Correlation of Quantitated Intravascular Volume with Blood Pressure in Patients with Systemic Hypertension.

Volume management is an essential component of anti-hypertensive therapy. Different volume phenotypes have been proposed. We sought to study the total blood volume (TBV), plasma volume (PV), and red blood cell volume (RBV) in hypertensive patients. We included patients followed in an outpatient cardiology clinic from 1998 to 2003. Blood volume (BV) parameters were measured using radioisotope iodine-131-labeled albumin dilution technique. Values were expressed as percentage (%) deviation from ideal volumes. A total of 95 patients were included. The intravascular volume distribution as percent deviation from normal volume ranged from - 23 to + 28% for TBV, - 22 to + 36% for PV and - 29 to + 37% for RBV. There was no significant correlation between systolic BP and any of the BV parameters (TBV and SBP, r = - 0.03; PV and SBP, r = - 0.12; RBV and SBP, r = - 0.08). Patients with hypertension have a wide variation in BV parameters. BV does not correlate with SBP.

Postural pseudoanemia: posture-dependent change in hematocrit.

OBJECTIVE: To determine the magnitude of posture-related changes in blood components. SUBJECTS AND METHODS: Twenty-eight healthy subjects were studied between 1995 and 2004 at the Vanderbilt Autonomic Dysfunction Center, Nashville, Tenn. Lying and standing plasma volume (PV) and hematocrit (Hct) values were determined for each subject. RESULTS: Individual PV decreases on standing ranged from 6% to 25%. The absolute mean +/- SD PV shift was 417+/-137 mL (range, 149-717 mL). The mean +/- SD change in Hct was from 37.7%+/-2.8% while supine to 41.8%+/-3.2% within 30 minutes of standing. This absolute increase in Hct of 4.1%+/-1.3% represents a relative increase of 11.0%+/-3.6% from lying to standing. CONCLUSIONS: Changes in posture can lead to substantial changes in Hct, which may be attributed mistakenly to blood loss or acute anemia and result in a cascade of unnecessary diagnostic costs. In reality, these changes represent postural pseudoanemia, a normal physiological response to a change in position from standing to lying (and vice versa).

Biodistribution studies of BSA loaded gelatin microspheres after peroral application.

Biodistribution studies of radiolabelled [131I]BSA loaded gelatin microspheres were carried out on BALB/c mice after peroral administration. To two groups, the radiolabelled [131I]BSA gelatin microspheres with different mean particle size, 1.196+/-1.961 and 7.028+/-1.231 microm were administered orally. To the control group, a solution of [131I]BSA was also orally administered. Biodistribution was followed periodically within 15 days as a percent of total radioactivity present in stomach, small intestine with Peyer's patches and mesentery, colon with Peyer's patches, appendix and mesentery, liver, spleen, blood, kidney, lungs and heart. The biodistribution data confirmed that uptake in mice into Peyer's patches and passage to the liver and spleen via the mesentery lymph supply and nodes, increased with decreasing particle size.

Augmentation of intrapericardial nitric oxide level by a prolonged-release nitric oxide donor reduces luminal narrowing after porcine coronary angioplasty.

BACKGROUND: Nitric oxide (NO) is a potent vasodilator and antiplatelet agent that suppresses vascular smooth muscle cell proliferation. Hypothesizing that generating NO in the pericardial space would reduce luminal narrowing after coronary angioplasty without affecting systemic hemodynamics, we have determined the effect of a novel NO donor on vascular healing after balloon overstretch. METHODS AND RESULTS: Diazeniumdiolated bovine serum albumin (D-BSA; molecular weight 74 kDa, half-life for NO release 20 days) was radioiodinated and found by intravital gamma-imaging to have a longer residence time in pig pericardium than a low-molecular-weight (0.5 kDa) analogue (22 versus 4.6 hours, respectively). Intrapericardial injection of D-BSA immediately before 30% overstretch of normal left anterior descending and left circumflex coronary arteries dose dependently reduced the intimal/medial area ratio by up to 50% relative to controls treated with underivatized albumin when measured 2 weeks after intervention. Positive remodeling was also noted, which increased luminal area relative to control. CONCLUSIONS: Perivascular exposure of coronary arteries to NO via intrapericardial D-BSA administration reduced flow-restricting lesion development after angioplasty in pigs without causing significant systemic effects. The data suggest that intrapericardial delivery of NO donors for which NO release rates and pericardial residence times are matched and optimized might be a beneficial adjunct to coronary angioplasty.

Alveolar epithelial barrier functions in ventilated perfused rabbit lungs.

We employed ultrasonic nebulization for homogeneous alveolar tracer deposition into ventilated perfused rabbit lungs. (22)Na and (125)I-albumin transit kinetics were monitored on-line with gamma detectors placed around the lung and the perfusate reservoir. [(3)H]mannitol was measured by repetitive counting of perfusion fluid samples. Volume of the alveolar epithelial lining fluid was estimated with bronchoalveolar lavage with sodium-free isosmolar mannitol solutions. Sodium clearance rate was -2.2 +/- 0.3%/min. This rate was significantly reduced by preadministration of ouabain/amiloride and enhanced by pretreatment with aerosolized terbutaline. The (125)I-albumin clearance rate was -0.40 +/- 0.05%/min. The appearance of [(3)H]mannitol in the perfusate was not influenced by ouabain/amiloride or terbutaline but was markedly enhanced by pretreatment with aerosolized protamine. An epithelial lining fluid volume of 1.22 +/- 0.21 ml was calculated in control lungs. Fluid absorption rate was 1.23 microl x g lung weight(-1) x min(-1), which was blunted after pretreatment with ouabain/amiloride. We conclude that alveolar tracer loading by aerosolization is a feasible technique to assess alveolar epithelial barrier properties in aerated lungs. Data on active and passive sodium flux, paracellular solute transit, and net fluid absorption correspond well to those in previous studies in fluid-filled lungs; however, albumin clearance rates were markedly higher in the currently investigated aerated lungs.

Technique and results of hyperthermic isolated hepatic perfusion with tumor necrosis factor and melphalan for the treatment of unresectable hepatic malignancies.

BACKGROUND: For a variety of histologies, the liver represents the only or the dominant site of metastatic disease. Regional treatment of the liver has the theoretic advantage of maximizing drug delivery while minimizing systemic toxicity. This article describes the technique of isolated hepatic perfusion using tumor necrosis factor and melphalan under conditions of moderate hyperthermia for the treatment of unresectable liver tumors. STUDY DESIGN: Fifty patients with biopsy-proved unresectable primary or metastatic cancer to the liver were treated. Isolated hepatic perfusion was performed for 60 minutes under conditions of moderate hyperthermia during a laparotomy with inflow through the gastroduodenal artery and outflow through an isolated segment of inferior vena cava. During isolated hepatic perfusion portal and infrahepatic blood flow were shunted externally by a centrifugal pump to the axillary vein. Complete vascular isolation was confirmed intraoperatively using a continuous 131I-labeled serum albumin leak monitoring system. Operative and perfusion parameters were recorded. RESULTS: By using a standard operative technique to achieve complete vascular isolation of the liver during perfusion, there was no leak ofperfusate detected in 48 of 50 patients as determined by the continuous leak monitoring system and absence of detectable systemic tumor necrosis factor levels. Operating time, transfusion requirements, and blood loss were within the range expected for a major operative procedure. Stable hemodynamic and perfusion parameters were achieved consistently and all patients successfully completed the 60-minute perfusion. Two patients (4%) died as a result of treatment and significant tumor regression was observed in 75%. CONCLUSIONS: Isolated hepatic perfusion is a technique that can be used to deliver high doses of chemotherapy or biologic therapy regionally and without systemic exposure. By using a standard operative technique, continuous intraoperative leak monitoring, and an external veno-veno bypass circuit, this procedure can be done safely and with acceptable morbidity and mortality. This article demonstrates that sustained and complete vascular isolation of the liver can be achieved and indicates further study is warranted to better define the role of isolated hepatic perfusion in the treatment of unresectable liver tumors.

Brain-blood permeability: TNF-alpha promotes escape of protein tracer from CSF to blood.

The objective of this study was to determine the effect of tumor necrosis factor (TNF)-alpha on the efflux of protein from the central nervous system to blood based on assessing the clearance of radiolabeled albumin from the cerebrospinal fluid (CSF) to blood in rats. (125)I-labeled human serum albumin ((125)I-HSA) was injected into a lateral ventricle, and venous blood was sampled hourly to determine the basal CSF protein clearance into the blood. After this, rats were intraventricularly infused with 10 microliter TNF-alpha and 10 microliter (131)I-HSA (n = 6) or 10 microliter saline and 10 microliter (131)I-HSA (n = 6). Venous blood was sampled hourly for 3 h. (131)I-HSA tracer recovery increased threefold in the venous blood and was significantly higher in the spleen, muscles, and skin in animals treated with TNF-alpha. No significant changes were observed in control animals treated with saline. The data suggest that TNF-alpha promotes the clearance of protein macromolecules from the CSF to the venous blood.

Pharmacokinetics and consistency of pericardial delivery directed to coronary arteries: direct comparison with endoluminal delivery.

BACKGROUND AND HYPOTHESIS: Pharmacologic modulation of the contents of the pericardial space has been shown to influence the response of coronary arteries to balloon injury. Endoluminal (EL) local delivery of various drugs into coronaries has been found to be limited by short residence time, as well as by highly variable deposited agent concentration. We hypothesized that compounds placed into the pericardial space (P) would penetrate into coronary tissue with greater consistency than seen after EL delivery and provide for prolonged coronary exposure to agents. METHODS AND RESULTS: 125I-labeled basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), albumin, or 131I-labeled diazeniumdiolated albumin (NONO-albumin) were delivered as model/therapeutic proteins into the porcine pericardial space (n = 15 pigs) or into coronaries using an EL delivery catheter (n = 48 arteries). In subjects receiving 125I-labeled proteins, the delivery target or mid-regions of the left anterior descending (LAD) and left circumflex (LCx) arteries were harvested at 1 h or 24 h for gamma-counting and autoradiography, and fractional intramural delivery (FID) or retention measured as percent agent in 100 mg artery/agent in infusate for both time points. In the animals receiving 131I-labeled NONO-albumin, serial gamma imaging was employed to evaluate the rate of redistribution in individual animals following either pericardial or endoluminal delivery. At 1 h, FID values ranged from 0.00064 to 0.0052% for P delivery (median 0.0022%), and from 0.00021 to 6.7 for EL delivery (median 0.27%). At 24 h, FID values ranged from 0.00011 to 0.003 for P delivery (median 0.0013), and from 0.0002 to 1.4 for EL delivery. The estimated T1/2 for bFGF redistribution from the vascular tissue was 22 h (P) and 7 h (EL), respectively, while the directly determined T1/2 values for NONO-albumin redistribution from the delivery region were 22.2 h (P) and 2.5 h (EL). CONCLUSIONS: These data show that pericardial fluid contents can access coronary arteries with intramural concentrations which typically vary by 10-15-fold, while EL delivery results in a remarkably wide intramural concentration range with up to 33,000-fold variability. The apparent redistribution rate is more rapid following EL delivery, possibly due to sustained diffusive tissue loading from the pericardial space. Pericardial delivery appears to offer substantial advantages over EL administration with respect to residence time and reproducibility.

Determination of volumetric cerebrospinal fluid absorption into extracranial lymphatics in sheep.

We estimated the volumetric clearance of cerebrospinal fluid (CSF) through arachnoid villi and extracranial lymphatics in conscious sheep. Catheters were inserted into both lateral ventricles, the cisterna magna, multiple cervical lymphatics, thoracic duct, and jugular vein. Uncannulated cervical vessels were ligated. 125I-labeled human serum albumin (HSA) was administered into both lateral ventricles. 131I-HSA was injected intravenously to permit calculation of plasma tracer loss and tracer recirculation into lymphatics. From mass balance equations, total volumetric absorption of CSF averaged 3.37 +/- 0.38 ml/h, with 2.03 +/- 0.29 ml/h (approximately 60%) removed by arachnoid villi and 1.35 +/- 0.46 ml/h (approximately 40%) cleared by lymphatics. With projected estimates for noncannulated ducts, total CSF absorption increased to 3.89 +/- 0.33 ml/h, with 1.86 +/- 0.49 ml/h (48%) absorbed by lymphatics. Additionally, we calculated total CSF drainage to be 3.48 +/- 0.52 ml/h, with 54 and 46% removed by arachnoid villi and lymphatics, respectively, using previously published mass transport data from our group. We employed estimates of CSF tracer concentrations that were extrapolated from relationships observed in the study reported here. We conclude that 40-48% of the total volume of CSF absorbed from the cranial compartment is removed by extracranial lymphatic vessels.

Serum albumin distribution in early treated anorexia nervosa.

We investigated the effects of malnutrition and refeeding on albumin distribution and metabolism in patients undergoing treatment for anorexia nervosa. Using autologous 125I-labelled albumin, we measured the fractional catabolic rate and calculated the relative sizes of the plasma and extravascular albumin pools in 6 female anorexia nervosa subjects and 6 matched controls. We were unable to demonstrate any differences in either the catabolic rate of albumin (fractional or absolute) or in serum albumin concentration between anorexia nervosa and control subjects. There was a large expansion of the extravascular albumin pool in the anorexia nervosa subjects--36% when expressed in relation to body weight. We conclude that, at the time of study, there were no effects of anorexia nervosa on albumin catabolism in these subjects. However, the condition and its treatment are associated with a significant relative expansion of the extravascular albumin pool. This contrasts to some extent with previous work, which suggested that in protein depletion the plasma albumin pool is maintained at the expense of the extravascular albumin pool. The expansion of the extravascular albumin pool is possibly related to the relative excess of interstitial fluid seen in starvation and in the initial phases of refeeding.

Quantitation of lymphatic drainage of the peritoneal cavity in sheep: comparison of direct cannulation techniques with indirect methods to estimate lymph flow.

OBJECTIVE: It has been suggested that lymphatics may contribute to ultrafiltration failure in patients on continuous ambulatory peritoneal dialysis (CAPD) by absorbing dialysate and ultrafiltrate from the peritoneal cavity. In most studies lymphatic drainage has been estimated from the disappearance of an instilled tracer from the peritoneal cavity or estimated from the appearance of an intraperitoneally administered tracer in the bloodstream. However, in sheep it is possible to cannulate several of the relevant lymphatics that drain the peritoneal cavity and assess lymph drainage parameters directly. The purpose of this study was to estimate lymph drainage from the peritoneal cavity in sheep using the disappearance of tracer from the cavity and the appearance of intraperitoneally instilled tracer in the bloodstream and to compare these results with those obtained from our previous studies using cannulation techniques. DESIGN: Experiments were performed in anesthetized and nonanesthetized animals. Volumes of 50 mL/kg of Dianeal 4.25% containing 25 microCi of 125I-albumin were infused into the peritoneal cavity. RESULTS: In anesthetized sheep the calculated peritoneal lymph drainage from monitoring the disappearance of tracer from the peritoneal cavity over 6 hours was 1.873 +/- 0.364 mL/kg/hour. Monitoring the appearance of tracer in the blood gave significantly lower peritoneal lymph flow rates of 1.094 +/- 0.241 mL/kg/hour. Directly measured lymph flow rates from our earlier publication were lower still and ranged from 0.156 +/- 0.028-0.265 +/- 0.049 mL/hour/kg, depending on how we estimated the right lymph duct contribution to peritoneal drainage, since we could not cannulate this vessel. We repeated these experiments in conscious sheep. The value for lymph flow estimated from the disappearance of tracer from the peritoneal cavity was 2.398 +/- 0.617 mL/hour/kg and from the appearance of tracer in the blood, 1.424 +/- 0.113 mL/hour/kg. The lymph flow rates monitored from indwelling lymphatic catheters ranged from 1.021 +/- 0.186-1.523 +/- 0.213 mL/hour/kg (again, depending on our estimates for the right lymph duct). CONCLUSIONS: Lymph flow rates measured from indwelling lymphatic catheters provided the most conservative values for lymphatic drainage of the peritoneal cavity under dialysis conditions. Estimates of lymphatic drainage based on the appearance of tracer in the blood gave values that were on average higher. The method using the disappearance of tracer from the cavity to estimate lymph flows overestimated peritoneal lymph drainage. Fluid was lost from the peritoneal cavity, and the estimated proportion of liquid lost through lymphatic drainage depended on the technique used to measure lymph flow rates.

Flare-up of antigen-induced arthritis in mice after challenge with oral antigen.

Mice with unilateral chronic mBSA-induced arthritis were orally challenged with mBSA. Three hours after antigen challenge clear flare-up of the chronic arthritis was demonstrable as detected by an increase in the 99mTc uptake of the knee joint and the reaction continued for at least 2 days. The contralateral non-arthritic knee joint was not affected. The dose of mBSA needed to induce a flare-up in nearly all mice within a group was in the order of 20 mg. After oral challenge with 10 or 5 mg of mBSA the incidence was lower and flare-up reactions were only rarely observed after challenge with 2.5 or 1.25 mg mBSA. Histology of knee joints taken at 24 h after oral challenge of 20 mg mBSA revealed an increase in the number of cells in the infiltrate in the synovial tissue and exudate in the joint space, the most conspicuous sign being the increase of PMN. Passage of macromolecules through the gastrointestinal mucosa may be an important principle in the perpetuation of human chronic arthritis.

[Cystography of the spinal cord for delineating tactics for surgical treatment of syringomyelia]. / Kistografiia spinnogo mozga v opredelenii taktiki khirurgicheskogo lecheniia siringogidromielii.

Radiocontrast study of cystic cavities of the spinal cord was conducted in 23 patients with the clinical picture of syringomyelia and syringobulbia. Diffuse cystic cavities were demonstrated in the cervical and thoracic segments of the spinal cord in 22 patients. In 9 patients, the spinal cysts communicated with the cavity of the fourth ventricle. In 2 cases, the cysts extended to the region of the spinal cord terminal filament. The information obtained allowed a differential approach to the choice of the method and tactics of surgical treatment of syringohydromyelia. Macrosurgical operations on the craniovertebral level with tamponade of the communication between the spinal cord cyst and the cavity of the fourth ventricle were carried out in patients with the communicating form of syringomyelia. Operations for dividing the terminal filament of the spinal cord or myelotomy with drainage of the cyst at the cervical or thoracic level were performed in other cases.

The arterially perfused enucleated rabbit eye as a model for studying aqueous humor formation.

The rate of turnover of aqueous humor (Kout), as measured by the decay of radioactive inulin from the anterior chamber of the enucleated eye, was similar to the rate of loss of 125I-RISA (radioiodinated serum albumin) from the eye of a living rabbit. Arterial perfusion with 125I-RISA or rabbit serum showed that the permeability characteristics of the blood-aqueous barrier to protein molecules are unaffected in the enucleated eye. The viability of the enucleated eye for secretion of ascorbic acid was also examined, but the results were inconclusive.

Etamsylate (Dicynone) reduces aqueous humor formation and intraocular pressure in rabbits.

The rate of aqueous humor production (measured by the clearance of 125I-labeled albumin administered into the anterior chamber) and the intraocular pressure (measured via an electronic transducer) fell after subconjunctival infection of 37 mg (0.3 ml) of etamsylate (Dicynone) in rabbits. The differences between treated and untreated animals with respect to both variables were statistically significant. It is conjectured that the action of etamsylate in lowering intraocular pressure may be mediated at least in part by its reduction of aqueous humor formation.

Chronic pulmonary inflammation modulates the fate of proteins administered by the respiratory tract. Organ distribution of radiolabeled proteins.

In a previous report we found that, following intrapulmonary administration of radiolabeled albumin, blood concentrations were higher in rabbits with BCG-induced chronic pulmonary inflammation (CPI) than in normal rabbits. The present study demonstrates that this increased blood concentration was not the result of decreased blood clearance by other organs, indicating that increased absorption through the respiratory tract occurred in the inflamed lungs. In addition, rabbits with BCG-induced CPI had larger hilar lymph nodes and larger concentrations of radioactivity in the hilar lymph nodes, suggesting that the pulmonary lymphatics are a route of increased absorption through inflamed lungs.

The effect of angiotensin II on in vivo albumin transport in normal rabbit aortic tissue.

Angiotensin II and other vasoactive amines may have a direct effect on the permeability of the arterial wall. We have investigated the effect of angiotensin II in vivo albumin transport across the aortic wall in rabbits following intravenous injection of [125I]albumin. Transmural concentration profiles of 125I-labeled albumin across the intima and media of the aorta, generated during 25 min of either angiotensin or saline infusion, were measured by a serial-sectioning technique. The uptake of labeled albumin through the aortic wall was found to be dependent on position and to increase from the descending thoracic up to the arch. Angiotensin infusion increased albumin uptake in the region of the aorta proximal to the first pair of intercostal arteries and magnified the position dependence. Angiotensin infusion did not change the uptake of albumin in the descending thoracic aorta between intercostal arteries. The arterial blood pressure elevation associated with angiotensin infusion was not of prime importance in producing the uptake patterns described above.