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Background: Dextran-70 is a more potent plasma volume expander than albumin but use has been hampered because of its antithrombotic properties. However, also albumin has antithrombotic properties and little is known about relative effects of these two colloids on coagulation in vivo when controlling for differences in efficacy as plasma volume expanders., Aim: Compare effects of dextran-70 and albumin on coagulation at a dose resulting in equal plasma volume expansion., Methods: Guinea pigs were subjected to a 25 mL/kg hemorrhage during 20 min and randomized to resuscitation with either 6% dextran-70 at a dose of 15 mL/kg or 5% albumin at a dose of 25 mL/kg (n = 14 in each group) during 30 min starting 1 h of shock. Blood samples were collected at the completion of resuscitation and at 4 h. Plasma volume was measured using I-albumin and the effect on coagulation was evaluated using whole blood thrombelastography (TEG), measurement of plasma fibrinogen and von Willebrand factor (vWF) concentrations and vWF glycoprotein 1b (GP1b) A activity., Results: Plasma volumes after resuscitation were similar in the groups at both time points. Dextran-70 resulted in a transient prolongation of TEG clot amplification time (K) at the completion of resuscitation compared with albumin. TEG clot initiation (R) and strength (MA) did not differ between the treatments at any of the time points. Albumin reduced vWF concentrations to a larger extent than dextran at both time points, whereas no difference in vWF GP1bA activity or in plasma fibrinogen and could be detected., Conclusion: In equipotent doses with regard to plasma volume expansion, dextran-70 transiently prolongs clot amplification time more than albumin whereas dextran-70 reduces plasma vWF concentrations less than albumin.

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.

Rationale: Sepsis-induced acute kidney injury (AKI) is a common condition with high morbidity and mortality. Neutrophil-derived heparin-binding protein (HBP) induces vascular leakage and is a promising biomarker of sepsis-induced organ dysfunction. It remains unknown if HBP is prognostic of AKI in septic shock and if HBP could play a role in the pathophysiology of sepsis-induced AKI., Objectives: To determine the association of plasma HBP levels with development of AKI, investigate the role of HBP in the pathophysiology of sepsis-induced AKI, and test the effect of blocking HBP using heparin derivatives., Methods: In 296 septic shock patients from the randomized multicenter Vasopressin and Septic Shock Trial (VASST) plasma HBP levels were associated with development of AKI and need for renal replacement therapy (RRT). Human renal tubular cells were exposed to recombinant HBP to evaluate inflammation and heparin derivatives were used to abrogate these effects. Finally, mice were exposed to HBP with and without heparin derivatives and the kidneys examined for signs of inflammation., Findings: Plasma HBP levels were significantly higher in patients with AKI and those requiring RRT. HBP levels identified patients with moderate AKI with an area under curve (AUC) of 0.85. HBP increased IL-6 production in renal tubular epithelial cells. Different heparin derivatives abrogated the HBP-induced increased inflammatory response in vitro and in vivo., Conclusion: Elevated plasma HBP is associated with development of sepsis-induced AKI and HBP is involved in its pathophysiology. Our studies suggest that heparin(s) could be tested for efficacy and safety of prevention of sepsis-induced AKI.

Background: It is believed that the effectiveness of colloids as plasma volume expanders is dependent on the endothelial permeability for macromolecules. The objective of this study was to test the hypothesis that the plasma volume expanding effect of 5% albumin relative to that of a crystalloid solution is reduced if microvascular permeability is increased., Methods: A control group was resuscitated with either 5% albumin (8 ml/kg) or Ringer's acetate (36 ml/kg) immediately after a hemorrhage of 8 ml/kg (n = 29). In a second group, permeability was increased by inducing sepsis through cecal ligation and incision (n = 28). Three hours after cecal ligation and incision, the animals were resuscitated with either 5% albumin in a ratio of 1:1 relative to the volume of lost plasma, or Ringer's acetate in a ratio of 4.5:1., Results: In the hemorrhage group, plasma volumes at 15 min after resuscitation with albumin or Ringer's acetate had increased by 9.8 ± 2.6 ml/kg (mean ± SD) and 7.4 ± 2.9 ml/kg and were similar at 2 and 4 h. Plasma volume 3 h after cecal ligation and incision had decreased by approximately 7 ml/kg, and at 15 min after resuscitation with albumin or Ringer's acetate it had increased by 5.7 ± 2.9 and 2.4 ± 3.0 ml/kg, respectively (P < 0.05). At 2 and 4 h after resuscitation, plasma volumes did not differ between the groups., Conclusion: This study does not support the hypothesis that the plasma-volume-expanding effect of albumin relative to that of crystalloids is decreased under conditions characterized by increased permeability.

Objective: To compare the intracranial pressure after resuscitation to normovolemia by using 20% albumin or normal saline in a cat model of meningitis., Design: Prospective, randomized animal study., Setting: University hospital laboratory., Subjects: Twenty adult, male cats., Interventions: Meningitis was induced by intrathecal injection of Escherichia coli-derived lipopolysaccharide (0.8 × 10 units/kg). Four hours after the lipopolysaccharide injection, the animals were randomized to intravenous treatment with 0.4 mL/kg/hr of 20% albumin or 7.5 mL/kg/hr of 0.9% sodium chloride for 6 hrs (n = 7 per group). A control group receiving lipopolysaccharide but no fluid was also studied (n = 6)., Measurements and Main Results: Effects on intracranial pressure, mean arterial pressure, plasma volume (I-albumin technique), plasma oncotic pressure, and brain metabolism via cerebral interstitial lactate/pyruvate ratio and glycerol and glucose levels (microdialysis technique) were evaluated. Plasma volume decreased by approximately 20% and intracranial pressure increased from 10 to approximately 20 mm Hg at 4 hrs after the lipopolysaccharide injection. Six hours later, plasma volume had returned to baseline in both fluid groups while there was a further reduction in the control group. Intracranial pressure was higher in the saline group than in the albumin and control groups and was 25.8 ± 2.8 mm Hg, 18.3 ± 0.6 mm Hg, and 20.4 ± 1.7 mm Hg, respectively. Plasma oncotic pressure was higher in the albumin group than in the saline and control groups. Mean arterial pressure and microdialysis data were within normal range and did not differ among the groups., Conclusions: The results showed that the choice of resuscitation fluid may influence intracranial pressure in meningitis. The lower intracranial pressure in the colloid group may be explained by a higher plasma oncotic pressure and less fluid distribution to the brain interstitium.

Background: It has been hypothesized that resuscitation with crystalloids after brain trauma increases brain edema compared with colloids, but previous studies on the subject have been inconclusive. To test this hypothesis, the authors compared groups resuscitated with either colloid or crystalloid., Methods: After fluid percussion injury, rats were subjected to a controlled hemorrhage of 20 ml/kg and were randomized to 5% albumin at 20 ml/kg (A20), isotonic Ringer's acetate at 50 ml/kg (C50), or 90 ml/kg (C90). After 3 or 24 h, water content in the injured cortex was determined using a wet/dry weight method. Blood volume was calculated from plasma volume, measured by 125I-albumin dilution, and hematocrit. Oncotic pressure and osmolality were measured with osmometers., Results: At 3 h, blood volume was equal in the A20 and C90 groups and lower in the C50 group. Oncotic pressure was reduced by 35-40% in the crystalloid groups and unchanged in the albumin group. Cortical water content in the A20 group was lower than in the C90 group (81.3 +/- 0.5% vs. 82.1 +/- 1.1%, P < 0.05), but it was not different from the C50 group (81.8 +/- 1.1%). At 24 h, oncotic pressure and blood volume were normalized in all groups, and cortical water content was significantly lower in the albumin group than in the crystalloid groups. Osmolality and arterial pressure were equal in all groups throughout the experiment., Conclusions: When given to the same intravascular volume expansion, isotonic crystalloids caused greater posttraumatic brain edema than 5% albumin at 3 and 24 h after trauma.

The objective of the present study was to develop an experimental model suitable for studying the effects of a nonhemorrhagic soft tissue trauma on plasma volume (PV) and microvascular permeability. Anesthetized Sprague-Dawley rats were exposed to a sham procedure or a laparotomy followed by a standardized trauma to the abdominal rectus muscle. We evaluated the effects of trauma on transcapillary escape rate and on PV (3 h after trauma) using 125I-albumin as tracer and on edema formation in the traumatized muscle with a wet- versus dry-weight method. The effects of the trauma on the cytokines IFN-gamma, IL-4, IL-6, IL-10, and TNF-alpha were investigated 1 and 3 h after trauma in a separate group. Transcapillary escape rate was 13.9% per hour in the sham animals compared with 18.5% per hour in the traumatized animals (P < 0.05). Because arterial and venous blood pressures were not altered by the trauma, the change in transcapillary escape rate most likely reflects a change in microvascular permeability. Plasma volume decreased from 42 mL/kg at baseline to 31 mL/kg at the end of the experiments (P < 0.05) in the trauma group, whereas PV remained unchanged in the sham group. Only 15% of the PV loss could be referred to edema in the traumatized muscle. Trauma induced a significant increase in IL-6 and IL-10 after 1 h. We conclude that the present nonhemorrhagic trauma induces an increase in microvascular permeability in the traumatized tissue and in other parts of the body, resulting in hypovolemia. The model may be used for the evaluation of different therapeutic interventions aimed at the correction of hypovolemia.

Background: Increased microvascular permeability inducing leakage of plasma from the intravascular to the extravascular space after trauma is a pathophysiologic event of great clinical significance. A substance reducing an increased microvascular permeability, and especially an increased protein permeability, therefore could be of value to maintain normovolemia and to reduce the need for plasma substitution. Prostacyclin is suggested to have permeability-reducing properties as shown for fluid permeability, but its effects on protein permeability, which may be controlled by partly different mechanisms, are unclear. The present study evaluates whether prostacyclin at a low, clinically relevant, nonvasodilating dose can reestablish an increased protein permeability after trauma., Methods: The study was randomized, blinded, and performed on surgically traumatized, autoperfused, and denervated cat calf muscle. Relative changes in the osmotic reflection coefficient for albumin after 1.5 hours of prostacyclin (1 ng/min/kg) (n = 7) or vehicle (n = 7) treatment were used as a measure of altered protein permeability from a state of increased permeability after trauma., Results: We found that the osmotic reflection coefficient for albumin was increased by about 35% in the prostacyclin group compared with the vehicle-treated group (p < 0.001)., Conclusion: If applicable to humans, prostacyclin is a potential therapy for reducing plasma leakage in the critically ill trauma patient by restoring permeability from an increased level.

Objective: To study the effects of the hypertonic solutions 15% mannitol, 3% and 7.5% saline, and 30% urea at clinically relevant plasma concentrations with regard to absorption and rebound effects on tissue volume in skeletal muscle., Design: A prospective, experimental study., Setting: University laboratory., Subjects: Twenty-eight anesthetized cats., Interventions: The study was performed on an autoperfused and denervated cat calf muscle placed in a fluid-filled plethysmograph. Muscle volume changes and capillary filtration coefficient (reflecting capillary fluid conductivity) were measured before, during, and after intra-arterial infusion (4 mL/hr) of the hypertonic solutions. Mannitol and 3% saline have the same osmolality and were compared specifically in an attempt to distinguish osmotic effects from those specific to the compound., Measurements and Main Results: All solutions reduced muscle volume during the infusion (p < .05). The maximum volume reduction persisted after 2 hrs of infusion for 3% and 7.5% saline, whereas there was a tendency for volume recovery during the urea infusion and a complete recovery back to control for mannitol. After discontinuation of the infusions, the muscle volume increased for all four solutions, stabilizing at the initial control for 3% and 7.5% saline, whereas it increased to levels above control for mannitol and urea (p < .05). Capillary filtration coefficient was increased by hypertonic saline (p < .05) but was unaffected by mannitol and urea., Conclusions: The effectiveness of a hypertonic solution in reducing tissue volume and its tendency to cause a rebound volume increase depends not only on the osmolality of the solution. Hypertonic saline may in the long run be superior to mannitol and urea to increase plasma volume or decrease tissue volume of an organ, because it lacks rebound effects. Alterations in capillary filtration coefficient (fluid conductivity) may reflect volume changes of the capillary endothelial cell and thereby differences in cell membrane permeability for the hypertonic solutions, also consistent with the obtained differences in tissue volume effects.