Activated neutrophils increase microvascular permeability in skeletal muscle: role of xanthine oxidase

To determine the role of xanthine oxidase in the microvascular dysfunction produced by activated granulocytes, we examined the effect of xanthine oxidase depletion or inhibition on the increase in microvascular permeability produced by infusion of the neutrophil activator phorbol myristate acetate (PMA). Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient for total plasma proteins (sigma) in rat hindquarters subjected to PMA infusion in xanthine oxidase-replete and -depleted animals, in animals pretreated with the xanthine oxidase inhibitor oxypurinol, and in animals depleted of circulating neutrophils by pretreatment with antineutrophil serum (ANS). Xanthine oxidase depletion was accomplished by administration of a tungsten-supplemented (0.7 g/kg diet) molybdenum-deficient diet. In animals fed the tungsten diet, muscle total xanthine dehydrogenase plus xanthine oxidase activity was decreased to less than 10% of control values. Estimates of sigma averaged 0.84 +/- 0.04 in control hindquarters, whereas PMA infusion was associated with a marked increase in microvascular permeability (decrease in sigma to 0.68 +/- 0.03). PMA infusion also caused an increase in the amount of the radical-producing oxidase form of xanthine oxidase (from 3.9 +/- 0.05 to 5.6 +/- 0.4 mU/g wet wt). ANS pretreatment attenuated this permeability increase (sigma = 0.77 +/- 0.04) and diminished the rise in xanthine oxidase activity (4.9 +/- 0.5 mU/g wet wt). Xanthine oxidase depletion with the tungsten diet or pretreatment with oxypurinol had no effect on this neutrophil-mediated microvascular injury (sigma = 0.69 +/- 0.06 and 0.67 +/- 0.03, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased albumin plasma efflux contributes to hypoalbuminemia only during early phase of sepsis in rats

The mechanisms leading to hypoalbuminemia in sepsis were explored by measuring plasma volume, albumin distribution, plasma albumin transcapillary escape rate (TER), and efflux (TER x albumin intravascular pool). These parameters were quantified in infected rats, injected intravenously with live Escherichia coli, and pair-fed and well-fed rats using an injection of (35)S-albumin and measuring plasma and whole body albumin concentrations. Animals were studied on days 1, 6, and 10 after infection. In pair-fed rats, neither albumin distribution nor exchange rate between the intra- and extravascular compartments was modified. The increase of plasma volume after infection partly explained hypoalbuminemia. Infection resulted in a reduction of the total albumin pool of the body all along the experimental period, indicating a net loss of the protein. Albumin TER (%/day) was significantly increased 1 and 6 days after infection, but the absolute efflux was increased only on day 1. Normal values were observed on day 10. Therefore, an accelerated plasma efflux contributes to hypoalbuminemia only during the early period of sepsis. During this phase, the protein was retained in the extravascular space where it was probably catabolized. Later on, other factors are probably involved.     

Insulin-like growth factor binding protein-3 in patients with liver cirrhosis

Aim of the study was to evaluate serum levels of insulin-like growth factor binding protein-3 in patients with liver cirrhosis and to compare serum IGFBP-3 levels with other liver function tests. Fifty-one patients with liver cirrhosis were selected for our study. We measured IGFBP-3 (1.67+/-1.06 mg/l, mean+/-SD), albumin (32+/-8 g/l), prealbumin (0.22+/-0.14 g/l), AST (2.29+/-2.38 microkat/l), ALT (2.11+/-4.83 microkat/l) and cholinesterase (mean 78.6+/-45.2 microkat/l) in the serum. There was a significant positive correlation of serum IGFBP-3 with serum albumin and serum cholinesterase. The correlation coefficient was much lower between serum IGFBP-3 and serum prealbumin. There was no significant correlation between serum AST, ALT and IGFBP-3. Serum IGFBP-3 proves to be a better marker for the hepatic synthetic capacity than serum albumin or cholinesterase.     

The role of serum fructosamine as a screening test for gestational diabetes mellitus

The serum fructosamine concentration indicates the degree of glycation of serum proteins, particularly albumin, and reflects an average blood glucose level over the previous 1-3 weeks. Serum fructosamine, glycated haemoglobin (HbA1c), total serum protein, serum albumin, fasting plasma glucose and oral glucose tolerance test (OGTT) have been measured in 127 healthy control subjects, 102 type 1 and 152 type 2 diabetes mellitus patients and 106 nondiabetic pregnant women. Fructosamine concentration of 2.24 +/- 0.16 and 3.21 +/- 0.41 mmol/l (mean +/- S.D.) has been found in control subjects and diabetics respectively (P less than 0.001). During the second trimester a significantly lower fructosamine level (1.92 +/- 0.21 mmol/l) has been found in pregnant women, most likely due to the low serum albumin concentration (31.35 +/- 3.97 g/l). None of them had a fructosamine level above the normal limit of 2.55 mmol/l. On the other hand, 12 pregnant women showed a disturbed OGTT with normal fructosamine. If the serum fructosamine concentration was adjusted for 40 g/l albumin, then a mean fructosamine of 2.16 +/- 0.24 mmol/l was found in patients with gestational diabetes. Our results show that serum fructosamine has a similar diagnostic value as HbA1c for non-pregnant adults, but neither can replace OGTT for the diagnosis of gestational diabetes.     

Effects of protamine, heparinase, and hyaluronidase on endothelial permeability and surface charge

We undertook studies in the isolated perfused rat lung to determine 1) the effects of endothelial charge neutralization with the polycation protamine sulfate on microvascular permeability, lung water, and anionic ferritin binding to the endothelium and 2) the role of heparan sulfate and hyaluronate, negatively charged cell surface glycosaminoglycans, on permeability. Capillary permeability was determined by tissue 125I-albumin accumulation in isolated perfused rat lungs. In control lungs the 5-min albumin uptake was 0.50 +/- 0.05 cm3.s-1.g dry tissue-1 X 10(-3). It was increased by 132 +/- 7.8% (P less than 0.001) by protamine (0.08 mg/ml) and 65 +/- 12% (P less than 0.01) by heparinase (5 U/ml), whereas hyaluronidase (25 NFU/ml) was without effect. In control lungs total water was 4.83 +/- 0.15 ml g/dry tissue. Protamine increased lung water 12 +/- 2% (P less than 0.05). Heparinase caused a 9 +/- 3% increase (P less than 0.05), and hyaluronidase had no effect. Electron microscopy demonstrated that protamine increased anionic ferritin binding to the surface of endothelial cells. We conclude that protamine sulfate neutralization of negative charge in the pulmonary microcirculation leads to increased microvascular permeability. Heparin sulfate may be responsible for this charge effect.     

Oleic acid reduces pulmonary microvascular sieving capacity in sheep

Changes in pulmonary microvascular permeability in sheep, after oleic acid injection, were studied using estimations of the osmotic reflection coefficient (sigma d) for total protein, albumin, immunoglobulins (Ig) G and M and calculation of the equivalent small and large pores of the microvessels. A chronic lung fistula was prepared in eight sheep. After a base-line period, left atrial pressure (Pla) was increased. Oleic acid (0.05 mg/kg body wt) was injected after a filtration-independent state had been obtained, and the spontaneously ventilating animals were then followed for 2 h. The sigma d for the normal lung was 0.65 +/- 0.03, 0.59 +/- 0.02, 0.72 +/- 0.04, and 0.84 +/- 0.02 for total protein, albumin, IgG, and IgM, respectively. The equivalent pore radii were 54 and 225 A. After oleic acid infusion, arterial pressure and arterial O2 tension decreased and leukocytes and platelets were consumed. At the end of the experiment, sigma d's were 0.27 +/- 0.04, 0.24 +/- 0.07, 0.33 +/- 0.06, and 0.55 +/- 0.04 for total protein, albumin, IgG, and IgM, respectively. The equivalent pore radii were 54 and 275 A, and the number of large pores was increased by 195%. The results indicate that oleic acid produces an increased vascular permeability by increasing the size and the numbers of large pores of the pulmonary microvascular walls.     

Systemic and microvascular responses to hemorrhagic shock and resuscitation with Hb vesicles

A phospholipid vesicle encapsulating hemoglobin (Hb vesicle, HbV) has been developed to provide O(2)-carrying capacity to plasma expanders. Its ability to restore systemic and microcirculatory conditions after hemorrhagic shock was evaluated in the dorsal skinfold window preparation of conscious hamsters. The HbV was suspended in 8% human serum albumin (HSA) at Hb concentrations of 3.8 g/dl [HbV(3.8)/HSA] and 7.6 g/dl [HbV(7.6)/HSA]. Shock was induced by 50% blood withdrawal, and mean arterial pressure (MAP) at 40 mmHg was maintained for 1 h by the additional blood withdrawal. The hamsters receiving either HbV(3.8)/HSA or HbV(7.6)/HSA suspensions restored MAP to 93 +/- 14 and 93 +/- 10 mmHg, respectively, similar with those receiving the shed blood (98 +/- 13 mmHg), which were significantly higher by comparison with resuscitation with HSA alone (62 +/- 12 mmHg). Only the HSA group tended to maintain hyperventilation and negative base excess after the resuscitation. Subcutaneous microvascular blood flow reduced to approximately 10-20% of baseline during shock, and reinfusion of shed blood restored blood flow to approximately 60-80% of baseline, an effect primarily due to the sustained constriction of small arteries A(0) (diameter 143 +/- 29 microm). The HbV(3.8)/HSA group had significantly better microvascular blood flow recovery and nonsignificantly better tissue oxygenation than of the HSA group. The recovery of base excess and improved tissue oxygenation appears to be primarily due to the increased oxygen-carrying capacity of HbV fluid resuscitation.     

Intense exercise stimulates albumin synthesis in the upright posture.

We tested the hypothesis that an elevation in albumin synthetic rate contributes to increased plasma albumin content during exercise-induced hypervolemia. Albumin synthetic rate was measured in seven healthy subjects at 1-5 and 21-22 h after 72 min of intense (85% peak oxygen consumption rate) intermittent exercise and after 5 h recovery in either upright (Up) or supine (Sup) postures. Deuterated phenylalanine (d(5)-Phe) was administrated by a primed-constant infusion method, and fractional synthetic rate (FSR) and absolute synthetic rate (ASR) of albumin were calculated from the enrichment of d(5)-Phe in plasma albumin, determined by gas chromatography-mass spectrometry. FSR of albumin in Up increased significantly (P < 0.05) from 4.9 +/- 0.9%/day at control to 7.3 +/- 0.9%/day at 22 h of recovery. ASR of albumin increased from 87.9 +/- 17.0 to 141.1 +/- 16.6 mg albumin. kg body wt(-1). day(-1). In contrast, FSR and ASR of albumin were unchanged in Sup (3.9 +/- 0.4 to 4.0 +/- 1.4%/day and 74.2 +/- 8.9 to 85.3 +/- 23.9 mg albumin. kg body wt(-1). day(-1) at control and 22 h of recovery, respectively). Increased albumin synthesis after upright intense exercise contributes to the expansion of greater albumin content and its maintenance. We conclude that stimuli related to posture are critical in modulating the drive for albumin synthesis after intense exercise.     

Albumin Kinetics in Patients Undergoing Major Abdominal Surgery

Background

The drop in plasma albumin concentration following surgical trauma is well known, but the temporal pattern of the detailed mechanisms behind are less well described. The aim of this explorative study was to assess changes in albumin synthesis and transcapillary escape rate (TER) following major surgical trauma, at the time of peak elevations in two well-recognized markers of inflammation.

Methods

This was a clinical trial of radiolabeled human serum albumin for the study of TER and plasma volume. Ten patients were studied immediately preoperatively and on the 2nd postoperative day after major pancreatic surgery. Albumin synthesis rate was measured by the flooding dose technique employing incorporation of isotopically labelled phenylalanine.

Results

Fractional synthesis rate of albumin increased from 11.7 (95% CI: 8.9, 14.5) to 15.0 (11.7, 18.4) %/day (p = 0.027), whereas the corresponding absolute synthesis rate was unchanged, 175 (138, 212) versus 150 (107, 192) mg/kg/day (p = 0.21). TER was unchanged, 4.9 (3.1, 6.8) %/hour versus 5.5 (3.9, 7.2) (p = 0.63). Plasma volume was unchanged but plasma albumin decreased from 33.5 (30.9, 36.2) to 22.1 (19.8, 24.3) g/L. (p<0.001).

Conclusion

Two days after major abdominal surgery, at the time-point when two biomarkers of generalised inflammation were at their peak and the plasma albumin concentration had decreased by 33%, we were unable to show any difference in the absolute synthesis rate of albumin, TER and plasma volume as compared with values obtained immediately pre-operatively. This suggests that capillary leakage, if elevated postoperatively, had ceased at that time-point. The temporal relations between albumin kinetics, capillary leakage and generalised inflammation need to be further explored.

Trial Registration

clinicaltrialsregister.eu: EudraCT 2010-08529-21 ClinicalTrials.gov NCT01194492     

Interstitial fluid pressure, composition of interstitium, and interstitial exclusion of albumin in hypothyroid rats

Lack of thyroid hormones may affect the composition and structure of the interstitium. Hypothyrosis was induced in rats by thyroidectomy 4-12 wk before the experiments. In hypothyroid rats (n = 16), interstitial fluid pressure measured with micropipettes in hindlimb skin and muscle averaged +0.1 +/- 0.2 and +0.5 +/- 0.2 mmHg, respectively, with corresponding pressures in control rats (n = 16) of -1.5 +/- 0.1 (P < 0.001) and -0.8 +/- 0.1 mmHg (P < 0.001). Interstitial fluid volume, measured as the difference between the distribution volumes of (51)Cr-EDTA and (125)I-labeled BSA, was similar or lower in skin and higher in hypothyroid muscle. Total protein and albumin concentration in plasma and interstitial fluid (isolated from implanted wicks) was lower in hypothyroid compared with control rats. Hyaluronan content (n = 9) in rat hindlimb skin was 2.05 +/- 0.15 and 1.92 +/- 0.09 mg/g dry wt (P > 0.05) in hypothyroid and control rats, respectively, with corresponding content in hindlimb skeletal muscle of 0.35 +/- 0.07 and 0.23 +/- 0. 01 mg/g dry wt (P < 0.01). Interstitial exclusion of albumin in skin and muscle was measured after (125)I-labeled rat serum albumin infusion for 120-168 h with an implanted osmotic pump. Relative excluded volume for albumin (V(e)/V(i)) was calculated as 1 - V(a)/V(i), and averaged 28 and 28% in hindlimb muscle (P > 0.05), 44 and 45% in hindlimb skin (P > 0.05), and 19 and 32% in back skin (P < 0.05) in hypothyroid and control rats, respectively. Albumin mass was higher in back skin in spite of a lower interstitial fluid albumin concentration, a finding explained by a reduced V(e)/V(i) in back skin in hypothyroid rats. These experiments suggest that lack of thyroid hormones in rats changes the interstitial matrix again leading to reduced interstitial compliance and changes in the transcapillary fluid balance.     

Thrombin-induced increase in albumin permeability across the endothelium

We studied the effect of thrombin on albumin permeability across the endothelial monolayer in vitro. Bovine pulmonary artery endothelial cells were grown on micropore membranes. Morphologic analysis confirmed the presence of a confluent monolayer with interendothelial junctions. Albumin permeability was measured by the clearance of 125I-albumin across the endothelial monolayer. The control 125I-albumin clearance was 0.273 +/- 0.02 microliter/min. The native enzyme, alpha-thrombin (10(-6) to 10(-10) M), added to the luminal side of the endothelium produced concentration-dependent increases in albumin clearance (maximum clearance of 0.586 +/- 0.08 microliter/min at 10(-6) M). Gamma (gamma) thrombin (10(-6) M and 10(-8) M), which lacks the fibrinogen recognition site, also produced a concentration-dependent increase in albumin clearance similar to that observed with alpha-thrombin. Moreover, the two proteolytically inactive forms of the native enzyme, i-Pr2 P-alpha-thrombin and D-Phe-Pro-Arg-CH2-alpha-thrombin, increased the 125I-albumin clearance (0.610 +/- 0.09 microliter/min and 0.609 +/- 0.02 microliter/min for i-Pr2 P-alpha-thrombin and D-Phe-Pro-Arg-CH2-alpha-thrombin at 10(-6) M, respectively). Since the modified forms of thrombin lack the fibrinogen recognition and active serine protease sites, the results indicate that neither site is required for increased albumin permeability. The increase in albumin clearance with alpha-thrombin was not secondary to endothelial cell lysis because lactate dehydrogenase concentration in the medium following thrombin was not significantly different from baseline values. There was also no morphological evidence of cell lysis. Moreover, the increase in 125I-albumin clearance induced by alpha-thrombin was reversible by washing thrombin from the endothelium. The basis for the increased albumin permeability following the addition of alpha-thrombin appears to be a reversible change in endothelial cell shape with formation of intercellular gaps.     

Oxidative modifications impair albumin quantification

Background

Hypoalbuminemia is a measure of malnutrition, inflammation and a predictor of mortality in uremia. It is controversial whether albumin levels per se are associated with the clinical outcomes in uremic patients. The co-occurrence of hypoalbuminemia and oxidative stress in hemodialysis (HD) patients led us to hypothesize that oxidative modifications of albumin decrease its detection and influence albumin quantification.

Methods

Albumin levels are determined in clinical laboratories mainly by the bromocresol green (BCG) spectrophotometric assay. The detection of serum albumin was investigated in HD patients and in healthy controls using an “albumin-detection index”, defined as the ratio between BCG read-out (albumin-specific) to total albumin. The detection efficacy of albumin was also investigated in vitro, after glycoxidation, HOCl-mediated-oxidation, and metal-catalyzed-oxidation. Oncotic pressure was measured to assess albumin function.

Results

The albumin-detection index of patients was significantly lower compared with controls, correlating negatively with oxidative stress markers (serum advanced oxidation protein products-AOPP and glycoxidized serum albumin) and positively with serum albumin levels. The albumin-detection index was also decreased after in vitro oxidation.

Conclusions

The study shows, both in vivo and in vitro, decreased detection of oxidized albumin by a commonly-used clinical assay, thus providing the molecular link between oxidative stress and hypoalbuminemia. Oxidative stress as reflected by hypoalbuminemia, rather than actual albumin levels, may be related to cardiovascular morbidity outcomes in HD patient.     

Albumin transport across pulmonary capillary-interstitial barrier in anesthetized dogs

To evaluate albumin transport across the pulmonary capillary endothelial and interstitial barriers, we simultaneously measured blood-to-tissue (QA,t) and blood-to-lymph (QA,l) clearances of 125I-radiolabeled albumin as well as endogenous albumin clearance (Qa,l) in the canine lung in vivo (n = 10). Steady-state prenodal lung lymph flows (Qw,l) and protein clearances were measured over a 2-h period at a constant capillary pressure (Pc, 13-33 cmH2O). Comparison between QA,t and QA,l as a function of Pc suggests that little of the albumin that crossed the capillary wall remained in the lung tissue, with most leaving in the lymph. Qw,l increased significantly as Pc increased, but lung tissue water was minimally affected. From the ratio of the clearance-Pc slopes for albumin and water, the albumin reflection coefficient was estimated to be 0.81 using QA,l and Qw,l and 0.56 using Qa,l and Qw,l. The permeability surface area product for the sum of blood-to-tissue and blood-to-lymph fluxes of labeled albumin (QA,t + QA,l) was 31 +/- 9 microliters/min, whereas that calculated from the blood-to-lymph flux of endogenous albumin (Qa,l) was 97 +/- 22 microliters/min. These data suggest that 1) both tissue and lymph accumulations of albumin must be considered when microvascular permeability is evaluated using protein tracers; 2) lymph clearance, but not tissue accumulation of albumin, was filtration dependent; and 3) lymph flow was an important contributor to the safety factor against edema formation over a moderate range of capillary pressures.     

Heparan sulfate depletion amplifies TNF-alpha-induced protein leakage in an in vitro model of protein-losing enteropathy

Protein-losing enteropathy (PLE), the excessive loss of plasma proteins through the intestine, often correlates with the episodic loss of heparan sulfate (HS) proteoglycans (HSPG) from the basolateral surface of intestinal epithelial cells. PLE onset is often associated with a proinflammatory state. We investigated whether loss of HS or treatment with the proinflammatory cytokine TNF-alpha directly causes protein leakage and whether a combination of both exacerbates this process. We established the first in vitro model of PLE and measured the flux of albumin/FITC through a monolayer of intestinal HT29 or Caco-2 cells grown on transwells and determined the integrity by transepithelial electrical resistance (TER). Loss of HS from the basolateral surface, either by heparanase digestion or by inhibition of HS synthesis, increased albumin flux 1.58 +/- 0.09-fold and reduced TER by 23.4 +/- 6.5%. TNF-alpha treatment increased albumin flux 4.04 +/- 0.03-fold and reduced TER by 75.7 +/- 4.7% but only slightly decreased HS content. The combined effects of HS loss and TNF-alpha treatment were not only additive, but synergistic, with a 7.00 +/- 0.11-fold increase in albumin flux and a 83.9 +/- 8.1% reduction of TER. Coincubation of TNF-alpha with soluble HS or heparin abolished these synergistic effects. Loss of basolateral HS directly causes protein leakage and amplifies the effects of the proinflammatory cytokine TNF-alpha. Our findings imply that loss of HSPGs renders patients more susceptible to PLE and offer a potential explanation for the favorable response some PLE patients have to heparin therapy.     

Extreme hemodilution with PEG-hemoglobin vs. PEG-albumin

Isovolemic hemodilution to 11% systemic hematocrit was performed in the hamster window chamber model using 6% dextran 70 kDa (Dx 70) and 5% human serum albumin (HSA). Systemic and microvascular effects of these solutions were compared with polyethylene glycol (PEG)-conjugated 5% albumin (MPA) and PEG-conjugated 4.2% Hb (MP4). These studies were performed for the purpose of comparing systemic and microvascular responses of PEG vs. non-PEG plasma expanders and similar oxygen-carrying vs. noncarrying blood replacement fluids. Mean arterial blood pressure was statistically significantly reduced for all groups compared with baseline (P < 0.05), HSA, MPA, and MP4 higher than Dx 70 (P < 0.05). MP4 and MPA had a significantly higher cardiac index than HSA and Dx 70, in addition to a positive base excess. Microvascular blood flow and capillary perfusion were significantly higher for the PEG compounds compared with HSA and Dx 70. Intravascular PO2 for MP4 and MPA was higher in arterioles (P < 0.05) compared with HSA and Dx 70, but there was no difference in either tissue or venular PO2 between groups. Total Hb in the MP4 group was 4.8 +/- 0.4 g/dl, whereas the remaining groups had a range of 3.6-3.8 g/dl. The hemodilution results showed that PEG compounds maintained microvascular conditions with lower concentrations than conventional plasma expanders. Furthermore, microvascular oxygen delivery and extraction in the window chamber tissue were significantly higher for the PEG compounds. MP4 was significantly higher than MPA (P < 0.05) and was not statistically different from baseline, an effect due to the additional oxygen release to the tissue by the Hb MP4.     

Normal responsiveness of serum parathyroid hormone to beta-adrenergic blockade in patients with secondary hyperparathyroidism

Infusion of calcium gluconate (15 mg Ca++/kg body weight in 4 h) to 6 patients with secondary hyperparathyroidism (due to mild renal insufficiency) decreased serum parathyroid hormone (PTH) levels to the same degree (on a percent basis) as in normal subjects. Serum PTH values at 4 h were 60 +/- 4.5 (SEM)% of baseline in the patients and 59 +/- 2.9% of baseline in the normal subjects. Infusion of propranolol (1 mg i.v. bolus followed by an infusion of 60 micrograms/min for 2 h) to 7 additional patients with secondary hyperparathyroidism also decreased serum PTH to the same degree as in normal subjects. Serum PTH values at 2 h were 68 +/- 10.4% of baseline in the patients and 68 +/- 3.3% of baseline in the normal subjects. The studies indicate normal responsiveness of serum PTH to calcium or beta-adrenergic blockade in secondary hyperparathyroidism due to mild renal insufficiency.     

Arginine vasopressin reduces intestinal oxygen supply and mucosal tissue oxygen tension

We investigated intestinal oxygen supply and mucosal tissue PO2 during administration of increasing dosages of continuously infused arginine vasopressin (AVP) in an autoperfused, innervated jejunal segments in anesthetized pigs. Mucosal tissue PO2 was measured by employing two Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Microvascular blood flow was assessed by laser-Doppler velocimetry. Systemic hemodynamic variables, mesenteric venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. Measurements were performed at baseline and at 20-min intervals during incremental AVP infusion (n = 8; 0.007, 0.014, 0.029, 0.057, 0.114, and 0.229 IU.kg(-1).h(-1), respectively) or infusion of saline (n=8). AVP infusion led to a significant (P < .05), dose-dependent decrease in cardiac index (from 121 +/- 31 to 77 +/- 27 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) and systemic oxygen delivery (from 14 +/- 3 to 9 +/- 3 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) concomitant with an increase in systemic oxygen extraction ratio (from 31 +/- 4 to 48 +/- 10%). AVP decreased microvascular blood flow (from 133 +/- 47 to 82 +/- 35 perfusion units at 0.114 IU.kg(-1).h(-1)), mucosal tissue PO2 (from 26 +/- 7 to 7 +/- 2 mmHg at 0.229 IU.kg(-1).h(-1)), and microvascular hemoglobin oxygen saturation (from 51 +/- 9 to 26 +/- 12% at 0.229 IU.kg(-1).h(-1)) without a significant increase in mesenteric venous lactate concentration (2.3 +/- 0.8 vs. 3.4 +/- 0.7 mmol/l). We conclude that continuously infused AVP decreases intestinal oxygen supply and mucosal tissue PO2 due to a reduction in microvascular blood flow and due to the special vascular supply in the jejunal mucosa in a dose-dependent manner in pigs.     

Platelet-activating factor increases lung vascular permeability to protein

We studied the effects of platelet-activating factor (PAF) on pulmonary hemodynamics and microvascular permeability in unanesthetized sheep prepared with lung-lymph fistulas. Since cyclooxygenase metabolites have been implicated in mediating these responses, we also examined the role of the cyclooxygenase pathway. PAF infusion (4 micrograms X kg-1 X h-1 for 3 h) produced a rapid, transient rise in pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), plasma thromboxane B2 concentration (TxB2), and pulmonary lymph flow (Qlym). The lymph-to-plasma protein concentration ratio (L/P) did not change from base line. Pretreatment with the cyclooxygenase inhibitor, sodium meclofenamate, prevented the generation of TxB2 and the hemodynamic changes but did not prevent the increase in Qlym. The estimated protein reflection coefficient decreased from a control value of 0.66 +/- 0.04 to 0.43 +/- 0.06 after PAF infusion. We also studied the effects of PAF on endothelial permeability in vitro by measuring the flux of 125I-albumin across cultured bovine pulmonary artery endothelial cells (EC) grown to confluency on a gelatinized micropore filter and mounted within a modified Boyden chemotaxis chamber. PAF (10(-8) to 10(-4) M) had no direct effect on EC albumin permeability, suggesting that the increase in permeability in sheep was not the direct lytic effect of PAF. In conclusion, PAF produces pulmonary vasoconstriction mediated by cyclooxygenase metabolites. PAF also increases pulmonary vascular permeability to protein that is independent of cyclooxygenase products and is not the result of a direct effect of PAF on the endothelium.     

IL-2 induces pulmonary edema and vasoconstriction independent of circulating lymphocytes

We investigated the effect of IL-2 in the isolated guinea pig lung perfused with phosphate-buffered Ringer's solution (containing 0.5 g/100 ml albumin and 5.5 mM dextrose) to determine the mechanism of IL-2-induced pulmonary edema. IL-2 (0 to 10,000 U/ml) was added to the perfusate following a 10 min baseline steady-state period. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight (as a measure of developing pulmonary edema) were recorded at 0, 10, 30, 40, and 60 min. The capillary filtration coefficient (Kf.c), an index of vascular permeability to water, was measured at 30 and 60 min. Infusion of IL-2 increased Ppc (from 3.9 +/- 0.1 cm H2O at baseline to 8.8 +/- 1.1 cm H2O at 60 min for IL-2 at 2000 U/ml, p less than 0.01; and from 3.8 +/- 0.1 cm H2O at baseline to 8.9 +/- 0.6 cm H2O at 60 min for IL-2 at 10,000 U/ml, p less than 0.01. The lung weight also increased (32% at IL-2 concentration of 2000 U/ml, and 26% at IL-2 concentration of 10,000 U/ml) The capillary filtration coefficient did not change with IL-2 infusion. The IL-2 response was prevented using the pulmonary vasodilator, papaverine. The infusion of IL-2 was associated with the generation of thromboxane A2(TxA2) in the effluent perfusate. Inhibition of TxA2 synthetase using Dazoxiben prevented the pulmonary vasoconstriction and edema response to IL-2. In addition, IL-2 had no effect on the transendothelial clearance of 125I-albumin. The results indicate that IL-2 causes pulmonary edema secondary to an increase in Ppc. The response is mediated by IL-2 stimulation of TxA2 generation from the lung.     

The Roles of Albumin Levels in Head and Neck Cancer Patients with Liver Cirrhosis Undergoing Tumor Ablation and Microsurgical Free Tissue Transfer

Objective

To evaluate the changes of serum albumin levels during the peri-operative period, and correlate these changes to surgical outcomes, postoperative morbidity and mortality in head and neck cancer patients with cirrhosis.

Methods

57 patients with liver cirrhosis out of 3,022 patients who underwent immediate free flap reconstruction after surgical ablation of head and neck cancer performed over a 9-year period were included in the study. Two sets of groups were arranged based on the preoperative albumin (>3.5 g/dL vs. ≤ 3.5 g/dL) and POD1 albumin (>2.7 g/dL vs. ≤ 2.7 g/dL) levels and were compared with respect to patient-related variables, surgical outcomes, medical and surgical complications, and mortalities.

Results

All patients had significant decreases in albumin levels postoperatively. Hypoalbuminemia, both preoperative and postoperative, was associated with the model for end-stage liver disease (MELD) score, the amount of blood loss, the duration of ICU stay and hospital stay, and postoperative medical and surgical complications. In particular, preoperative hypoalbuminemia (serum albumin ≤ 3.5 g/dL) was associated strongly with medical complications and mortality, while postoperative hypoalbuminemia (serum albumin ≤ 2.7 g/dL) with surgical complications.

Conclusion

Our study demonstrated the prognostic values of albumin levels in head and neck cancer patient with liver cirrhosis. The perioperative albumin levels can be utilized for risk stratification to potentially improve surgical and postoperative management of these challenging patients.