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Objectives: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable., Design: Multicenter, interventional randomized clinical trial., Setting: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis)., Patients or Subjects: In total, 540 patients with septic shock and 418 patients with severe sepsis., Interventions: Either 20% human albumin and crystalloids or crystalloid solutions alone., Measurements and Main Results: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05-4.93]; p = 0.04) and 90-day mortality (2.04 [1.02-4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34-7.20]; p = 0.008) and 90-day mortality (2.69 [1.26-5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes., Conclusions: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability.

Objectives: Our objectives were to determine first whether albumin prevents heparin-binding protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma heparin-binding protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock., Design: In vitro human endothelial and renal cell model and observation cohort of septic shock., Settings: Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial)., Patients: Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr)., Interventions: In vitro: heparin-binding protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation., Measurements and Main Results: Transendothelial electrical resistance-a marker of permeability-of human endothelial cells was measured using a voltohmmeter. We measured plasma heparin-binding protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an heparin-binding protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited heparin-binding protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher heparin-binding protein-to-albumin ratio (1.6 vs 0.89; p < 0.001) and heparin-binding protein (38.2 vs 20.8 ng/mL; p < 0.001) than patients without acute kidney injury. The highest heparin-binding protein-to-albumin ratio (> 3.05), heparin-binding protein quartiles (> 69.8), and heparin-binding protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-binding protein and heparin-binding protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of heparin-binding protein-to-albumin ratio and heparin-binding protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality., Conclusions: Albumin inhibits heparin-binding protein-induced increased human endothelial cell permeability and heparin-binding protein greater than 30 ng/mL and heparin-binding protein-to-albumin ratio greater than 3.01-but not serum albumin-identified patients at increased risk for acute kidney injury in septic shock.

Objective: Improved means to monitor and guide interventions could be useful in the intensive care unit. Metabolomic analysis with bioinformatics is used to understand mechanisms and identify biomarkers of disease development and progression. This pilot study evaluated plasma proton nuclear magnetic resonance spectroscopy as a means to monitor metabolism following albumin administration in acute lung injury patients., Design: This study was conducted on plasma samples from six albumin-treated and six saline-treated patients from a larger double-blind trial. The albumin group was administered 25 g of 25% human albumin in 0.9% saline every 8 hrs for a total of nine doses over 72 hrs. A 0.9% concentration of saline was used as a placebo. Blood samples were collected immediately before, 1 hr after, and 4 hrs after the albumin/saline administration for the first, fourth, and seventh doses (first dose of each day for 3 days). Samples were analyzed by proton nuclear magnetic resonance spectroscopy, and spectra were analyzed by principal component analysis and biostatistical methods., Interventions: None., Measurements and Main Results: After 1 day of albumin therapy, changes in small molecules, including amino acids and plasma lipids, were evident with principal component analysis. Differences remained 3 days after the last albumin administration. Analysis of data along with spectra from healthy controls showed that spectra for patients receiving albumin had a trajectory toward the spectra observed for healthy individuals while those of the placebo controls did not., Conclusion: The data suggest that metabolic changes detected by proton nuclear magnetic resonance spectroscopy and the bioinformatics tool may be a useful approach to clinical research, especially in acute lung injury.

Objective: There is continuing concern about the influence of hydroxyethylstarch on renal function in patients with compromised kidney function., Design: Prospective, randomized, single-center study., Setting: University-affiliated hospital., Patients: Fifty patients undergoing elective, first-time coronary artery bypass grafting using cardiopulmonary bypass with a preoperative serum creatinine between 1.5 and 2.5 mg/dL., Interventions: According to a prospective, randomized sequence, the patients received either hydroxyethylstarch with a low molecular weight (mean molecular weight 130 kD) and a low molar substitution (0.4) (6% hydroxyethylstarch 130/0.4) (n = 25) or 5% human albumin (n = 25). Volume was added to the priming (500 mL) and given perioperatively until the second postoperative day to keep pulmonary artery occlusion pressure or central venous pressure between 12 and 14 mm Hg., Measurements and Main Results: Serum creatinine and cystatin plasma levels were measured from arterial blood samples. From urine specimens, N-acetyl-beta-D-glucosaminidase, glutathione transferase-alpha, and neutrophil gelatinase-associated lipocalin were measured. Measurements were performed after induction of anesthesia, at the end of surgery, 5 hrs after surgery, and on the first and second postoperative days. A follow-up after discharge from the hospital (60 days) was also done. Similar amounts of hydroxyethylstarch and albumin were infused. Serum creatinine, glomerular filtration rate, and cystatin C plasma levels were without significant differences between the groups. Concentrations of kidney-specific proteins were elevated at baseline and increased significantly after surgery without showing group differences. Urinary levels of neutrophil gelatinase-associated lipocalin increased more in the albumin- than in the hydroxyethylstarch-treated patients. None of the patients developed acute renal failure requiring renal replacement therapy during the hospital stay and thereafter., Conclusions: A hydroxyethylstarch preparation with a low molecular weight and a low molar substitution given in cardiac surgery patients with preoperative compromised kidney function did not negatively influence kidney integrity compared with a human albumin-based volume replacement strategy.

Objective: Hypoproteinemia is a common condition in critically ill patients, associated with the development of acute lung injury and acute respiratory distress syndrome and subsequent worse clinical outcomes. Albumin with furosemide benefits lung physiology in hypoproteinemic patients with acute lung injury/acute respiratory distress syndrome, but the independent pharmacologic effects of these drugs are unknown., Design: Randomized, double-blinded, placebo-controlled multicentered trial., Setting: Eleven medical, surgical, and trauma intensive care units including 190 beds within two university hospital systems., Patients: Forty mechanically ventilated patients with acute lung injury/acute respiratory distress syndrome, whose serum total protein concentrations were <6.0 g/dL were included. Patients were excluded for hemodynamic instability or significant renal or hepatic failure., Interventions: Subjects were equally randomly allocated to receive furosemide with albumin or furosemide with placebo for 72 hrs, titrated to fluid loss and normalization of serum total protein concentration., Measurements and Main Results: The primary outcome was change in oxygenation from baseline to day 1, with secondary physiologic and clinical outcomes. There were no differences in baseline characteristics of the subjects in relation to group assignment. Albumin-treated patients had greater increases in oxygenation (mean change in Pao2/Fio2: +43 vs. -24 mm Hg at 24 hrs and +49 vs. -13 mm Hg at day 3), serum total protein (1.5 vs. 0.5 g/dL at day 3), and net fluid loss (-5480 vs. -1490 mL at day 3) throughout the study period (all p < .05). Fluid bolus administration to control patients reduced net negative fluid balance; control patients more frequently developed hypotension and had fewer shock-free days, which translated to differences in organ failure at study end., Conclusions: The addition of albumin to furosemide therapy in hypoproteinemic patients with acute lung injury/acute respiratory distress syndrome significantly improves oxygenation, with greater net negative fluid balance and better maintenance of hemodynamic stability. Additional randomized clinical trials are necessary to examine mechanisms and determine the effect on important clinical outcomes, such as the duration of mechanical ventilation.

Objective: To ascertain the influence of albumin on antioxidant status in patients with acute lung injury., Design: Prospective, randomized, placebo-controlled study., Setting: Intensive care units, teaching hospitals., Patients: Twenty patients meeting the American European Consensus criteria for acute lung injury., Interventions: Ten patients received albumin (25 g of a 25% solution every 8 hrs for a total of nine doses) and ten received placebo (normal saline administered in identical fashion and volume). All received supportive therapy appropriate for patients with acute lung injury. Plasma samples were obtained sequentially from all patients before, 30 mins after, and 4 hrs after albumin/placebo administration., Measurements and Main Results: Serum albumin and total protein, total antioxidant status, iron-binding antioxidant protection, iron-oxidizing antioxidant protection, lipid hydroperoxides, protein carbonyls, and plasma thiols were measured. Albumin administration increased plasma albumin concentrations (p <.05 compared with placebo) and decreased concentrations of protein carbonyls (p <.05 compared with placebo). By contrast, plasma lipid hydroperoxide concentrations were similar in both groups, both in absolute terms and relative to albumin content. For all other variables, no significant differences were apparent. For all patients, there was a positive correlation between albumin and plasma thiol concentrations (r =.983, p <.01) and albumin and antioxidant capacity (r =.885, p =.01). In the albumin treatment group, there was a strong correlation between thiols and antioxidant capacity (r =.876, p =.01). No such correlation was apparent in the placebo group. Plasma iron-binding antioxidant protection was negatively correlated (r = -.741, p <.05) with albumin content in the treatment group but not the placebo group., Conclusions: In patients with acute lung injury, albumin administration favorably influences plasma thiol-dependent antioxidant status as well as levels of protein oxidative damage.

Objective: To evaluate the effect of singular or sustained hemodilution, with alpha-alpha diaspirin crosslinked hemoglobin (DCLHb), on the area of hypoperfusion after subarachnoid hemorrhage., Design: Prospective animal study., Setting: Animal research laboratory., Subjects: Isoflurane anesthetized, mechanically ventilated rats., Interventions: Subarachnoid hemorrhage was induced by injecting 0.3 mL of blood into the cisterna magna. The animals were randomly assigned to one of the following groups (n = 16 in each hemodilution group; eight animals received a single treatment of hemodilution after subarachnoid hemorrhage; and, for eight animals, treatment was sustained for 48 hrs): control group (n = 8), no hematocrit (45%) manipulation; DCLHb group (n = 16), hematocrit decreased to 30% with DCLHb; or Alb group (n = 16), hematocrit decreased to 30% with human serum albumin. After 48 hrs, the area of hypoperfusion (cerebral blood flow < 40 ml/100g/min) was determined with 14C-iodoantipyrine in five coronal brain sections., Measurements and Main Results: For both singular and sustained treatment, the area of hypoperfusion was less in both hemodilution groups than in the control group (p<.05). For four of the five coronal brain sections, no differences were found between the DCLHb and Alb groups within a given hemodilution protocol. In addition, in four of the five coronal brain sections for the DCLHb hemodilution groups and in all five sections for the albumin hemodilution groups, the area of hypoperfusion was less for rats that received sustained hemodilution compared with their respective groups in the singular treatment protocol (p<.05)., Conclusions: These data support the hypothesis that hemodilution with molecular hemoglobin decreases hypoperfusion after subarachnoid hemorrhage and that sustained hemodilution is more effective than singular treatment. The data do not support the notion that intravascular DCLHb has an adverse effect on cerebral ischemia after subarachnoid hemorrhage.

Using an ovine model of acute hemorrhagic shock, we evaluated the utility of 5% albumin in lactated Ringer's (5% ALR) solution as a resuscitation solution. After instrumentation and obtaining baseline values for BP, mean arterial pressure (MAP), pulmonary capillary wedge pressure (WP), CVP, cardiac output, extravascular lung water (EVLW), and blood gases (mixed venous and arterial), animals were rapidly exsanguinated to an MAP of 50 mm Hg. After 30 min at this pressure, measurements were repeated and 5% ALR was administered until two of three variables (WP, MAP, cardiac output) were restored to baseline values. The administration of 5% ALR was continued as needed to maintain baseline values of these variables. Sixty minutes later, data were again recorded. For induction of shock, 15.7 +/- 5.2 ml of blood/kg body weight was removed. Pulmonary artery pressure, WP, MAP, and cardiac output all significantly decreased with shock. After resuscitation, all values except MAP returned to baseline. The resuscitation volume of 5% ALR was 25.2 +/- 18.4 ml/kg. There were no changes in EVLW or intrapulmonary shunt. Oxygen delivery was significantly compromised during shock but returned to baseline after resuscitation. We conclude that in a model such as ours, 5% ALR can reverse the hemodynamic effects of acute hemorrhagic shock.

Previously, we determined that a colloid concentration of about 3% was optimal for resuscitation of lethal ischemic intestinal shock model in rats. Maximal volumes of lactated Ringer's solution (RL) alone only expanded plasma volume (PV) to 80% of preshock level, while increasing volumes of 3% albumin (ALB) in RL linearly expanded PV up to twice the preshock level. This study compares the effect of RL and ALB on survival and PV in 175 rats. The solutions were given in volumes to induce suboptimal PV expansion, requiring 10 and 44 ml/100 g body weight (bwt) of ALB and RL, respectively. ALB (20 ml/100 g bwt) was then given to induce a PV above the preshock level. Shock was induced by exteriorizing the small intestine and occluding the superior mesenteric vessels for 75 min. PV was estimated using Hct. Therefore, infusions were given continuously for 6 h in volumes that maintained a stable Hct. Untreated shocked animals developed hemoconcentration (Hct 58%) corresponding to a PV of 56% of preshock level, with 2% (1/53) of the animals surviving 24 h. The maximum effect of RL (44 ml/100 g bwt) was to expand PV to 80% of preshock level, with a 32% 24-h survival rate. Only 23% as much ALB (10 ml/100 g bwt) was needed to induce similar blood volume expansion with 24-h survival rate of 46%. When the larger volume of ALB (20 ml/100 g bwt) was used, PV expanded to 115% of preshock level, and 24-h survival to 76%, greater than that achieved with either the smaller volume of ALB or RL alone (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

The administration of albumin in the initial resuscitation of shock remains highly controversial. Impaired coagulation in the critically injured patient has recently been added as an argument against the use of supplemental albumin. This study investigated the hemostatic effects of albumin therapy after hemorrhagic shock. Twenty mongrel dogs were bled to a systolic pressure of 60 mm Hg for 1 h. After the return of shed blood, the animals received either lactated Ringer's solution or 5% serum albumin (25 ml/kg) daily for the 3 days. Coagulation parameters were measured before bleeding, immediately after resuscitation, and on days 2, 3, and 4. The changes in platelet count, platelet function, and serum fibrinogen were similar in the albumin treated and control animals. Although the prothrombin time and partial thromboplastin time were more prolonged in the albumin group, the changes were not sufficient to produce clinical bleeding.