pilot randomized controlled trial. We aim to allocate 50 hemodynamically stable, hypoalbuminemic adult patients receiving diuresis to treatment with either 100 ml of either 25% albumin or normal saline placebo twice daily, for a total of six doses. Diuretics are to be prescribed by the caregiving team at least twice daily, and administered within 2 hours following study treatment. Patients, intensive care unit (ICU) clinicians, data collectors, and outcome adjudicators will be blinded to treatment allocation. Feasibility outcome measures include the proportion of patients receiving albumin within 2 hours of diuretic, the proportion of patients receiving the full six doses of study treatment, the proportion of patients who receive open label 25% albumin, and the rate of recruitment. Physiologic, laboratory, and clinical data are collected until discharge from the ICU or until 30 days.
Discussion
This is the first randomized trial to assess the use of hyperoncotic albumin in addition to diuretics in a general ICU population. Should this pilot study demonstrate feasibility, the primary outcome measure of the larger clinical trial will be the number of ventilator-free days, with secondary clinical outcome measures of duration of mechanical ventilation, length of ICU stay, episodes of hemodynamic instability and mortality. The addition of 25% albumin to standard diuretic therapy is a promising treatment in the post-resuscitation care of the critically ill patient.
Trial registration
ClinicalTrials.gov NCT02055872; ISRCTN70191881.
doi:10.1186/1745-6215-15-222
PMCID: PMC4059098  PMID: 24919684
Albumin; Critical care; Edema; Furosemide; Diuresis; Post-resuscitation
20.  Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units 
Critical Care  2010;14(5):R185.
Introduction
Recent evidence suggests that choice of fluid used for resuscitation may influence mortality in critically ill patients.
Methods
We conducted a cross-sectional study in 391 intensive care units across 25 countries to describe the types of fluids administered during resuscitation episodes. We used generalized estimating equations to examine the association between patient, prescriber and geographic factors and the type of fluid administered (classified as crystalloid, colloid or blood products).
Results
During the 24-hour study period, 1,955 of 5,274 (37.1%) patients received resuscitation fluid during 4,488 resuscitation episodes. The main indications for administering crystalloid or colloid were impaired perfusion (1,526/3,419 (44.6%) of episodes), or to correct abnormal vital signs (1,189/3,419 (34.8%)). Overall, colloid was administered to more patients (1,234 (23.4%) versus 782 (14.8%)) and during more episodes (2,173 (48.4%) versus 1,468 (32.7%)) than crystalloid. After adjusting for patient and prescriber characteristics, practice varied significantly between countries with country being a strong independent determinant of the type of fluid prescribed. Compared to Canada where crystalloid, colloid and blood products were administered in 35.5%, 40.6% and 28.3% of resuscitation episodes respectively, odds ratios for the prescription of crystalloid in China, Great Britain and New Zealand were 0.46 (95% confidence interval (CI) 0.30 to 0.69), 0.18 (0.10 to 0.32) and 3.43 (1.71 to 6.84) respectively; odds ratios for the prescription of colloid in China, Great Britain and New Zealand were 1.72 (1.20 to 2.47), 4.72 (2.99 to 7.44) and 0.39 (0.21 to 0.74) respectively. In contrast, choice of fluid was not influenced by measures of illness severity (for example, Acute Physiology and Chronic Health Evaluation (APACHE) II score).
Conclusions
Administration of resuscitation fluid is a common intervention in intensive care units and choice of fluid varies markedly between countries. Although colloid solutions are more expensive and may possibly be harmful in some patients, they were administered to more patients and during more resuscitation episodes than crystalloids were.
doi:10.1186/cc9293
PMCID: PMC3219291  PMID: 20950434
21.  Renal outcomes and mortality following hydroxyethyl starch resuscitation of critically ill patients: systematic review and meta-analysis of randomized trials 
Open Medicine  2009;3(4):e196-e209.
Background
Hydroxyethyl starch (HES) is a type of colloid fluid that is commonly used for volume resuscitation of patients admitted to the intensive care unit. Data regarding the renal consequences of HES are conflicting.
Purpose
To evaluate the effect of HES solutions on renal outcomes and mortality among critically ill patients requiring acute volume resuscitation.
Data sources
We searched electronic databases (MEDLINE, EMBASE, the Cochrane Central Registry of Controlled Trials and the SCOPUS database) from 1950 to 2008. Conference proceedings and grey literature sources were searched from 2002 to 2007.
Study selection
We included only randomized controlled trials of acute volume resuscitation of critically ill patients comparing HES fluid with an alternative resuscitation fluid.
Data synthesis
Two reviewers independently assessed trial eligibility, extracted data and evaluated trial quality. Random-effects models were used for all summary measures of effect.
Results
Twenty-two trials (n = 1865 patients) were included. Patients who received HES were more likely to have received renal replacement therapy (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.22–2.96, I2 9.5%, n = 749). There was no difference in overall mortality (OR 1.07, 95% CI 0.85–1.34, n = 1657). However, in trials that included patients with severe sepsis and septic shock, in high-quality and multicentre trials, and in trials with adequate allocation concealment, there was a trend toward increased risk of death in association with HES.
Limitations
Data regarding adverse events, including renal outcomes, were not reported in the majority of published randomized trials. Considerable clinical and methodologic heterogeneity existed among trials.
Conclusions
The use of HES for acute volume resuscitation of critically ill patients, and in particular those with severe sepsis and septic shock, appeared to be associated with increased use of renal replacement therapy. Further randomized controlled trials evaluating clinically important end points are required to examine the efficacy and safety of HES fluids for critically ill patients.
PMCID: PMC3090114  PMID: 21688756
22.  Are All Colloids Same? How to Select the Right Colloid? 
Indian Journal of Anaesthesia  2009;53(5):592-607.
Summary
The administration of intravenous fluids is one of the most common and universal interventions in medicine. Colloids are an alternative to the frequently used crystalloids, with highly variable use depending on a myriad of clinical variables. A colloid is defined as a high molecular weight (MW) substance that largely remains in the intravascular compartment, thereby generating an oncotic pressure. Colloids are considered to have a greater intravascular persistence when compared to crystalloids. All colloids, however, are clearly not the same. Differences in the physicochemical properties, pharmacokinetics and safety profile exist amongst various colloids. This review explores the different types of colloids, with their properties and usefulness as well as adverse effects. While all the available colloids are reviewed briefly (e.g., albumin, gelatin, dextran) with respect to their pharmacology, indications, advantages and disadvantages, particular emphasis is laid on the hydroxyethyl starches (HES) because of their rising prominence. It is shown that HES differ widely in their physicochemical and pharmacokinetic properties, composition, usefulness, and especially in their adverse effect profiles. The third generation HES (tetrastarches), in particular, seem to offer a unique combination of safety and efficacy. Several issues related to this are discussed in detail. This review of the available clinical data demonstrates that HES should not be regarded as one homogenous group, and data for one product should not be automatically extrapolated to another. Thus, among the synthetic colloids, the tetrastarches appear to offer the best currently available compromise between efficacy, safety profile, and cost. They also appear to be the best suited for use in the intensive care setting. Finally, balanced (rather than saline-based) HES solutions appear promising as a plasma-adapted volume replacement strategy and may further refine the ongoing quest of finding the ideal fluid therapy.
PMCID: PMC2900092  PMID: 20640110
Colloids; Albumin; Dextran; Gelatin; Hydroxyethyl starch; Tetrastarch
23.  Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis 
Objective To assess the effects of fluid therapy with hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin on mortality, kidney injury, bleeding, and serious adverse events in patients with sepsis.
Design Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.
Data sources Cochrane Library, Medline, Embase, Biosis Previews, Science Citation Index Expanded, CINAHL, Current Controlled Trials, Clinicaltrials.gov, and Centerwatch to September 2012; hand search of reference lists and other systematic reviews; contact with authors and relevant pharmaceutical companies.
Study selection Eligible trials were randomised clinical trials comparing hydroxyethyl starch 130/0.38-0.45 with either crystalloid or human albumin in patients with sepsis. Published and unpublished trials were included irrespective of language and predefined outcomes.
Data extraction Two reviewers independently assessed studies for inclusion and extracted data on methods, interventions, outcomes, and risk of bias. Risk ratios and mean differences with 95% confidence intervals were estimated with fixed and random effects models.
Results Nine trials that randomised 3456 patients with sepsis were included. Overall, hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin did not affect the relative risk of death (1.04, 95% confidence interval 0.89 to 1.22, 3414 patients, eight trials), but in the predefined analysis of trials with low risk of bias the relative risk of death was 1.11 (1.00 to 1.23, trial sequential analysis (TSA) adjusted 95% confidence interval 0.95 to 1.29, 3016 patients, four trials). In the hydroxyethyl starch group, renal replacement therapy was used more (1.36, 1.08 to 1.72, TSA adjusted 1.03 to 1.80, 1311 patients, five trials), and the relative risk of acute kidney injury was 1.18 (0.99 to 1.40, TSA adjusted 0.90 to 1.54, 994 patients, four trials). More patients in the hydroxyethyl starch group were transfused with red blood cells (1.29, 1.13 to 1.48, TSA adjusted 1.10 to 1.51, 973 patients, three trials), and more patients had serious adverse events (1.30, 1.02 to 1.67, TSA adjusted 0.93 to 1.83, 1069 patients, four trials). The transfused volume of red blood cells did not differ between the groups (mean difference 65 mL, 95% confidence interval −20 to 149 mL, three trials).
Conclusion In conventional meta-analyses including recent trial data, hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin increased the use of renal replacement therapy and transfusion with red blood cells, and resulted in more serious adverse events in patients with sepsis. It seems unlikely that hydroxyethyl starch 130/0.38-0.45 provides overall clinical benefit for patients with sepsis.
doi:10.1136/bmj.f839
PMCID: PMC3573769  PMID: 23418281
24.  The appropriate role of colloids in managing fluid imbalance: a critical review of recent meta-analytic findings 
Critical Care  2000;4(Suppl 2):S26-S32.
Three meta-analyses have recently been reported on the relationship between choice of resuscitation fluid and risk of mortality in critically ill patients. The relative risk of death (1.16-1.19) in two of the meta-analyses was slightly higher in colloid than crystalloid recipients; however, this observation was not statistically significant. In the third meta-analysis, 6% (95% confidence interval [CI], 3-9%) pooled excess mortality was documented in patients receiving albumin for hypovolaemia, burns or hypoalbuminaemia. The mortality difference in hypovolaemia patients (4%; 95% CI, 0-8%) was not statistically significant. A variety of serious limitations apply to the three meta-analyses, suggesting that their findings be interpreted cautiously. More than one-half of the randomized controlled trials (RCTs) included in the meta-analyses were reported prior to 1990 and hence do not reflect current practice. Each meta-analysis included only a subset of relevant RCTs, and therefore the scope of inferences to be drawn from the meta-analytic results is limited. The meta-analyses combined RCTs that were notably heterogeneous with respect to patient characteristics, type of illness, administered fluids and physiologic endpoints. Differences in illness severity, concomitant therapies and fluid management approaches were not taken into account. Very few of the RCTs were blinded. The meta-analyses do not support the conclusion that choice of resuscitation fluid is a major determinant of mortality in critically ill patients, nor do they support changes to current fluid management practice. Changes such as exclusive reliance on crystalloids would necessitate a reassessment of the goals and methods of fluid therapy. Since the effect on mortality may be minimal or non-existent, choice of resuscitation fluid should rest on whether the particular fluid permits the intensive care unit to provide better patient care.
doi:10.1186/cc967
PMCID: PMC3226172  PMID: 11255596
colloids; hetastarch; meta-analysis; mortality; serum albumin
25.  Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized clinical trials 
Critical Care  2008;12(2):R34.
Background
Small-volume resuscitation can rapidly correct hypovolemia. Hyperoncotic albumin solutions, long in clinical use, are suitable for small-volume resuscitation; however, their clinical benefits remain uncertain.
Methods
Randomized clinical trials comparing hyperoncotic albumin with a control regimen for volume expansion were sought by multiple methods, including computer searches of bibliographic databases, perusal of reference lists, and manual searching. Major findings were qualitatively summarized. In addition, a quantitative meta-analysis was performed on available survival data.
Results
In all, 25 randomized clinical trials with a total of 1,485 patients were included. In surgery, hyperoncotic albumin preserved renal function and reduced intestinal edema compared with control fluids. In trauma and sepsis, cardiac index and oxygenation were higher after administration of hydroxyethyl starch than hyperoncotic albumin. Improved treatment response and renal function, shorter hospital stay and lower costs of care were reported in patients with liver disease receiving hyperoncotic albumin. Edema and morbidity were decreased in high-risk neonates after hyperoncotic albumin administration. Disability was reduced by therapy with hyperoncotic albumin in brain injury. There was no evidence of deleterious effects attributable to hyperoncotic albumin. Survival was unaffected by hyperoncotic albumin (pooled relative risk, 0.95; 95% confidence interval 0.78 to 1.17).
Conclusion
In some clinical indications, randomized trial evidence has suggested certain benefits of hyperoncotic albumin such as reductions in morbidity, renal impairment and edema. However, further clinical trials are needed, particularly in surgery, trauma and sepsis.
doi:10.1186/cc6812
PMCID: PMC2447554  PMID: 18318896

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