Rapid Extravasation Research Articles

Blood Viscosity of the Neonate

After completing this article, readers should be able to: 1. List the determinants of blood viscosity in the neonate. 2. List the causes of polycythemia and hyperviscosity in the neonate. 3. List the signs, symptoms, and diagnostic criteria for polycythemia and hyperviscosity. 4. Describe steps for prevention and treatment of polycythemia and hyperviscosity in the neonate. Blood viscosity is defined as resistance to the movement of blood. In a circular vessel or tube, the resistance (R) increases with increasing viscosity (V) of the moving fluid and with the resistance resulting from the vessel geometry (Z): R=Z · V. Thus, blood viscosity describes the contribution of blood rheologic factors to blood flow resistance. However, blood viscosity depends on several factors, and the importance of these factors differs among various vessels. The major determinants of blood viscosity are the hematocrit, plasma viscosity, red blood cell (RBC) aggregation, RBC deformability, leukocyte properties, vessel diameter, and the shear forces acting on the RBC. (1) The hematocrit generally is assumed to be the most important determinant of blood viscosity. Blood viscosity rises exponentially with increasing hematocrit (Fig. 1). A marked rise in blood viscosity is seen when the hematocrit exceeds 0.65 L/L, which typically is defined as the threshold for hyperviscosity of the blood. However, in narrow arteries and arterioles and in capillaries, the plasma viscosity becomes the dominant determinant of blood viscosity. The fetal hematocrit increases from 0.33 L/L in the 12th week of gestation to 0.45 L/L in the 30th week and 0.50 L/L in the 40th week at term. At birth, the hematocrit may rise markedly as a result of “blood transfusion” from the placenta to the neonate. (2) A postnatal hematocrit of 0.45 to 0.65 L/L is considered normal in the healthy term neonate. Figure 1. Blood viscosity in tubes that have a diameter of 50 …

Massive gastrointestinal hemorrhage due to rupture of a donor pancreatic artery pseudoaneurysm in a pancreas transplant patient.

Enteric drainage of secretions by anastomosing the donor duodenum to the recipient's small bowel has become common in pancreatic transplantation. While it eliminates many problems, endoscopic access to the transplanted duodenum and pancreas is made difficult. After a pancreas kidney transplant, the patient presented with massive hematochezia. Upper and lower endoscopy revealed large amounts of red blood in the colon but no specific bleeding site. Mesenteric angiography was normal but pelvic angiography showed rapid extravasation of contrast from a pseudoaneurysm of the pancreatic transplant artery. This was successfully embolized with coils. To the best of our knowledge, this is the first case of massive gastrointestinal hemorrhage because of rupture of a pseudoaneurysm of the donor pancreatic artery in a pancreas transplant patient. We report this case and review our institution's experience with all forms of gastrointestinal bleeding in pancreas transplant patients.

Gemcitabine-induced systemic capillary leak syndrome

Systemic capillary leak syndrome (SCLS) is a rare disorder with a high mortality rate, characterized by rapidly developing edema, weight gain and hypotension, hemoconcentration and hypoproteinemia. This syndrome is caused by sudden, reversible capillary hyperpermeability with a rapid extravasation of plasma from the intravascular to the interstitial space. Even though SCLS has been suggested to be the pathogenic mechanism for the pulmonary toxicity of gemcitabine (GCB), a new deoxycytidine analogue with structural similarities to cytosine arabinoside, a direct correlation between GCB and SCLS has never been reported. We describe a case of repeated SCLS after GCB administration in a 51-year-old male with locally-advanced non-small-cell lung cancer treated with a combination of cisplatin and GCB. The detection of GCB-induced SCLS supports the hypothesis that SCLS could be the pathogenic way of GCB pulmonary toxicity. This finding can help to better understand and treat the potentially deadly GCB-related acute respiratory distress syndrome that is being recognized.

SCVIR Annual Meeting Film Panel Session: Diagnosis and Discussion of Case 3

A 68-year-old man with transitional cell carcinoma of the bladder presented with generalized weakness and left hip pain and thigh swelling. He reported multiple falls at home. In the evaluation for metastatic disease, a Tc-99m methylene diphosphonate (MDP) whole body bone scan was performed (Fig 1). The bone scan shows marked radiotracer accumulation extending from the region of the left kidney to the anterior left thigh. Findings are suspicious for urine leakage from the left kidney or proximal ureter. Further work-up included a contrast-enhanced computer tomographic (CT) scan of the abdomen and pelvis (Fig 2). This shows bilateral hydronephrosis secondary to a large, locally invasive bladder tumor. Additionally, there is a well-encapsulated fluid collection within the left psoas muscle, extending into the muscles and soft tissues of the left thigh. Delayed CT images (Fig 3) show accumulation of dense contrast material within the previously identified fluid collection. Based on these findings, the patient was referred to the interventional radiology department and a left percutaneous nephrostomy was performed. A nephrostogram from the procedure (Fig 4) demonstrates rapid extravasation of contrast from the proximal left ureter into an amorphous cavity in the left flank, confirming the suspicion of ureteral disruption.

Human eotaxin induces eosinophil extravasation through rat mesenteric venules: role of alpha4 integrins and vascular cell adhesion molecule-1.

Eotaxin is a potent eosinophil-specific CC-chemokine, which has been shown to play a role in the selective induction of eosinophil accumulation in a number of allergic models of inflammation. Many aspects of the mechanism by which eotaxin induces eosinophil accumulation in vivo remain unresolved. In the present study, we investigated the direct effect of synthetic human eotaxin on leucocyte/endothelial cell interactions within rat mesenteric venules, as quantified by intravital microscopy. Topical eotaxin (30 pmol) induced rapid firm adhesion and extravasation of leucocytes within the rat mesentery, the extravasated leucocytes all being eosinophils, as determined by histological analysis. Whilst eotaxin was unable to stimulate the interaction of rat eosinophils with vascular cell adhesion molecule-1 (VCAM-1) under static conditions in vitro, eotaxin-induced responses in vivo were significantly suppressed by anti-alpha4 integrin and anti-VCAM-1 monoclonal antibodies (mAbs). The anti-alpha4 integrin mAb, HP2/1 (3.5 mg/kg), inhibited the eotaxin-induced firm adhesion and extravasation, 60 min postapplication of the chemokine, by 89% and 84%, respectively. In the same set of experiments, the anti-VCAM-1 mAb, 5F10 (3.5 mg/kg), inhibited leucocyte adhesion and extravasation by 61% and 63%, respectively. These results demonstrate that eotaxin-induced migration of eosinophils through rat mesenteric venules in vivo is dependent on an alpha4 integrin/VCAM-1 adhesion pathway, the significance of which may only be evident under flow conditions and/or following the ligation of other adhesion molecules expressed on eosinophils.

Staphylococcal enterotoxin-A-induced in-vitro adhesion of HL-60 cells to endothelial cells involves both selectin and integrin families of cell adhesion molecules.

In-vivo exposure to the bacterial superantigen Staphylococcal enterotoxin-A (SEA) induces an inflammatory response characterized by rapid extravasation of leucocytes and release of excessive amounts of cytokines. We have utilized an in-vitro adhesion assay to understand the molecular mechanisms responsible for SEA-induced extravasation of leucocytes. Stimulation of human umbilical cord endothelial cells (HUVEC) with increasing concentrations of recombinant SEA (rSEA) did not influence the in-vitro adhesion of HL-60 cells to HUVEC, whereas stimulation of HUVEC by interleukin (IL)-1beta supported adhesion of HL-60 cells. Increased adhesion of HL-60 cells to HUVEC was noted upon stimulation of endothelium with culture medium obtained from human peripheral blood mononuclear cells (PBM) stimulated with recombinant SEA for 24 (CM-SEA 24 h), 72 (CM-SEA 72 h) and 120 h (CM-SEA 120 h), but not after stimulation with culture medium obtained from control human peripheral blood mononuclear cells (CM), suggesting that soluble factors present in the supernatants play a major role in SEA-induced cell adhesion. While CM-SEA 24 and 72 h induced both a rapid (4 h) and delayed type of adhesion, CM-SEA 120 h only induced a delayed type of adhesion. Stimulation of PBM by SEA resulted in increased levels of IL-1beta, IL-2 and interferon (IFN)-gamma after 24h. Further stimulation for 72-120h resulted in a significant increase in the levels of IL-1beta, IFN-gamma and tumour necrosis factor (TNF). Stimulation of PBM with SEA also resulted in increased levels of soluble and L-selectin in the cell supernatants. Increased cell-surface expression of E-selectin, ICAM-1, HLA-DR and VCAM-1 was detected on HUVEC stimulated with CM-SEA media. While E-selectin and VCAM were induced on HUVEC within a few hours, induction of ICAM and HLA-DR required a longer induction period. Adhesion of HL-60 cells to HUVEC treated with CM-SEA was inhibited by monoclonal antibodies (MoAbs) against both the selectin and integrin families of cell adhesion molecules, suggesting that multiple pathways contribute to SEA-induced leucocyte extravasation. The results suggested that selectin-dependent adhesion was more prominent during the early phase while integrin-induced adhesion occurred at a later stage.

Sequential observation of micrometastasis formation by bacterial lacZ gene-tagged Lewis lung carcinoma cells.

Sequential events in micrometastasis formation including entry into the blood circulation and arrest, extravasation and initial growth in the lung was investigated using bacterial lacZ gene-tagged Lewis lung carcinoma cells (4A1-1). Micrometastases in the lung could thereby be specifically detected at the single cell level by X-Gal staining. After intravenous injection, X-Gal positive tumor cells appeared to extravasate within hours, but most cells then degenerated or died in the alveolar space by 2-3 days postinjection. A decreased BrdU labeling index to a negligible level at 2 days postinjection and reduction of X-Gal positive foci to a basal level (less than 0.1% of injected cells) by 4 days are in line with rapid clearance of tumor cells from the lung. The size and BrdU labeling indices of the persisting X-Gal positive foci, however, started to increase from 4 days postinjection. Type IV collagen immunostaining demonstrated loss of pre-existing basement membranes with growth of micrometastases: When 4A1-1 cells were inoculated subcutaneously, lung micrometastases from resulting tumors were detected as single or small numbers of X-Gal positive cells at 2 weeks postinjection. Progressive development of micrometastasis to macroscopic metastasis was noted by 4-5 weeks postinjection. The results indicate that micrometastasis formation by Lewis lung carcinoma cells involves a sequence of events starting with rapid extravasation after arrest in the lung within 1 day, followed by death of most cells at 2-3 days and subsequent new growth and expansion of persisting tumor cells from 4 days postinjection.

Kaposi's Sarcoma, Vascular Permeability, and Scientific Integrity-Reply

In Reply. —Our JAMA article, in keeping with our original correspondence with Science on April 24,1992, July 30,1992, and September 3, 1992, sought clarification of three specific issues related to the enhanced vascular permeability reported in 12-hour KS in the Science article by Dr Nakamura and colleagues 1 : (1) intense diffuse EB staining of tails in untreated but not SP-PG—treated nude mice; (2) easy extraction of extravasated tissue-bound EB-albumin complex using overnight incubation in PBS at 4°C; and (3) extraordinarily rapid extravasation of EB-albumin complex into tiny 12-hour KS lesions within 15 minutes of tail vein EB injection. Whereas heightened vascular leakiness, in addition to well-documented lymphatic dysplasia and obstruction, 2 may contribute to edema in AIDS-associated KS and angioinhibitory agents theoretically lessen such edema, the report by Nakamura et al in Science , a letter sent by Dr Gallo to Science on June 9,1992, and Science 's two tiers

Dieulafoy Disease: Arteriographic Findings and Treatment

Dieulafoy disease is an unusual cause of massive and frequently fatal gastrointestinal tract hemorrhage that results from the erosion of a submucosal artery. Although the lesion has been found throughout the gastrointestinal tract, it most commonly occurs in the proximal stomach. Nine patients with this condition have been treated at the authors' institution during the past 5 years. The bleeding lesion was located before surgery with selective visceral arteriography in three patients. Rapid extravasation was demonstrated from an eroded but otherwise normal-appearing artery in all three cases. Hemorrhage was controlled successfully in one patient with selective embolization of the involved left gastric artery branch. The remaining eight patients were treated with surgical ligation.

Intraperitoneal injection of zymosan in mice induces pain, inflammation and the synthesis of peptidoleukotrienes and prostaglandin E 2

Intraperitoneal injection of zymosan in mice induced rapid extravasation and accumulation of plasma proteins in the peritoneal cavity. Neutrophils began to appear in the peritoneal cavity after a lag period of approximately 3 hours. The injected mice exhibited a pain response (writhing) during the first 30 minutes after injection, but writhing ceased before protein or cell accumulation had reached maximum levels. The injection of zymosan induced synthesis of PGE 2 (measured by RIA) which reached maximum levels of 30 minutes, then declined slowly. Peptido-leukotriene levels (detected by bioassay, RIA and HPLC) increased rapidly after injection, reached a peak within an hour of injection and declined to undetectable levels within 4 hours. The early peptido-LT was predominantly LTC 4, while later, LTE 4 was the major component. LTD 4 levels remained low throughout and no LTB 4 was detected at any time. Indomethacin treatment elevated levels of peptido-LTs, recued PGE 2 levels and inhibited writhing. Phenidone reduced peptido-LT levels. In vitro studies demonstrated that zymosan stimulates LTC4 synthesis by peritoneal cells whereas LTE 4, LTD 4, LTB 4 or monoHETES were not detectable (using HPLC methods). The source of enzymes responsible for the in vivo metabolism of LTC 4 to LTD 4 and LTE 4 could not be identified.

Selective targeting of magnetic albumin microspheres to the Yoshida sarcoma: Ultrastructural evaluation of microsphere disposition

Magnetic albumin microspheres (1 μ m average diameter) were selectively targeted to subcutaneous solid Yoshida sarcoma tumors (average size 450 mm 2) in Holtzman rats. This was accomplished by placing an external magnet adjacent to the tumor while the microspheres were infused. Microspheres contained ultra-fine particles of Fe 3O 4 and no drug (placebo). Placebo microspheres were used due to the previously demonstrated rapid tumoricidal effect of targeted low-dose doxorubicin microspheres. Animals were killed 10 min, 60 min, 30 min, 24 hr and 72 hr after microsphere administration and tumors were examined by transmission electron microscopy to determine the in vivo disposition of the magnetically targeted microspheres. Using placebo microspheres, we have demonstrated microspheres endocytosed in endothelial cells as early as 10 min after infusion. By 30 min microspheres can be seen in the extravascular compartment, sitting adjacent to tumor cells and occasionally in tumor cells. By 24 hr the majority of microspheres have been endocytosed by tumor cells. Microspheres were still observed within tumor cells as late as 72 hr after administration. The rapid extravasation and cellular uptake of magnetically focused microspheres explains the extremely rapid tumoricidal effect previously observed when doxorubicin-containing microspheres were targeted to the tumor.

Fetal and neonatal rat intestinal capillaries: permeability to carbon, ferritin, hemoglobin, and myoglobin.

The function of the mural components involved in vascular exchange (pinocytotic vesicles, fenestrations, intercellular junctions, and the basal lamina) was assessed by intravascular injection of tracers (carbon, carbon plus histamine, ferritin, hemoglobin, and myoglobin) on separate gestational days in fetal and neonatal rat intestinal capillaries. The continuous capillaries present through day 17 of gestation were impermeable, even at junctions, to all the tracers within the maximum circulation time studied (3 minutes). Most of the luminal pinocytotic vesicles were labeled within 3 minutes with myoglobin (3.3-nm diameter) or hemoglobin (5.5-nm diameter), while only occasional vesicles contained ferritin (11-nm diameter) and none contained carbon (25-50nm diameter). Even though luminal pinocytotic vesicles contained the smaller tracers, no vesicular transport and discharge were ever seen. The fenestrated vessels present from day 18 of gestation allowed a rapid extravasation of ferritin and hemoglobin via diaphragmed fenestrations. At no time period did extravasation of carbon take place, nor did the carbon plus histamine solution induce vascular leakage. Once a tracer gained access to the extravascular space, the developing basal lamina did not seem to retard its movement.

Micropinocytic ingestion of glycosylated albumin by isolated microvessels: possible role in pathogenesis of diabetic microangiopathy.

Microvessels isolated from rat epididymal fat exhibit differential vesicular ingestion rates for unmodified and non-enzymatically glycosylated rat albumin. While unmodified rat albumin is excluded from ingestion by endothelial micropinocytic vesicles, glycosylated albumin is avidly taken up by endocytosis. Interaction of albumin and glycosylated albumin with endothelium was studied with a double-label fluorescence assay of micropinocytosis. When glycosylated albumin was present at a concentration of 6% with respect to total albumin (the level found in "non diabetic" serum), only glycosylated albumin was ingested. At higher concentrations of glycosylated albumin (those found in diabetic serum), both albumin and glycosylated albumin are ingested. Glycosylation of endothelial membrane components results in stimulated ingestion of glycosylated albumin, persistent exclusion of unmodified albumin, and unaltered micropinocytic ingestion of native ferritin. These results indicate that nonenzymatic glycosylation of serum albumin may result in rapid vesicle-mediated extravasation of albumin. Chronic microvascular leakage of glycosylated albumin could contribute to the pathogenesis of diabetic microangiopathy.

Distribution of intravenously injected protein tracers in peripheral ganglia of adult mice

The distribution of intravenously administered horseradish peroxidase (HRP), cytochrome c, and ferritin was studied in peripheral ganglia of adult mice in order to detect any possible differences in their extra- and intracellular localization. There was a rapid extravasation of all tracers into the extracellular space of craniospinal and autonomic ganglia. Endothelial fenestrae were identified in vessels from all ganglionic types, and the present findings are in line with previous reports that leakage of tracers takes place through fenestrae and open intercellular junctions. A few minutes after intravenous injection, HRP and cytochrome c penetrated between the satellite cell processes and nerve cell bodies in trigeminal ganglia and were also present in the periaxonal spaces of unmyelinated axons. The concentration of ferritin in the perineuronal space was low even 4 h after injection. HRP and ferritin were rapidly taken up by macrophages, but only small amounts of cytochrome c were detected inside these cells. Accumulation and intracellular digestion in macrophages seem to be important mechanisms for elimination of foreign proteins from the extracellular space. Nerve cells took up small quantities of HRP by endocytosis but no ferritin or cytochrome c was observed in neurons. The possible causes for differences in uptake of tracers are discussed.

Evaluation of 99mTc-albumin dilution curve with simultaneous injection of 99mTc- and 131I-albumins.

A critical comparison of radiocardiograms with 99mTc- and 131I-albumins was made to determine whether or not 99mTc-albumin can be used as a tracer for measuring blood volume (BV) and cardiac output (CO). Simultaneous injection of both isotopes was given to twenty-two patients to obtain radiocardiograms for each by means of a single scintillation counter with two pulse height analyzers. Such method allows for the determination of the energy levels for both 99mTc and 131I. The radiocardiographic pattern was somewhat different between 99mTc- and 131I-radiocardiograms: The ratio of left to right peak height was 16% on the average lower in the 99mTc-radiocardiogram in the 131I-one. The reason for the lower ratio is explained by greater absorption of 99mTc-radioactivity within the soft tissue interposing between the scintillation probe and heart. The values for 99mtc-derived blood volume were 7.4% on the average larger than those for 131I-derived blood volume (p less than 0.01), although the correlation was excellent (r = 0.98, p less than 0.01). There was no systemic difference between cardiac output determined by 99mTc- and 131I-albumins since the overstimation of blood volume can compensate for the understimation of CO/BV by 99mTc-study. In view of its rapid extravasation, 99mTc-albumin is not so appropriate tracer for accurate measurements of BV and CO/BV, although it may be used for measurement of cardiac output.

Cerebrovasculature permeability changes following experimental cerebral angiography: A light- and electron-microscopic study

Morphological alterations of the cerebral vasculature as related to the permeability of plasma proteins and angiographic contrast media following unilateral cerebral angiography were studied. Both Evans blue albumin and horseradish peroxidase were employed as protein tracers for light and electron microscopy investigation respectively. Grey matter regions of the cerebral cortex, cerebellum, corpus striatum, hippocampus and midbrain showed the most extensive and consistent leakage of these protein tracers. The most extensive penetration of EBA was noted at 1 hr following cerebral angiography as compared to the 5 or 30 min sample times. Permeability changes were noted in small venules and arterioles as well as capillaries. The extent of permeability, however, was appreciably greater in the capillaries as evidenced by rapid extravasation of HRP into the surrounding neuropil extracellular spaces. The glial basement membrane surrounding the perivascular spaces of small venules and arterioles precluded rapid penetration of HRP into the neuropil interstitium. Opening of the tight junctions between the endothelial cells was primarily responsible for the extravasation of HRP in all vessel types. Furthermore, it is our opinion that the hyperosmolar nature of the contrast medium is responsible for opening of these tight junctions.

125I-serum albumin assay of edema in rat skin with and without vasoconstriction after cryosurgery type freezing

Quantitative measurements of edema following standardized freezing traumas of depilated rat skin have been made by means of intravenously injected 125I human albumin. It is shown that the edema following a vigorous, cryosurgerytype freezing develops fully in about 30 min, after which it remains on a constant level for the duration of the experimental period. Little or no edema results if the tissues are treated with epinephrine before they are frozen. The rapid extravasation of a macromolecular substance such as human albumin is taken as an indication of severe vascular damage. It is believed that this vascular damage can to some extent be prevented by application of vasoconstrictors to the tissues prior to freezing.