Experimental studies of the effects of abnormal venous valves on fluid flow.

The effects of variations in the venous valve anatomy are studied experimentally using an artificial system that mimics the bicuspid valves normally found in veins in the lower extremities. The artificial valves are constructed from thin-walled, latex tubing and polyurethane film. The experimental variables in the study are the gap width between the leaflet attachments at the vein wall and the ratio of the sinus depth to vein diameter. The results show that the antegrade mass flow rate is not affected to the same degree when compared to retrograde flow by the various valve configurations examined in this study. The results also indicate that increases in the gap width, which serve to increase the degree of imperfect wall attachment, have less effect on retrograde mass flow rate in valves with deeper sinuses.

Infection in patients after implantation of an orthopedic device.

During the last several decades, the use of appropriate antibiotics has significantly improved our ability to prevent and treat infection that occurs after implantation of an orthopedic device. Despite improved prevention and treatment of this condition, patients who develop an infection secondary to implantation of an orthopedic device face increased mortality, morbidity, and/or delayed recovery. The presence of an orthopedic device significantly reduces the number of bacteria required to produce colonization and decreases the ability of the body's own defense mechanism and antibiotics to resolve this condition. Efforts devoted to prevention of infection are much more effective than those spent treating the condition once it has developed. Pretreatment of patients with antibiotics and the use of ultra clean surgical rooms have been shown effective. Prevention will become increasingly important as antibiotic resistant strains of bacteria become more prevalent and the number of arthroplasty procedures performed also increases.

Does axial limb rotation affect the alignment measurements in deformed limbs?

The long-term outcome of total knee arthroplasty and femoral or tibial osteotomy is related to the ability of the surgeon to achieve the desired alignment based on preoperative planning. This study evaluates the effect of axial rotation on measured tibiofemoral angles and the angle formed between the anatomic and mechanical axes of the femur in lower extremities with valgus and varus deformities. A comparison study of the measured tibiofemoral angles indicated a statistically significant effect in models with severe vagus or varus deformity when rotated 10 degrees internally or externally. In the second part of the study, the measured angle between the anatomic and mechanical axes of the femur never varied by more than 1 degree, despite a 40 degrees are of rotation. The results of the study indicate the tibiofemoral angle measurements are more sensitive to axial limb rotation in lower extremities with valgus or varus deformity than are normally aligned limbs. In preoperative planning of total knee arthroplasty, the measured angle between the anatomic and mechanical axes of the femur is less effected by limb rotation, regardless of the degree of valgus or varus deformity.

Circulatory dissemination of 15-mu particles from the immature rat femur.

Venous drainage from the femur of adult animals is not interrupted by occlusion of the blood supply in the soft tissue surrounding the diaphysis of the bone. Previous studies have shown that the metaphyseal drainage system is capable of rapidly transporting particles up to 100 mu in diameter to the lungs. The present study was performed to determine if venous drainage from the femur of immature animals possesses similar characteristics. Three-week-old rats were given a 5-microliters intramedullary injection containing radioactively labeled 15-mu-diameter microspheres. In the intact animal, the particles moved from the injection site in the femur to the lungs within two minutes; however, obliteration of blood flow in the soft tissue surrounding the femoral diaphysis significantly reduced this movement in most animals. The ratio of particles moving through the lungs into the peripheral arterial circulation was slow and similar to that found in adult animals.

Altering local soft-tissue circulation fails to halt venous drainage from the femur.

It has been suggested that tourniquet application proximal to bone biopsy in an extremity can reduce the number of tumor cells spread through circulation. This study investigates the anatomical pathway through which rapid cell spread could occur. Radioactively labeled 15-mu microspheres were injected into the medullary canal of rat femurs. The ratio of injected particles found in the femur was compared among groups that received application of a tourniquet prior to injection, no tourniquet, or transection of all soft tissue proximal to the injection site. Obliteration of circulation in the soft tissue surrounding the femur with a tourniquet or tissue transection did not alter the spread of particles from the femur. The pulmonary circulation trapped approximately 95% of particles reaching the lungs, limiting their access to peripheral arterial circulation. If the number of particles injected into the femur was increased, the number of particles leaving the femur increased at an even greater rate. These data suggest that (1) a particle can exit the femur without traveling through the soft tissue surrounding the femur; (2) most particles that reach the lung are retained; and (3) the injected bone acts as a sponge, retaining some particles and permitting the rest to enter the venous drainage.

Increased microvascular permeability in canine endotoxic shock: protective effects of ibuprofen.

The ability of sodium ibuprofen to prevent endotoxin-induced changes in vascular permeability was examined in an anesthetized canine model. Ibuprofen was administered i.v. (3.75 mg/kg) in two pretreatment doses before the administration of Escherichia coli endotoxin (0.5 mg/kg). Serum and left thoracic duct lymph samples were collected for measurement of total protein and separation by polyacrylamide gel electrophoresis. Four protein fractions with molecular weights (MW) ranging from 60,000 to 1,000,000 were consistently analyzed. Administration of endotoxin alone resulted in hypotension and was accompanied by an increase in microvascular permeability as evidenced by increases in lymph flow rate, protein flux, lymph/plasma protein ratio (L/P), and permeability-surface area product (PS). Pretreatment with ibuprofen attenuated the increase in permeability as reflected by significantly lower lymph flow rate, protein flux, L/P, and PS. Electrophoretic data illustrate partial to complete protection for all four MW fractions. These results suggest that endotoxin damages microvascular integrity and increases extravasation of macromolecules as great as 1,000,000 MW. This damage is attenuated significantly by pretreatment with ibuprofen.

Endotoxemia and neutrophil activation in vivo.

There is a growing body of data to suggest that marginated granulocytes mediate much of the pulmonary damage observed during endotoxemia. The mechanism(s) by which endotoxemia initiates neutrophil margination and cytotoxicity remain either controversial or unknown. The objectives of this study were 1) to determine the temporal relationship between endotoxin-induced decreases in mean arterial pressure and circulating neutrophils, 2) to monitor neutrophil activation in vivo by measuring myeloperoxidase (MPO) activity in the plasma and lymph, and 3) to assess the interaction between endotoxin and complement in activation of neutrophilic oxidative metabolism in vitro. We found that a bolus injection of endotoxin causes a concurrent decrease in both mean arterial pressure and circulating neutrophils at 2 min postinfusion. Blood pressure recovered to approximately 70% of control values by 180 min, whereas circulating neutrophils remain depressed at 20% of control values for the entire experimental period. Using MPO as a marker for neutrophil activation, we found that infusion of endotoxin produces a dramatic increase in plasma and lymph MPO activity, suggesting activation of neutrophilic metabolism in vivo. In vitro data showed that both endotoxin and plasma were required for optimal neutrophilic degranulation and superoxide formation. We conclude that 1) the appearance of MPO in the plasma (or lymph) may be a useful neutrophil marker for neutrophil activation in vivo and may prove useful in following the course of neutrophil-mediated tissue injury during endotoxemia, and 2) endotoxin-activated complement (C5a) activates neutrophils to produce cytotoxic oxidants.

Venous drainage of the femur permits passage of 100-micron particles.

Iatrogenic metastasis of bone tumor is reportedly increased if aggregates of tumor cells enter the circulation. The current study used a previously developed animal model to explore the movement of 25-, 50-, and 100-micron-diameter particles from an experimental femur biopsy site into the circulation. The results indicate that cell aggregate-sized particles can enter the circulation from the femur at a rate similar to that of the 15-micron particles used in previous studies. Arterial blood samples collected during and after the injection of particles contained no 50- or 100-micron particles, suggesting that the lung is an effective filter for these larger particles.

Biomechanical and clinical evaluation of the expandable intramedullary fixation device.

The use of an expandable intramedullary device for internal fixation of metacarpal or phalangeal bones is described. The device is applicable to transverse fractures, short oblique fractures, or transverse osteotomies. The device consists of a cylindrical apparatus made of titanium that allows collapse in the circumferential diameter. It is introduced into the medullary canal in its collapsed state, and on release expands to its normal diameter in the canal with the fracture reduced over it. A biomechanical evaluation compared the stability of this device with other commonly employed fixation methods. A retrospective review is presented of the first 43 patients in whom the device was implanted.

The risk of deep venous thrombosis: a computerized epidemiologic approach.

The appropriate use of prophylactic measures to prevent deep venous thrombosis is dependent on the ability of physicians to identify high-risk patients. This problem has been the subject of numerous epidemiologic reports compiled during the last several decades. Described herein is a computerized technique to condense the literature on this subject into a form better suited for practical application. This technique comprises an interactive program that calculates a patient's relative risk of developing a thrombus on the basis of a comparative evaluation of his medical profile. The computer then reports the patient's calculated relative risk along with other information that may pertain to his risk of deep venous thrombosis.

Bradykinin does not contribute to hypotension in early canine endotoxemia.

Previous work in this and other laboratories has demonstrated that captopril exacerbates the hypotension produced in dogs by endotoxin. This depressor effect of captopril could result from the potentiation of bradykinin (BK) or inhibited formation of angiotensin II (AII). Anesthetized adult mongrel dogs were used in the current study. In each, the right femoral vein and artery were cannulated for the administration of drugs and monitoring of arterial pressure. A tracheostomy was performed, and the animal was respired with room air. It was found that after injection of endotoxin, AII receptor blockade (Sar1, Ile8-AII) produced a mean arterial pressure (MAP) response statistically similar to that elicited by captopril in combination with endotoxin. Although these results indicate no production of BK, the possibility of BK receptor inactivation during endotoxin shock cannot be disregarded. Additional studies suggested that in the dog, injections of BK can augment the depression of MAP caused by endotoxin and that this further depression can be prolonged by captopril. On the basis of these results, it can be concluded that in the early phases of canine endotoxin shock, AII plays a significant role in the maintenance of MAP and that BK is not produced in quantities sufficient to lower MAP.

Cardiorespiratory alterations produced by centrally administered thyrotropin-releasing hormone during canine endotoxin shock.

Endogenous opiates have been implicated in the pathophysiology of endotoxin, hemorrhagic, and spinal shock. Blockade of these compounds with peripherally or centrally administered naloxone has been shown to produce beneficial effects. More recently, it has been suggested that thyrotropin-releasing hormone (TRH) may be able to block the detrimental effects of endogenous opiate compounds without removing their analgesic effects. Improved cardiovascular function during endotoxin shock has been demonstrated in rat and primate models; however, this drug has not been tested in the canine endotoxin shock model. The present study was designed to determine if TRH administered through ventriculocisternal (VC) perfusion could significantly improve cardiorespiratory function during canine endotoxin shock. Cardiac output, arterial pressure, end-tidal CO2, heart rate, respiratory rate, pulse pressure, and total peripheral resistance were determined for three separate groups of animals. One group of animals received TRH only and served as a drug control. One of the remaining groups received endotoxin only, while the other group received endotoxin plus TRH. The results of the study suggest that TRH administered centrally is capable of improving cardiac output during endotoxin shock. No significant difference was found in any of the other parameters measured. Based on these findings, it can be concluded that TRH has a minimal effect during canine endotoxin shock. The discrepancy between these results and those from other endotoxin shock models may result from species variation, TRH metabolism and sensitivity, and/or anesthetic effect.

Effects of methylprednisolone upon vascular permeability changes in endotoxic shock.

This study was designed to examine glucocorticoid effects on increases in vascular permeability caused by endotoxic shock in dogs anesthetized with pentobarbital sodium (30 mg/kg). Methylprednisolone sodium succinate was administered IV in two doses (30 mg/kg each) before Escherichia coli endotoxin was administered (0.5 mg/kg). Samples of serum and lymph from the left thoracic duct were collected for measurement of total protein and separation by polyacrylamide gel electrophoresis. The same four protein electrophoretic fractions with molecular weights (M.W.) ranging from 60,000 to 1,000,000 were consistently chosen for analysis. Methylprednisolone treatment given prior to endotoxin administration resulted in an attenuation of the early increase in total protein flux and lymph to plasma protein (L/P) ratio and prevented significant increases in the permeability surface area product observed in the group given endotoxin alone. Endotoxin administration alone resulted in significant increases in the permeability-surface area product and L/P ratio for all four electrophoretic fractions. Pretreatment with glucocorticoid partially attenuated the increase in the L/P ratio for only those fractions of 100,000 M.W. or less. These results suggest MP provides partial but not complete protection from increases in vascular permeability during endotoxic shock.

Experimental design and data evaluation in orthopaedic research.

It has been said that we can be of assistance to one person at a time in the operating room, several individuals at a time in the classroom, and multitudes through our work in the laboratory. This final statement is true only if the conclusions we draw from our studies are valid. Failure to adhere to the scientific method can invalidate the conclusions we report. This can occur from failure to define properly the question to be studied, failure to review the available literature adequately, improper randomization of the experimental subjects, introduction of investigator bias into the data collection process, and failure to include appropriate controls. Use of improper statistics can also invalidate the results of any study. Frequently, this error comes from multiple use of the Student's t test. When this occurs, the probability of reporting a difference when none exists increases proportionally to the number of comparisons performed. Random statistical comparisons among groups are inappropriate and can lead to a substantial increase in the risk of concluding that two sets of data differ when in fact no difference exists. Investigators who use statistics inappropriately and then restate their original hypothesis are guilty of scientific dishonesty. This inappropriate use of statistics represents a flagrant disregard of the scientific method of problem solving.

Blood volume changes in endotoxin shock.

Injection of E. coli endotoxin in dogs promotes hemodynamic changes in circulating blood volume and blood components. Adult mongrel dogs were given endotoxin and studied for 3 hours. Red-blood-cell (RBC) volume and whole-blood volume was measured using the Cr-51 RBC labeling method. Hematocrit and RBC counts were taken at various time periods. Whole-blood volume was not found to change significantly over the test period; however, plasma volume demonstrated a significant decrease by 60 minutes with a parallel increase in RBC volume. Hematocrit increased significantly by 60 minutes and continued its rise to a 30% increase at 3 hours. Circulating RBC counts demonstrated a 26% increase. RBC precursors such as reticulocytes and normoblasts were counted using standard microscopic methods and were observed to increase after injection of endotoxin. These data suggest that the increases in hemoconcentration after administration of endotoxin are caused not only by the loss of plasma from the circulation but also by release of RBCs from blood-forming organs.

Passive movement of radioactive microspheres from bone and soft tissue in an extremity.

Bone biopsy is the definitive method for bone tumor diagnosis. Unfortunately, the procedure is not without risk and may substantially increase the rate and extent of tumor cell metastasis. This study used radioactive microspheres (15 micron diameter) to explore the spread of cell-sized particles from the distal femur into the lymphatic system, venous drainage, and local tissue following a simulated biopsy in the canine model procedure. In the initial group of test animals the microspheres rapidly moved from the femur through the venous system to the lungs. There was no movement from the femur into the lymphatic system within 4 days. The lungs effectively filtered the 15 micron microspheres, thus preventing arterial dissemination. Additional groups were used to explore the movement of the cell-sized particles from the soft tissue surrounding the bone. At the end of the 4 day experimental period, microspheres were found in the iliac lymph nodes in two of nine animals. Microspheres were not detected in the lungs of any of these nine animals. These results suggest that tumor cell-sized particles can move rapidly from the bone venous system to the lungs following a bone biopsy. It appears that the lymphatic system does not contribute to this rapid dissemination. However, the role of lymphatics in a more chronic process remains unclear.

Changes in ambient temperature alter the blood pressure response to endotoxin and the effectiveness of naloxone.

At room temperature, naloxone, a competitive opiate antagonist, ameliorates the hypotensive effect of endotoxin, suggesting that endotoxin increases the secretion of endogenous opioids that have a cardiodepressor action. It was previously observed in our laboratory that reducing the ambient temperature from 24 degrees C to 19 degrees C blocked this protective effect of naloxone in dogs. This suggested that activation of peripheral cold receptors might also increase endogenous opioid activity and together with the opioid activity induced by endotoxin might be sufficient to override the competitive blockage by naloxone. In support of this, it was found in the present study that an increased dose of naloxone was effective at 19 degrees C. Studies done at 30 degrees C revealed that the hypotensive effect of endotoxin is inversely related to the ambient temperature, and naloxone is effective in low doses at the higher temperature. Core temperature was not altered significantly by the ambient temperatures used by naloxone, by endotoxin, or by any combination thereof. These findings suggest that, at least within moderate ranges, acute changes in ambient temperature induce inversely related changes in endogenous opioid activity, representing a specific thermal rather than a generalized stress response.

The spread of tumor-cell-sized particles after bone biopsy.

For the purpose of determining possible passive dissemination of tumor cells from a bone biopsy site, we created an animal model. A cortical window was placed in the canine femur and a measured quantity of radioactive microspheres was placed in the medullary canal. Local and distant spread of the microspheres were measured four days after the simulated biopsy. In the animals in which the cortical window was left open, spread of the microspheres was limited to the adjacent tissue and the regional lymph nodes. In the animals in which the bone window was plugged with methylmethacrylate, there was little or no local spread of the microspheres; however, there was significant uptake of the microspheres in the lung. In a separate trial, significant microsphere activity was present in the lung within twenty minutes after placement of the methylmethacrylate plug.

Hematoma formation after bone biopsy: a canine model.

Barium sulfate was used to study postoperative hematoma formation in 17 canine bone biopsies. If the bone window was left open, x-ray films showed a time-dependent spread of barium from the bone into the soft tissues. Wound drainage and cast immobilization of the extremity minimized this spread. A methylmethacrylate plug in the cortical window blocked extraosseous spread of the barium, but did not prevent spread of the barium through the medullary space. Injection of barium through a Craig needle into the bone resulted in spread of the barium along the needle track, with little barium remaining in the bone.

Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by hemorrhage or administration of endotoxin.

The present studies were undertaken to determine if bilateral lesions of the fastigial nuclei of the cerebellum would impair the recovery and maintenance of mean arterial blood pressure during hypotension caused by hemorrhage or administration of endotoxin. We had shown previously that cerebellectomy would produce such an impairment, and the fastigial nuclei were implicated as the specific area involved due to the known pressor response observed when they are stimulated electrically. Chloralose-anesthetized dogs were made hypotensive by administration of E. coli endotoxin or hemorrhage to 50 mm Hg and observed over the subsequent 3 h. Dogs with fastigial nucleus lesions had a significantly lower mean arterial pressure during both the recovery and maintenance phases when compared with intact animals under both hypotensive protocols. In the hemorrhage study, a significant number of lesioned animals died whereas none of the controls died. Lesion of the fastigial nuclei produced an impairment similar to that seen with cerebellectomy. It is concluded that the fastigial nuclei play an important role in the recovery of blood pressure following a hypotensive episode.