Experimental studies on the effective factors and the neural control system of intraosseous pressure in the patella of dogs

Physiological studies on the patellar intraosseous pressure gave the following results: The mean value of the intraosseous pressure was 12.5 mmHg (range 7-19.5 mmHg). The effects of femoral vascular occlusion and intravenous infusion of epinephrine or norepinephrine were similar to those reported on long bones. Not only the elevation of intraarticular pressure but also the compression of the infrapatellar fat pad increased intraosseous pressure during extension or flexion of the knee as a result of venous engorgement. The results of efferent nerve stimulation suggested that the femoral nerve carried the vasomotor fibers supplying the vessels of the patellar bone marrow. The afferent nerve responded to more than 20-39 mmHg elevation of the patellar intraosseous pressure.     

From marrow oedema to osteonecrosis: common paths in the development of post-transplant bone pain

Osteonecrosis, the calcineurin-inhibitor-induced pain syndrome and transient marrow oedema may occur after renal transplantation, are generally painful and can be diagnosed by X-ray, radionuclide scan or magnetic resonance imaging. They share features of increased intraosseous pressure, compromised vascular supply, marrow oedema and the development of a 'bone compartment syndrome'. Glucocorticoid dosage is the most commonly implicated risk factor for osteonecrosis. Mechanisms may include the differentiation of mesenchymal stem cells to adipocytes causing increased intraosseous pressure and collapse of marrow sinusoids, as well as increased osteoblast and osteocyte apoptosis. Some of these effects may be ameliorated by lipid lowering drugs. Calcineurin-inhibitors, particularly cyclosporine, may increase the risk of osteonecrosis because of vasoconstrictive effects and sirolimus may influence the development of osteonecrosis by potentiating the effects of calcineurin inhibitors or by influencing the lipid profile. For osteonecrosis, early stages are generally managed conservatively or with core decompression sometimes accompanied by bone grafting and more recently the injection of bone morphogenic protein. The use of iloprost to improve blood flow and bisphosphonates and RANK-ligand inhibition to reduce osteoclastic resorption of remaining trabecular structures are as yet unproven strategies. Unfortunately, the rate of total hip arthroplasty remains high. For the calcineurin-inhibitor-induced pain syndrome and transient marrow oedema, calcium channel blockers, the reduction or withdrawal of calcineurin-inhibitors and core decompression have been used. Although a lack of randomized controlled trials makes management decisions difficult, early recognition of these bone pain syndromes affords the best opportunity for avoiding prolonged pain or joint replacement surgery.     

Coagulopathies and osteonecrosis

Intravascular coagulation of the intraosseous microcirculation (capillaries and venous sinusoids) progressing to generalized venous thrombosis, and less commonly retrograde arterial occlusion, now appears to be the cause of nontraumatic osteonecrosis. However, this coagulopathy is only an intermediary event, which is always activated by some underlying etiologic risk factor(s). Conditions capable of triggering intravascular coagulation include familial thrombophilia (resistance to activated protein C, decreased protein C, protein S, or antithrombin III), hyperlipemia and embolic lipid (alcoholism and hypercortisonism), hypersensitivity reactions (allograft organ rejection, immune complexes, and antiphospholipid antibodies), bacterial endotoxic (Shwartzman) reactions and various viral infections, proteolytic enzymes (pancreatitis), tissue factor release (inflammatory bowel disease, malignancies, neurotrauma, and pregnancy), and other prothrombotic and hypofibrinolytic conditions.     

Relationship between hepatic hemodynamics and biliary pressure in dogs: Its significance in clinical shock following biliary decompression

The changes in the hepatic hemodynamics were promptly reflected in the biliary pressure in dogs. Both wedged hepatic venous pressure and portal venous pressure increased in response to the elevated biliary pressure, and conversely decreased following rapid biliary decompression, suggesting that the changes in the biliary pressure might affect the hepatic hemodynamics post-sinusoidally. It was supposed that too rapid biliary decompression might trigger the following consequences; 1) decrease in sinusoidal pressure, 2) increase in sinusoidal inflow, and 3) extravasation of intravascular fluid in the perivascular space. When these were not sufficiently compensated, they could trigger shock in the jaundiced patients.     

Intraosseous hypertension and venous congestion in osteonecrosis of the knee

To determine whether an angiogenic factor affects the pathogenesis of the idiopathic osteonecrosis of the medial femoral condyle, intraosseous pressure and venogram in 11 knees with osteonecrosis were compared with intraosseous pressure and venogram in 11 knees with the medial type of osteoarthritis. Patients were matched by age, gender, obesity index, blood pressure, tibiofemoral angle, and clinical evaluation. The intraosseous pressure of the medial condyle of the knees with osteonecrosis (62.8 +/- 27.3 mm Hg) was significantly higher than that in the lateral condyle of the knees with osteonecrosis (25.4 +/- 18.9 mm Hg) and those of both condyles of the knees with osteoarthritis (medial, 31.6 +/- 17.4 mm Hg; lateral, 29.5 +/- 11.0 mm Hg). In contrast, there was no significant difference in the pressure between the medial and lateral condyles of the knees with osteoarthritis. Venography showed a marked disturbance of venous drainage in all patients with osteonecrosis. In addition, the average clearance time of the medium in the medial femoral condyle was significantly more prolonged in patients with osteonecrosis (17.7 +/- 6.1 minutes) than in patients with osteoarthritis (5.5 +/- 1.6 minutes). These data support the hypothesis that venous stasis within the medullar canal in the condyle increases intraosseous pressure and decreases arteriovenous pressure difference, leading to osteonecrosis.     

Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis.

The etiology of steroid-induced osteonecrosis (ON) is unclear. This study was designed to determine whether bone marrow fat cell size, intraosseous pressure, and blood flow rate differed between steroid-treated rabbits with ON and those without. Twenty-nine rabbits were intramuscularly injected once with 20 mg/kg of methylprednisolone acetate (MPSL), and five rabbits were injected once with physiologic saline (PS) as a control. Intraosseous pressure and blood flow rate in the proximal femur were determined before and at 2 weeks after the injection. After these measurements, both femora and humeri were histopathologically examined for the presence of ON, and size of bone marrow fat cells were morphologically examined. At 2 weeks after steroid injection, the intraosseous pressure was significantly higher in rabbits with ON than in those without (p = 0.0251), and the blood flow rate had decreased significantly more in rabbits with ON than in those without (p = 0.0051). The size of the bone marrow fat cells was significantly (p = 0.0004) larger in rabbits with ON (diameter, 63.5 +/- 5.8 microm) than in those without (diameter, 53.3 +/- 6.9 microm). Injection of PS (5 rabbits), 1 (10 rabbits), 5 (10 rabbits), and 20 (10 rabbits) mg/kg of body weight of MPSL showed that a larger dose of steroid increased both fat cell size and prevalence of ON. These results suggest that bone marrow fat cell enlargement and a rise in intraosseous pressure may be important when considering the pathophysiology of steroid-induced ON in rabbits.     

Intravascular coagulation and osteonecrosis.

Current evidence suggests that intravascular coagulation (IC), an intermediary mechanism, is the most likely final common pathway by which intraosseous fat embolism causes nontraumatic osteonecrosis (ON). Stage 1A lesions (fatty osteocytic necrosis) appear to progress to classic Stage 1B lesions (ischemic degeneration of necrotic osteocytes and adipocytes) when the ischemic threshold is exceeded by absolute subchondral fat overload with insufficient local clearance of procoagulants, especially tissue thromboplastin. The result is vascular stasis, hypercoagulability, endothelial damage (by free fatty acids) and IC, especially if there is coexistent subchondral vasoconstriction and impaired secondary fibrinolysis. Osteonecrosis can be produced in animals by IC, which begins in the vulnerable subchondral microcirculation (Arthus phenomenon). Cartography (embolic scintimetry with superselective angiography) indicates early complete devascularization of the femoral head, suggesting progressive venous and retrograde arterial thrombosis. Increased plasma fibrinopeptide A and direct histologic evidence of intraosseous thromboses and peripheral hemorrhages further indicate that IC is the final pathway. Best evidence are 51 ON lesions complicating disseminated IC in eight children (Shwartzman phenomenon), with collateral histologic evidence of intraosseous thrombosis and ON.     

Dysbaric osteonecrosis. Etiological and pathogenetic concepts

Dysbaric osteonecrosis appears to be independent of decompression sickness. The 2 conditions, however, may share etiologic and pathogenetic factors. The incidence of osteonecrosis is influenced by the number of hyperbaric exposures, extent of pressure, decompression profile and possibly by the rate of compression and degree of obesity. Though etiology and pathogenesis are unclear, osteonecrosis is probably due to ischemia, with gas bubbles causing direct or indirect circulatory impairment. In vitro experiments, as well as human and animal studies, suggest multiple pathogenetic mechanisms: intraosseous vessel compression by extravascular bubbles; vessel obstruction by bubbles, fibrin thrombi, platelet aggregates, clumped erythrocytes or coalesced lipids; and narrowing of arterial lumina by bubble-induced myointimal thickening. Obstructing materials, whether autochthonous or embolic, may result from blood-bubble interface reactions. Rheologic changes and blood flow redistribution could play contributing roles. It seems likely that multiple pathogenetic factors act in concert or sequentially. Proposed nonischemic changes, such as hyperoxic injury gas-induced osmosis, or autoimmunity, lack sufficient supporting evidence. The peculiar vulnerability of bone may be related to gas supersaturation of the fatty marrow; sensitivity to extravascular gas pressure because of tissue rigidity; poor vascularization; and the presence of uranium 238 which promotes nucleation and subsequent gas bubble formation.     

Vasoactive substances in subchondral bone of the dog knee

The purpose of the present study was to investigate regulatory mechanisms for subchondral bone blood flow. A model including elevation of joint cavity pressure in the immature dog knee was applied. The role of prostaglandins in bone blood flow regulation was indirectly examined by indomethacin blockade. In six puppies, both venous tamponade of the joint cavity [50% of the mean arterial blood pressure (MAP)] and arterial tamponade (150% of MAP) resulted in a significant increase in the intraosseous pressure of the distal femoral epiphyses (p less than 0.05). During venous tamponade no changes were registered in pO2, pCO2, pH, potassium, and lactate in blood withdrawn from the distal femoral epiphyses. Arterial tamponade resulted in hypoxia, a decrease in pH, and increased lactate. Inhibition of the prostaglandin synthesis did not alter this response pattern. Thus, the present study suggests the presence of a regulatory mechanism for subchondral bone blood flow since venous tamponade did not significantly alter intraosseous gas tensions, pH, lactate, or potassium in spite of elevated venous outlet resistance. The study does not allow any conclusion as to the exact nature of the regulatory mechanism, but local metabolic regulation is likely to be involved as indicated by accumulation of vasoactive substances at higher tamponade levels. Prostaglandins are probably of minor importance in this regulation.     

Sildenafil prevents cardiovascular changes after bone marrow fat embolization in sheep

BACKGROUND: Sudden, intraoperative cardiovascular deterioration as a result of pulmonary embolization of bone marrow fat is a potentially fatal complication during total hip and knee arthroplasty, intramedullary nailing, and spine surgery. Anesthetic management is challenging in the presence of increased right ventricular afterload due to pulmonary hypertension. Selective pulmonary vasodilation may be an appropriate prophylactic or therapeutic measure. The effect of sildenafil (phosphodiesterase inhibitor) on cardiovascular deterioration after bone marrow fat embolization was therefore investigated. METHODS: Bone cement (polymethylmethacrylate) was injected into three lumbar vertebrae in 12 sheep. Invasive blood pressures and heart rate were recorded continuously until 60 min after the last injection. Cardiac output and arterial and mixed venous blood gas variables were measured at selected time points. Before the first cement injection, 6 animals received a bolus injection (0.7 mg/kg) of sildenafil, with continuous infusion (0.2 mg . kg . h) thereafter. Postmortem lung and kidney biopsies were taken for semiquantitative analysis of intravascular fat. RESULTS: Fat embolism was associated with a transient increase (21 +/- 7mmHg) in pulmonary arterial pressure. A transient decrease in arterial blood pressure and temporary increases in central venous pressure and dead space were also observed. No significant changes in any cardiovascular variable were observed after fat embolism in the sildenafil group. There was significantly (P < 0.05) less intravascular fat in the lungs of the sildenafil (median count of 5 emboli per microscopic view) compared with the control group (median count of 1). CONCLUSIONS: Administration of sildenafil prevented the acute cardiovascular complications after bone marrow fat embolism in sheep.     

Arteriovenous shunting is not associated with venous congestion in bone. Knee tamponade studied with 15-microns and 50-microns microspheres in immature dogs

Blood flow in the hind-limb bones of 8 immature labrador dogs with unilateral knee joint tamponade at 75 percent of the mean arterial pressure was measured with 15-microns and 50-microns microspheres to determine whether or not arteriovenous shunting occurs in bone with venous congestion caused by increased outflow resistance. The intraosseous pressure was 43 percent of the mean arterial pressure in the experimental distal femoral epiphysis versus 14 percent in the control knee (P less than 0.001). No pressure changes were found in the distal femoral metaphysis. Regional blood flow with 15-microns microspheres decreased centrally in the distal femoral epiphysis and increased centrally in the proximal tibial epiphysis. Metaphyseal blood flow was largely unchanged. A net shift in the preferred embolization site of 50-microns microspheres relative to that of 15-microns microspheres from central to peripheral regions occurred within both juxtaarticular epiphyses, indicating arteriolar vasodilation, but the relation between the uptake of the two microsphere sizes was unchanged when the epiphyses and other bony flow compartments were viewed in toto. The result speaks against the hypothesis of arteriovenous shunting in intraosseous hypertension.     

Diagnosis and treatment of idiopathic necrosis of the femoral head

Fourteen cases, 25 hips, of idiopathic necrosis of femoral head (INFH) were included in our series. The role of radiographs, isotopic bone scanning, intraosseous pressure measurement and intraosseous venography in diagnosis of INFH was evaluated. Radiological examination cannot reveal early case, while isotopic bone scanning was more sensitive. There was increase of intraosseous pressure in most diseased hips. Intraosseous venography was abnormal in all examined hips. These two tests could therefore detect early INFH. Core decompression was performed on 21 hips. The operated hips were followed for 3.5 months to 20 months. Functional evaluation of 18 hips were good or excellent. Radiographic re-examination of 20 hips remained unchanged. The postoperative intraosseous pressure measurement and intraosseous venography in examined hips revealed a decrease of intraosseous pressure and improvement of venous drainage. Core decompression is therefore an ideal method of treatment for early INFH.     

Hemodynamics of the Juvenile Knee in Relation to Increasing Intra-Articular Pressure: An Experimental Study in Dogs

The relationships between intraosseous pressure and regional blood flow in the juxta-articular epiphyses were determined in the knees of immature dogs. Intraosseous pressures were continously registered in one knee. Regional blood flow rates were simultaneously determined by the microsphere technique before and after venous tamponade of both knee joint capsules.

During complete venous tamponade the intraosseous pressure of the distal femoral epiphyses rose 268%, while flow increased 122%. A concurrent 20-fold flow increase of the knee capsule and 3-4-fold flow increase of the proximal femoral bone was observed. Evacuation of the knee joints resulted in an immediate drop of the intraosseous pressure of the distal femoral epiphyses, whereas hyperaemia prevailed for at least half an hour and was most pronounced in the distal femoral epiphyses and knee joint capsule. Intraosseous pressure registration did not significantly influence regional blood flow.

It is suggested that the changes of intraosseous pressures during knee joint tamponade reflect changes in the venous outlet resistance. The results demonstrate the significance of intra-articular pressure increase on the hemodynamics of the juxta-articular tissues of the knee and proximal femoral bone. These findings may be of importance in the pathogenesis of growth disturbances observed in juvenile degenerative arthritis.     

Hydraulic resistance: a measure of vascular outflow obstruction in osteonecrosis

This study introduces hydraulic resistance (HR) as a new method to measure intraosseous vascular outflow resistance in the human proximal femur. HR is the standard measure of resistance to fluid flow in porous matrices and is derived from serial pressure/flow determinations. Eighteen hips were studied in 11 patients taken to surgery for core decompression therapy of presumable atraumatic osteonecrosis of the femoral head. HR was much higher in osteonecrotic (174 +/- 29 mm Hg min/ml, SE) than in normal human cadaveric femora (14 +/- 6) and was also higher in subcapital (253 +/- 39) than intertrochanteric sites (78 +/- 17). HR correlated highly with baseline intraosseous pressure (r = 0.74, p less than 0.001). HR testing is a simple, practical method which quantifies outflow obstruction of the intraosseous circulation. We believe this test will be helpful in the diagnosis of atraumatic osteonecrosis and in the understanding of its underlying pathophysiology.     

Fat embolism and osteonecrosis

Clinical and experimental data accumulated within the past 2 decades explain the relationship between fat embolism and osteonecrosis, which now appears to be more causal than coincidental. Evidence for fatty liver, coalescence of endogenous plasma lipoproteins, and/or disruption of depot or marrow fat, all resulting in continuous or intermittent fat embolism, is related to 13 different clinical conditions associated with osteonecrosis, most recently including pregnancy, carbon tetrachloride poisoning, and possibly Legg-Calvé-Perthes disease. Intraosseous fat embolism, then, appears to trigger a three-phase thrombotic process of focal intravascular coagulation that results in osteonecrosis.     

Glucocorticoid induces micro-fat embolism in the rabbit: a scanning electron microscopic study.

The objective was to identify fat emboli in the arterioles of the femoral bone marrow by scanning electron microscopy (SEM) after glucocorticoid administration. Female adult rabbits weighing 3.5-4.0 kg received a single injection of prednisolone at a dose of 4 mg/kgBW. The day after injection was designated as day 1. Control rabbits were injected with only physiological saline and killed on day 14. The femoral bone marrow was obtained on days 5, 8, and 14, and processed for SEM. Aortic blood serum was passed through a filter, and the filter was processed for SEM. Some SEM specimens were embedded in a plastic resin and sectioned for correspondence of SEM-photomicroscopy (PM) or SEM-transmission electron microscopy (TEM). In the controls, small fat globules were present in sinusoids and venules but were absent from the arterioles. On day 5, fat globules were found in the lumina of both sinusoids and arterioles, possibly due to the effect of glucocorticoid. Complete arteriolar occlusion was not found. On day 8, fat globules were often encountered in the venous and arteriolar lumina. Some small arterioles were completely occluded by fat emboli. On day 14, fat globules were present in the arterioles, and some small and large arterioles were completely occluded. Blood drawn from the aorta contained fat globules in both the controls and rabbits injected with prednisolone. A small amount of prednisolone induced the presence of fat globules in arterioles as early as day 5, complete occlusion of small arterioles on day 8, and occlusion of large arterioles on day 14.     

Sildenafil Prevents Cardiovascular Changes after Bone Marrow Fat Embolization in Sheep

Background: Sudden, intraoperative cardiovascular deterioration as a result of pulmonary embolization of bone marrow fat is a potentially fatal complication during total hip and knee arthroplasty, intramedullary nailing, and spine surgery. Anesthetic management is challenging in the presence of increased right ventricular afterload due to pulmonary hypertension. Selective pulmonary vasodilation may be an appropriate prophylactic or therapeutic measure. The effect of sildenafil (phosphodiesterase inhibitor) on cardiovascular deterioration after bone marrow fat embolization was therefore investigated.

Methods: Bone cement (polymethylmethacrylate) was injected into three lumbar vertebrae in 12 sheep. Invasive blood pressures and heart rate were recorded continuously until 60 min after the last injection. Cardiac output and arterial and mixed venous blood gas variables were measured at selected time points. Before the first cement injection, 6 animals received a bolus injection (0.7 mg/kg) of sildenafil, with continuous infusion (0.2 mg [middle dot] kg-1 [middle dot] h-1) thereafter. Postmortem lung and kidney biopsies were taken for semiquantitative analysis of intravascular fat.

Results: Fat embolism was associated with a transient increase (21 +/- 7mmHg) in pulmonary arterial pressure. A transient decrease in arterial blood pressure and temporary increases in central venous pressure and dead space were also observed. No significant changes in any cardiovascular variable were observed after fat embolism in the sildenafil group. There was significantly (P < 0.05) less intravascular fat in the lungs of the sildenafil (median count of 5 emboli per microscopic view) compared with the control group (median count of 1).     

Immunologic factors in the pathogenesis of osteonecrosis

Osteonecrosis is a disease in which death of cellular elements of bone occurs as a result of diminished arterial blood supply. The pathogenetic mechanisms of osteonecrosis remain unresolved. Extravascular pressure and subsequent tamponade of the arterial vessels or an intravascular thrombosis have been suggested. Immunologic factors may also play an important role. In autoimmune disorders, small vessel vasculitis or other disease-associated features, as well as antiphospholipid antibodies, have been involved in the development of osteonecrosis.     

Intraosseous circulation from physiology to disease

Blood flow within bones is unique in two ways: (1) the blood circulates within a closed cavity in which pressure must remain constant, a feat achieved in part thanks to the considerable distensibility of the intraosseous vessels and, above all, veins; (2) the intraosseous circulation allows traffic of minerals between the blood and bone tissue and sends the blood cells produced within the bone marrow into the systemic circulation. In contrast, the arterioles and capillaries within bones have the same anatomic structure as those located elsewhere in the body and are susceptible to arteriosclerosis, arteritis, or thrombosis. The mechanisms that regulate blood flow within bone are incompletely understood, probably because they are difficult to study in vivo. The cytokines and growth factors that regulate intraosseous angiogenesis also regulate bone remodeling, and close links exist between the blood supply to bone and bone formation and resorption: most diseases characterized by increased bone resorption are associated with increased bone vascularization. The vascular bud located at the center of bone multicellular units (BMUs) may determine the timing of bone resorption and bone formation. Avascular bone necrosis and bone infarction may result from acute blood vessel occlusion (thrombosis, lipid emboli, fat cell hypertrophy with compression of intraosseous capillaries), whereas arteriosclerosis may contribute to the development of osteoporosis.     

Mechanisms of venous occlusion during canine penile erection: an anatomic demonstration

Hemodynamic studies have clearly demonstrated that intracorporeal injection of papaverine causes an increase of venous outflow resistance, and we therefore undertook a study of the venous drainage of the canine penis to delineate the anatomic changes in the venular structure during papaverine-induced erection. In 11 dogs, the corpora cavernosa were examined by corrosion casting in six and serial trichrome staining and histologic sectioning in five. Low-power scanning electron microscopy of the corrosion casts demonstrated the existence of a venular plexus interposed between the tunica albuginea and the sinusoidal spaces. After papaverine injection, this subalbugineal venular plexus is compressed between the dilated sinusoids from below and the tunica albuginea from above, such that venous drainage is effectively impeded. Examination of two cadaveric human penile corrosion casts by low-power scanning electron microscopy revealed evidence of a similar subalbugineal venular plexus draining into the emissary veins along the shaft of the penis. Based on the above, a model for the anatomic basis of venous occlusion during penile erection is outlined. Along with arteriolar and sinusoidal smooth-muscle relaxation, this can account for the three basic hemodynamic changes necessary for erection: increased arterial inflow, increased intracorporeal pressure, and increased venous outflow resistance.