Intensive Care Med DOI 10.



The SAFE Study Investigators

Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis

Abstract Purpose: To determine the effect of random assignment to fluid resuscitation with albumin or Ó Copyright jointly held by Springer and saline on organ function and mortality ESICM 2010 in patients with severe sepsis. Methods: Pre-defined subgroup The Saline versus Albumin Fluid Evaluation (SAFE) Study is a collaboration analysis of a randomized controlled of the Australian and New Zealand trial conducted in the intensive care Intensive Care Society Clinical Trials Group (ANZICS CTG), the Australian Red units of 16 hospitals in Australia and New Zealand. Results: Of 1,218 Cross Blood Service, and the George Institute for International Health. The patients with severe sepsis at basewriting committee (Simon Finfer, Suzanne line, 603 and 615 were assigned to McEvoy, Rinaldo Bellomo, Colin receive albumin and saline, respecMcArthur, John Myburgh, and Robyn Norton) takes responsibility for the content tively. The two groups had similar of this article. The SAFE Study baseline characteristics. During the Investigators are listed in full in the first 7 days mean arterial pressure Appendix. was similar in the two groups, but patients assigned albumin had a lower Electronic supplementary material The online version of this article heart rate on days 1 and 3 (p = 0.002 (doi:10.1007/s00134-010-2039-6) contains and p = 0.03, respectively) and a supplementary material, which is available higher central venous pressure on to authorized users. days 1–3 (p \ 0.005 each day). There was no difference in the renal or total Sequential Organ Failure Assessment The SAFE Study Investigators ()) score of the two groups; 113/603 The SAFE Study Investigators, (18.7%) of patients assigned albumin c/o ANZICS CTG (Prof. S. Finfer), were treated with renal replacement Level 3, 10 Ievers St., Carlton, therapy compared to 112/615 (18.2%) VIC 3053, Australia assigned saline (p = 0.98).The unade-mail:; justed relative risk of death for
Received: 31 December 2009 Accepted: 22 July 2010

albumin versus saline was 0.87 [95% confidence interval (CI) 0.74–1.02] for patients with severe sepsis and 1.05 (0.94–1.17) for patients without severe sepsis (p = 0.06 for heterogeneity). From multivariate logistic regression analysis adjusting for baseline factors in patients with complete baseline data (919/1,218, 75.5%), the adjusted odds ratio for death for albumin versus saline was 0.71 (95% CI: 0.52–0.97; p = 0.03). Conclusions: Administration of albumin compared to saline did not impair renal or other organ function and may have decreased the risk of death. Keywords Critical care Á Fluid therapy Á Sepsis Á Mortality Á Multicenter randomized clinical trial

The type of fluid indicated for critically ill patients with severe sepsis is the subject of ongoing debate. In 2008, updated management guidelines for fluid resuscitation of patients with severe sepsis or septic shock were published

by the Surviving Sepsis Campaign [1]. No specific recommendations were made in relation to the type of fluid to be used, and the authors considered there was insufficient evidence to recommend the use of colloids over crystalloids. Surveys of clinicians’ preferences and practices support the view that the absence of strong evidence

The primary outcome was all-cause mortality within 28 days of randomization. Patients admitted to the ICU after cardiac surgery. heart rate. The conduct of the SAFE study was approved by the ethics . In this report we describe baseline characteristics of the patients in detail and report the effect of albumin administration compared to saline on organ function and mortality. for intravenous drug administrations.. CSL Limited. a detailed report of this cohort of patients has not been published. This double-blind. Secondary outcomes were length of stay in the ICU. CVP. 3 or 4. serum albumin concentration and renal. Definitions Severe sepsis at baseline was defined by the presence of a defined focus of infection and at least two of the four systemic inflammatory response syndrome (SIRS) criteria and infection-related organ dysfunction [12]. To account for withinpatient correlation.g. hepatic. a prospectively defined subgroup of patients with severe sepsis at the time of randomization suggested a differential treatment effect favoring albumin. in a randomized controlled trial in patients with cirrhosis and spontaneous bacterial peritonitis.9% sodium chloride (saline) for all fluid resuscitation in the ICU until death. Furthermore. respiratory. Eligible adult patients were randomly assigned to receive either 4% albumin (ALBUMEXÒ. Melbourne. hepatic and coagulation [14]. 11]. cardiovascular SOFA score of 1. where the admission diagnosis did not specify the source of sepsis. Possible explanations for this finding include imbalance in baseline risk factors for mortality. particularly some starch solutions. A defined focus of infection was indicated by either (1) an organism cultured from blood or a sterile site. as were resuscitation endpoints (for example. randomized controlled trial was conducted in the multidisciplinary ICUs of 16 hospitals in Australia and New Zealand between November 2001 and June 2003. Statistical analysis All analyses were run in SPSS Version 14. The source of sepsis was derived from the ICU admission diagnosis. this was determined by retrospective review of the original medical record. cardiovascular. Organ dysfunction was compared between groups based on the mean daily ICU SOFA score for the following components: renal. Independent sample t tests were conducted to assess differences in daily mean volume of fluid administered by treatment group on days 1 to day 3. Materials and methods Study setting and subjects Detailed descriptions of the SAFE Study have been published elsewhere [10. hematologic or hepatic SOFA score greater than 1. pneumonia. There is accumulating evidence that colloids. duration of mechanical ventilation and duration of renal replacement therapy.0. coagulation and total SOFA scores through the first 7 days were also analyzed using a linear mixed model with compound symmetry covariance structure.has resulted in wide variations in both preferences and practice [2. skin or soft tissue infection). We documented the administration of study fluid. in two randomized studies of children with severe malaria. imbalance in intravascular volume expansion or other concomitant treatments or that resuscitation with albumin confers a mortality benefit. respiratory. Infection-related organ dysfunction was defined using the Sequential Organ Failure Assessment (SOFA) score that most closely reflects organ dysfunction criteria commonly used in sepsis trials [13]. the addition of an albumin infusion to antibiotic treatment significantly reduced the incidence of renal impairment and death [9]. liver transplantation or for the treatment of burns were excluded. or (2) an abscess or volume of infected tissue (e. length of stay in hospital. blood products and non-study fluid. The mean volume (±SD) of fluid administered in the ICU by treatment allocation for days 1–7 was calculated. The Saline versus Albumin Fluid Evaluation (SAFE) Study was a blinded. or renal SOFA score greater than 2. Australia) or 0. Descriptive analyses were conducted to illustrate the baseline characteristics of patients with and without severe sepsis and to compare the baseline characteristics of patients with severe sepsis assigned to albumin or saline. However. peritonitis. committees of the University of Sydney and of each participating institution. While mortality at 28 days for this group has been reported. the overall differences by treatment group in mean arterial pressure. randomized controlled trial that reported no material difference in the overall risk of death for a heterogeneous population of adult patients administered albumin or saline for intravascular fluid resuscitation in intensive care units (ICUs) [10]. 3]. may increase morbidity and mortality in patients with septic shock [4–6]. cardiovascular. albumin conferred a survival advantage when compared with both normal saline and gelatin [7. Organ dysfunction was considered to be present if as at least one of the following was present: respiratory. Non-study fluid included intravenous fluids given as maintenance fluids. discharge or 28 days after randomization. mean arterial pressure and central venous pressure (CVP)) over the same timeframe. 8]. However. parenteral and enteral feeding solutions and any oral intake.

04.218 patients with severe sepsis at baseline. 113/603 (18. respiratory.3) (Fig. The mean CVP was significantly higher on days 1–3 in the albumin group. saline 11.78–1. Levene’s test for equality of variances was reviewed.2 vs. Compared to those without severe sepsis at enrollment. majority of patients with severe sepsis were admitted as medical patients (78. days on mechanical ventilation and days on renal replacement therapy. patients with severe sepsis were significantly older. p = 0.1) versus 72.We report the effect of treatment allocation on 28-day mortality for patients with severe sepsis at baseline.0–2. each baseline parameter was assessed in a series of univariate models with mortality as the outcome.0%) of patients did not have a CVP recorded prior to randomization. For the latter.03. Patients with severe sepsis assigned to albumin or saline had similar baseline characteristics except that the mean (SD) mean arterial pressure was higher in those assigned to saline. All analyses other than the multivariate analyses were conducted on an intent-to-treat basis. The hepatic SOFA score was significantly higher in the albumin group during the first 7 days.5) mmHg. to be receiving renal replacement.6 (15.2%) assigned saline (OR 1. Patients allocated to saline received significantly higher volumes of the study fluid for the first 3 days. the ratio of volume of saline to albumin administered on days 1–3 was 1.5 (16.7%) assigned albumin compared to 112/615 (18. 95% CI for difference 1. The number of patients treated with renal replacement therapy was similar in the two groups. Results The baseline characteristics of the two treatment groups for all randomized patients were similar and have been published previously [10].8 vs. namely the mean number of days in the ICU. 1). 95% CI 0.1) (Fig.7. 95% CI for difference -1. saline 99. 74. packed red cells. the maximal difference was on day 2 (albumin 12. The effect of treatment allocation on secondary outcomes. Of the variables collected as baseline characteristics. renal or coagulation systems during the first 7 days. To confirm the exclusion of these variables. There were 1. 1). we report mortality by baseline serum albumin concentration dichotomized a priori at 25 g/l [15]. 1). renal. and the variable was excluded if the LR test p C 0. Additionally.15 were included in the multivariate model.3 to -6. At each step. Source of sepsis was similar in the two groups (Table 1). There were no significant differences by treatment group in the proportion of patients treated with mechanical ventilation or vasopressors or inotropic drugs during the study period. of whom 603 were assigned to receive albumin and 615 to receive saline. hospital. The mean heart rate measurements were significantly higher on days 1 and 3 in the saline group. CVP was excluded from the analysis because 707 (58. number of days in hospital. difference 1. other) within 28 days by treatment allocation was also assessed. There were no significant differences in mean arterial pressure over days 1–7 by treatment group (Fig. the likelihood ratio (LR) test assessed a change in the model. difference -3. 1). 2. were more likely to have acute respiratory distress syndrome.0 beats per minute. There were no significant differences in the volume of other fluids administered during the first 3 days (or subsequently–data not shown). total fluids and number of patients treated with mechanical ventilation or vasopressors or inotropic agents in the 3 days following randomization are shown in Tables 2 and 3. respiratory. A survival analysis was conducted and presented as Kaplan-Meier curves.05 and/or removal resulted in a change of less than 20% in the coefficient of the treatment arm variable. hepatic and coagulation domains for patients remaining in the ICU are presented in Fig. p = 0. we undertook a complete case analysis approach and excluded patients from the multivariate analysis if any baseline parameter other than CVP was missing. In addition. and the average serum albumin levels were significantly higher in the albumin group throughout the 7-day period (Fig. we conducted a multivariate analysis to assess 28-day mortality by treatment group after adjustment for baseline characteristics. Progress in the ICU The volume of study and non-study fluids administered.98).43. and the appropriate results are given. were also examined. The . Otherwise. the maximal difference was on day 1 (albumin 95.2%). a likelihood ratio test was undertaken between the ‘base’ model. Organ dysfunction Daily mean (SD) SOFA scores for the cardiovascular. v2 tests were performed for the analysis of categorical variables and independent sample t tests for continuous variables. and to have higher Acute Physiology and Chronic Health Evaluation (APACHE) II [16] and SOFA scores (Electronic supplement Table E1). There was no significant difference between groups in the SOFA scores for the cardiovascular.1 mmHg. Following analysis of baseline characteristics. parameters with a p value of \0.38. Location of death (ICU. that being mortality status as the outcome variable and treatment arm as a forced independent variable.7.

5%).6 ± 15.97.1 351 (57. heart rate (17/1.0. p value for heterogeneity = 0.5%) 27 (4..218: 2.33) 39 (6.5%) 4 (0.74. Unadjusted mortality rates by treatment group for this sample were similar to the whole cohort for patients assigned to both albumin [137/452 (30.2) 8 (1.8 72.0%).8) 266 (44.3) 25..0) 2 (0. %) APACHE IIa score (mean ± SD) Mean arterial pressure (mean ± SD.3%) 53 (8.71. ..8) 365 (59.3) 9 (1.4%) in the saline group died within 7 days.2) 1 (0.8%) 5 (0.2 359 (59.2%) 4 (0..5%) 3 (0. mmHg) Renal replacement therapy (no.5%) assigned saline died elsewhere in the hospital.7%) 27 (4.0%) 3 (0.9%).3 n total number of patients per group a Acute physiology and chronic health evaluation b Septic shock indicates cardiovascular Sequential Organ Failure Assessment (SOFA) score of 3 or 4 (data missing for two patients assigned albumin and one assigned saline) Primary and secondary outcomes Mortality Among patients with severe sepsis. SOFA coagulation score (32/1.Table 1 Comparison of baseline characteristics of patients with severe sepsis assigned albumin or saline Characteristic Age (mean ± SD in years) Gender: male (no.5%) 7 (1.5) 21.218: 2.50–1. 95% CI 0.9%) 144 (23. renal SOFA score (24/1.35 0.218: 1. Variables with missing data at baseline included CVP (707/1.1%) 130 (21. 95% CI 0... 185 (30.21 1 1 0. mmHg) Septic shockb (no. ventilation status (2/1. 121 patients (20.57–1. In most cases the data were missing because a parameter or laboratory value had not been measured prior to commencing fluid resuscitation.218: 11.4) 258 (41.3%) 6 (1.83%) 17 (2. The results of the multivariate analysis are given in Table 4.03).02.1%) 14 (2.218: 2. %) Traumatic brain injury (no.35 0.6%) 7 (1.1) 143 (23. %) Adult respiratory distress syndrome (no.2 23 (3.33%) 6 (1. cardiovascular SOFA score (3/1.6%) assigned albumin and 40 (6. %) Trauma (no. 34 patients (5. 185/603 (30. serum albumin concentration (109/1. 95% CI 0.218: 58%).10. no patients with severe sepsis at baseline died following hospital discharge.16%). p = 0.3%) vs.8) 21.1%) 38 (6.5 ± 17.1 229 (37.7%).7%) 9 (1. assignment to albumin was independently associated with a decreased odds ratio for death at 28 days (OR 0.4 17 (2.218: 0.7 74.3%) 47 (7.6 0. The treatment effect was similar in patients whose baseline serum albumin concentration was B25 g/l or [25 g/l (OR 0.4%) 35 (5.2%) Saline group (n = 615) 61.4%) 8 (1. %) Admission: surgical (no.09.6%).8) 25. Overall.0% of the albumin group and 177.8%) 7 (1. %) Source of sepsis Pulmonary Intra-abdominal Blood Skin and soft tissue Urinary tract Vascular catheter-related Central nervous system Bone Pleural Cardiac ENT Gynecological Neutropenic sepsis No confirmed source Multiple sources suspected Albumin group (n = 603) 60.7%)] and saline [166/ 467 (35. 28.218: 11. 217/615 (35. most patients died in the ICU (151.87.218: 0.80: see electronic supplement for Kaplan-Meier estimates for probability of survival for patients with baseline serum albumin concentration was B25 g/l or [25 g/l).0 ± 7.5 ± 16. Mortality adjusted for potential baseline confounding The final sample for multivariate analysis was 919 patients.2 ± 7.62 0.5% of the initial sample.6 ± 7. 95% confidence interval 0.03 0.36 0.8 ± 7. 75.2%).33%) 42 (6.11 and OR 0.002%).3%) assigned saline died (odds ratio 0.5) 2 (0.5 209 (34. %) Serum albumin (mean ± SD.6%) 37 (6.218: 8.0 ± 17.109 patients: 541 assigned albumin and 568 assigned saline.3%) p value 0.4%) and mean arterial pressure (33/1.8% of the saline group). Baseline serum albumin concentration was available for 1.52–0. During the 28-day follow-up period.8) 342 (56.7%) 45 (7.69 0. %) Mechanical ventilation (no.5%) vs.3) 2 (0. after adjustment for baseline characteristics.17%) 7 (1.34 0.79. hepatic SOFA score (136/1..2% 1 (0. Table 3).1%) in the albumin group and 138 patients (22.7%) assigned albumin died. and 217 (35. Of these. p = 0. respiratory SOFA score (140/1.74–1..82 0.6) 122 (20. 25.3%)].

35 (0.66–1.591 (94.0) 112 ± 320 (17.1) 77 ± 227 (13.7) 283 ± 560 (33.56 -0.80–2.55 0.7) 36 (8.2 1.8) 77 ± 271 (11.26 0.746 ± 1.66 to to to to 0.5) 3.16 0.58 (-1.49 (-1.Table 2 Treatments administered during the first 3 days in the ICU Severe sepsis at baseline Albumin group No.53 0.004 0.4) 88 ± 277 (12.412 (99.1 ± 9.5) 2.001 0.20) 0.22 0. and (%) receiving 1.5 ± 6.101 3.924 3.339 ± 1.575 ± 1.3) 26 (6.24 0.08 0.5) 416 (73.0) Saline group No.764 3.382 ± 2.6) 135 (35. packed cells.2 1.0) 2.8) 78 ± 269 (11.56 0.5) 142 (38.069 (57.9 5.267 ± 2. saline) p value Study fluid Day 1a 599 Day 2 556 Day 3 467 Non-study fluidb Day 1a 593 Day 2 556 Day 3 466 Packed cells Day 1a 599 Day 2 556 Day 3 467 Total fluidsc Day 1a 601 Day 2 556 Day 3 467 Mechanical ventilation a Day 1 602 Day 2 560 Day 3 468 Vasopressorsd a Day 1 597 Day 2 558 Day 3 466 614 567 458 613 567 457 613 567 458 615 567 457 614 567 459 613 565 458 -407 -434 -176 -69 -52 -43 -1 24 21 -511 -426 -223 \0.55 0.21 No. Subsequent days were 24-h periods apart from the day of discharge from the ICU.5) 2.69 -0.342 (99. which also varied according to the time of discharge Refers to non-study.2) 7.28) 0.09 0. replacement therapy mean ± standard deviation for continuous variables a Duration of mechanical ventilation and renal replacement therapy is per group.3) 8.347 (99.011 ± 1. non-blood product fluids—includes fluid given for drug delivery. and (%) receiving 1.8) 338 (72.522 ± 2.1 0.0) 1.001 \0.149 (98.2 ± 7.31 (-0.0 ± 3.4) 340 (74.0) 2.023 439 (71.3) 754 ± 1.19) -0.841 ± 2.506 ± 1.87 (0.09 0.188 ± 1.7 15.001 0. maintenance hydration and both enteral and parenteral nutrition c Includes study and non-study fluids. denominator is all patients in group .63) 0.0) 459 ± 897 (41.0 ± 7.2) 1.42 0.28 (-1.7) 56 ± 249 (8.755 ± 1. ranging up to 24 h.842 ± 1.894 ± 1.47 -0.159 ± 1.5) 3. Study fluid (ml) mean ± SD or no.15 0.393 (100. This means that the duration of day 1 was variable in length.97 0. (%) Dead Alive in ICU Alive in hospital Duration of stay in ICU (days) Duration of hospital stay (days) Duration of mechanical ventilation (daysa) Duration of renal replacement therapy (daysa) Albumin group (n = 603) 185 (30. fresh frozen plasma and platelets d Vasopressors indicates number of patients with cardiovascular SOFA score of 3 or 4 Table 3 Primary and secondary outcomes in patients with severe sepsis Outcome Severe sepsis at baseline Status at 28 days: no.6 Saline group (n = 615) 217 (35.19 \0.3) 402 (71.5 16.4 ± 6.02) 1.34 0.001 \0.6) 395 (69.7 6.7) 261 (56.6) 1.09) 0.798 ± 1.2 ± 3.6 ± 9.88 (0. represents the number of patients in each group still in the ICU Mean ± standard deviation (SD) rounded to the nearest integer a Day 1 was the period between randomization and the end of the first day as defined by a given ICU.2) 382 (64.507 4.801 411 (68.0) 372 (66.64 0. Study fluid (ml) mean ± SD or no.1) 402 (65.40 0.11) 0.529 (99.0) b Mean difference (albumin vs.772 (66.9) 275 (60.14 Odds ratio (95% CI) Absolute difference (95% CI) p value whether or not they received mechanical ventilation and renal Referent group = saline Absolute number and percentage for categorical variables.090 (94.74–1.

. less likely to have been admitted to the ICU following surgery and had higher APACHE II and SOFA scores indicating greater severity of illness and greater degree of organ dysfunction. Discussion Statement of principal findings In comparison with patients without severe sepsis. mortality at 28 days was lower in those assigned albumin. mean number of days on renal replacement therapy and mean number of days on mechanical ventilation (Table 4).0002 Albumin Saline Serum Albumin (g/L) 30 25 20 15 10 5 0 P<0. were similar in those assigned to albumin or saline except that those assigned to albumin had modestly but statistically significantly lower mean arterial pressure. the difference fell short of statistical significance.Mean arterial pressure (mmHg) Fig. including source of sepsis. For the first 7 days following randomization. the cardiovascular SOFA score was lower in those assigned albumin. was worse in those assigned albumin on each of the first 7 days. The baseline characteristics of patients with severe sepsis. which is derived from the serum bilirubin concentration. those with severe sepsis at baseline were somewhat older. mean arterial pressure was similar in the two groups. However.3056 Albumin Saline 82 80 78 76 74 72 70 P=0. but other indices of intravascular volume status (heart rate and CVP) suggested greater intravascular volume expansion in those resuscitated with albumin. Analysis of SOFA scores indicated that hepatic SOFA score. 1 Mean (SD) mean arterial pressure. mean number of days in hospital. (p value from linear mixed model with compound symmetry covariance structure) 90 88 86 108 106 104 102 100 98 96 94 92 90 88 86 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 P=0.0001 6 7 0 1 2 3 4 5 6 7 Day Day Albumin Still in ICU Alive but not in ICU Dead Saline Still in ICU Alive but not in ICU Dead Randomization 603 0 0 615 0 0 1 561 17 25 570 13 29 2 475 70 58 464 81 70 3 388 133 82 388 135 92 4 328 174 101 331 174 110 Day 5 288 204 111 286 205 124 6 253 225 125 250 227 138 7 213 252 138 209 252 154 Secondary outcomes There was no significant difference between groups in the mean number of days in the ICU. and the difference reached borderline statistical significance after correction for baseline characteristics. and while this is indicative of less vasopressor use in those assigned albumin. central venous pressure and serum albumin concentration at baseline (day 0) and on days 1–7 post-randomization for patients still in the ICU. heart rate. For patients remaining in the ICU.9801 Albumin Saline Heart rate (bpm) 84 Day 16 40 Albumin Saline 35 Day Central venous pressure (mmHg) 14 12 10 8 6 4 0 1 2 3 4 5 P=0.

4 3. A further weakness is that not all patients could be included in the multivariate analysis. for example to 90 days. number of observations per day given in table Strengths and weaknesses of the study The strengths of study include that the data derive from an a priori subgroup of a large blinded.5 1 0.2085 Albumin Saline 6 7 0 1 2 3 4 5 6 7 Day Day Albumin Still in ICU Alive but not in ICU Dead Saline Still in ICU Alive but not in ICU Dead Randomization 603 0 0 615 0 0 1 561 17 25 570 13 29 Day 2 475 70 58 464 81 70 3 388 133 82 388 135 92 4 328 174 101 331 174 110 5 288 204 111 286 205 124 Day 6 253 225 125 250 227 138 7 213 252 138 209 252 154 Fig. Patients were excluded on the basis of data missing primarily because fluid resuscitation was not delayed to collect non-routine samples for laboratory data or was commenced before parameters such as the CVP could be measured.0816 2.5 2 1. early goal-directed therapy [21]. randomized clinical trial. such as drotrecogin alfa (activated) [13]. The choice of all-cause mortality at 28 days may be considered a relative weakness as recent trials suggest that longer follow-up.5 0 0 1 2 3 4 5 6 7 P=0. As patients were excluded based on pre- . to date. we were unable to collect detailed microbiological data or data on concomitant treatments.1606 Albumin Saline 15 12.5 5 2. the largest group of patients with severe sepsis to have been randomly assigned to one of two resuscitation fluids and their baseline characteristics are similar to previously reported cohorts [17–19].5 0 0 1 2 3 4 5 P=0.5 0 0 1 2 3 4 5 6 7 P=0.5 Total SOFA score SOFA score SOFA score 2. and an imbalance in concomitant treatments favoring those assigned to albumin might have influenced the results.5 0 0 1 2 3 4 5 6 7 P=0. low-dose corticosteroids [22] and intensive insulin therapy [23].5 1 0. are now questioned [20.5 1 0.5 0 0 1 2 3 4 5 P=0. As the SAFE study was a large pragmatic trial.9206 Albumin Saline 6 7 Day 4 3.5 0 P=0. the efficacy of treatments. However.5 2 1.5 3 4 Day 20 Day Hepatic Albumin Saline 3.1992 2.5 3 4 Cardiovascular Albumin Saline 3.5 2 1.5 10 7.5 3 Coagulation 17. The weaknesses of our study are that it is a subgroup of a larger trial and so the sample size was not predetermined. and the trial was not primarily designed to examine the relative benefits of albumin and saline in severe sepsis.0001 2. (p value from linear mixed model with compound baseline (Day 0) and for days 1–7 post-randomization for patients symmetry covariance structure) still in the ICU. 24–26].5 1 0. 2 Mean (SD) SOFA scores by domain and total SOFA at below figure. This subgroup is.5 3 Renal SOFA score SOFA score SOFA score 2.5 3 Respiratory Albumin Saline 4 3. is needed to determine the important effects of treatments in critically ill patients [20].5 2 1. all of which appeared promising at the time the SAFE study was conducted.5 2 1.5 1 0.

01 1. In addition.05 1. the difference in the mean heart rate and CVP was small and probably undetectable in normal clinical practice. which weakens the inferences that can be drawn from these data. for acute physiology and chronic health evaluation II score. liver Heart rate Serum albumin Sepsis source Pulmonary Intra-abdominal Urinary Other confirmed source Reference or unit of change Saline Female Per 1 year increase Non-operative Per 1 point increase Per 1 point increase Per 1 point increase Per 1 point increase Per 1 g/l decrease No confirmed source p value Odds ratio (95% CI) 0. this contrasts with the result observed in the whole SAFE study cohort where the relative risks of death for these groups of patients were 0.71 (0. these include increasing plasma anti-oxidant capacity [27]. coagulation SOFA. Of note.25 0. our data raise the possibility that on a population basis. although the difference did not reach statistical significance. 31].01 0.03–1. for SOFA score. Nevertheless.34–1.00–1. the cardiovascular SOFA score was lower in those patients assigned albumin. Another possibility is that correcting hypoalbuminemia may be beneficial in patients with severe sepsis as the mean serum albumin concentration was higher in those assigned albumin.62) (0.27–1.001 0.03–1.15 1.40 1.04 0.03–1. per 1 beat per minute increase in rate.80) (1.2 0.87 and 1.05 0.10–0. inhibiting TNFa-induced expression of vascular cell adhesion molecule-1 and nuclear factor-jB (NF-jB) activation [28]. per 1 point increase.30–0.005 \0.001 \0.03 0.001 0.04 0.39) (0.09 \0. The increased bilirubin concentration is most likely explained by the presence of bilirubin in albumin solutions (such as the ALBUMEXÒ used in the SAFE study) prepared by chromatographic fractionation [32].19–0. per 1 unit increase in g/L randomization events at which time treatment allocation was concealed.37) (1.58 (1. Our study was not designed to investigate cellular or molecular mechanisms.69 0.02) (1. the same ratio as in the entire cohort of the SAFE Study [10]. and similar to the ratio reported by other trials comparing crystalloid and colloid solutions in patients with severe sepsis.07) (1. The ratio of saline to albumin volume administered during the first 3 days was 1.52–0. SOFA scores were not collected after patients were discharged from the ICU. and as such it does not represent an adverse effect of albumin administration per se.08) (0.02–1.43 0. or improving lung function [29]. per 1-year increase in age. it is unlikely that these exclusions have materially influenced our results.001 0. respectively [15]. which suggested that adverse effects were limited to hyperoncotic colloid solutions [6]. for heart rate.04 \0.49 1.05) (0. However. the renal component of the SOFA score and the number of patients treated with and duration of treatment with renal replacement therapy were similar in the two groups.003 0. .3 0.4:1. the relative risk of death for patients assigned albumin versus saline was similar in patients whose baseline serum albumin concentration was less than or equal to 25 g/l or greater than 25 g/l.20 1.03–1. We did observe increased hepatic SOFA scores in those assigned albumin. This is consistent with the results of the CRYCO study.Table 4 Odds ratios (95% CI) for 28-day mortality for albumin relative to saline adjusted for baseline covariates Characteristic Treatment assignment Albumin Baseline covariates Male Age Postoperative admission APACHE-II Score SOFA.96) (0. In contrast with studies of other fluids [5.41) (0.97) 1.24) For age.93) (1.98–1. A simpler explanation for our results may be that albumin resulted in better intravascular volume expansion as evidenced by higher CVP and lower heart rates between days 1 and 3.09. and does not provide support for the hypothesis that albumin improves lung function as the respiratory SOFA scores were not reduced in the patients who received albumin. small differences in intravascular volume status might give rise to significant differences in mortality. indicating that the bilirubin concentration was increased. we did not detect evidence that resuscitation with albumin adversely affected renal function. Meaning of the study in relation to other results There are a number of potential mechanisms by which albumin might exert beneficial effects in patients with severe sepsis. This apparent inconsistency is explained by the latter group containing the majority of patients with traumatic brain injury in whom assignment to albumin was associated with increased mortality [30]. for serum albumin. per 1-point increase in score.

Manuela Schmidt. NSW: Catherine Powell. NSW: Lesley Francis. New Zealand. Bruce Neal. Anne O’Connor. Sameer Pandey. Robyn Norton. and while there are a number of mechanisms by which albumin might exert a beneficial effect. NSW: Rosemary Carroll. John Hunter Hospital. NSW = New South Wales. Newcastle. Bruce Neal. Victoria: Catherine Boyce. Julie Potter. Middlemore Hospital. Statistical analysis The George Institute for International Health. Judi Tai. Health Department of Western Australia. Stephen MacMahon. Royal Hobart Hospital. Victorian Department of Human Services. Austin & Repatriation Medical Centre. CSL Limited has paid travel expenses for Professor Simon Finfer and Professor Rinaldo Bellomo to present the results of the SAFE study at scientific and industry sponsored meetings. Anthony Williams. Alfred Hospital. Brisbane. Colin McArthur. no studies conducted to date can be considered definitive. Iveta Hynesova. John Myburgh and Robyn Norton. Tasmania: Anthony Bell. Robyn Norton. Ian Seppelt. Australian Red Cross Blood Service. Christopher Joyce. Sandra Kaplan. Shirley Vallance. Melbourne. Stephen MacMahon. Appendix: SAFE Study Investigators Writing Committee Simon Finfer (Chair). Megan Robertson. Northern Territory Health Services. SAFE Study Management Committee Robyn Norton (Chair). Laurent Billot. New South Wales Health Department. Gordon Doig. However. Qiang Li. Royal Darwin Hospital. Auckland Hospital. Melbourne. Theresa Kelly. Victoria. Jeffrey Presneill. Lorraine Little. Charles Sprung and J. Royal Hobart Hospital. Sydney. Victoria: Samantha Bates. Clive Woolfe. . John Myburgh. Tasmania. Victoria: Julie Charlton. Kathy Jayne. Melbourne. Andrew Davies. Louise Cole. Sydney. Victoria: Neil Boyce. Julie French. The funding bodies played no part in the conduct or analysis of the study. Melbourne. Site investigators Alphabetically by institution and surname. Australia unless stated. Dorrilyn Rajbhandari. Australian Commonwealth Department of Health and Aged Care. Competing interests and the role of SAFE study funders: The SAFE study was part funded by CSL Limited. D. Anthony Limpus. Melbourne. Mary Hayek. Fremantle. John Myburgh. Princess Alexandra Hospital. Sydney. Royal North Shore Hospital. NSW: Gordon Doig. Peter Saul. NSW: Kathryn Girling. Our data do. John Myburgh. John Cade. Mary Hayek and Sheridan O’Donnell. Julie French. University of Sydney. Western Australia: David Blythe. Peter Saul. Robyn Moore. NZ = New Zealand. Anthony Bell. Suzanne McEvoy. Fremantle Hospital. Kathy Marsden. Duncan Young. Nepean Hospital. Michael Fitzharris. Northern Territory: Dianne Stephens. James Cooper. Health Research Council of New Zealand. Donna Goldsmith. Catherine Harry. Mark Woodward. Brett McFadyen. provide prima facie evidence to support the conduct of suitably powered. Stephanie Creed. Juliet Powell. Royal Melbourne Hospital. Rinaldo Bellomo. Christopher Joyce. John Cade. South Australian Department of Human Services. David Blythe. New Zealand. Jeffrey Presneill. Middlemore Hospital. or the decision to publish the results. Royal Adelaide Hospital. Australian National Health and Medical Research Council. Siva Sivarajasingham. NSW. Rinaldo Bellomo. Suzanne McEvoy. Colin McArthur.Unanswered questions and future research Our study provides indicative evidence that resuscitation with albumin may reduce mortality in patients with severe sepsis [7]–[9]. Leonie Weisbrodt. Andrew Turner. South Australia: Marianne Chapman. Simon Finfer. Victoria: Craig French. Mamta Merai. Queensland Health Services Department. Naresh Ramakrishnan. Sheridan O’Donnell. SAFE Study Steering Committee Simon Finfer (Chair). Andrew Davies. Rinaldo Bellomo. Western Hospital. Alison Voss. Colin McArthur. Penrith. Neil Boyce. CSL Limited has acted as a sponsor for scientific meetings of the Australian and New Zealand Intensive Care Society and its Clinical Trials Group. Lynette Newby. Annamaria Palermo. University of Sydney. St George Hospital. Dianne Stephens. randomized trials of albumin versus crystalloid for fluid resuscitation of patients with severe sepsis. Acknowledgments Funding bodies are listed alphabetically (Australia unless otherwise stated): Auckland District Health Board. Julie French (Senior Project Manager). Michael Fitzharris. Auckland (NZ): Jane Clarke. these are at present unproven. Marianne Chapman. Marie Hodgetts. Royal Prince Alfred Hospital. Craig French. Andrew Turner. Jane Thomas. Ian Seppelt. Peter Sandercock. Queensland: Lisa Bradley. The George Institute for International Health. Suzanne McEvoy. CSL Limited. SAFE Study External Safety and Data Monitoring Committee Richard Peto (Chair). Lisa Higgins. James Cooper. Auckland (NZ): Janine Chadderton. Anthony Williams and Clive Woolfe. Justine Rivett. Rinaldo Bellomo. Simon Finfer. Belinda Howe. NSW: Louise Cole. Alina Jovanovska. however. Katherine Moulden.

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