Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions.

BACKGROUND: The role of bone morphogenetic proteins (BMPs) in osseous repair has been demonstrated in numerous animal models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions. The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone. MATERIALS AND METHODS: One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, partially blinded, multi-center clinical trial between February, 1992, and August, 1996, and were followed at frequent intervals over 24 months. Each patient was treated by insertion of an intramedullary rod, accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft. Assessment criteria included the severity of pain at the fracture site, the ability to walk with full weight-bearing, the need for surgical re-treatment of the nonunion during the course of this study, plain radiographic evaluation of healing, and physician satisfaction with the clinical course. In addition, adverse events were recorded, and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit. RESULTS: At 9 months following the operative procedures (the primary end-point of this study), 81% of the OP-1-treated nonunions (n = 63) and 85% of those receiving autogenous bone (n = 61) were judged by clinical criteria to have been treated successfully (p = 0.524). By radiographic criteria, at this same time point, 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had healed fractures (p = 0.218). These clinical results continued at similar levels of success throughout 2 years of observation, and there was no statistically significant difference in outcome between the two groups of patients at this point (p = 0.939). All patients experienced adverse events. Forty-four percent of patients in each treatment group had serious events, none of which were related to their bone grafts. More than 20% of patients treated with autografts had chronic donor site pain following the procedure. CONCLUSIONS: rhOP-1 (BMP-7), implanted with a type I collagen carrier, was a safe and effective treatment for tibial nonunions. This molecule provided clinical and radiographic results comparable with those achieved with bone autograft, without donor site morbidity.

Blood volume redistribution from a passive elastic permeable microcirculation due to hypovolemia.

We measured the variations in blood and plasma density for a cyclic hemorrhage protocol in conscious rabbits to calculate delta Vf [the volume of fluid restituted into the circulation from the time the blood volume was at its control to that after the hemorrhage of a blood volume (delta V)] and delta Vs (the volume shift from micro- to macrocirculation over the same time interval). We found that delta Vf is 7% of delta V and delta Vs 60% of delta V. They combine to reduce the effect of hemorrhage on macrovascular volume by 67% of delta V. Based on a two-resistor circulation model, the change in microcirculatory pressure (delta Pmic) from control to hemorrhage was estimated from the measured cardiac outputs and arterial and venous pressures. The computations indicate that delta Vs (or delta Vf) is linearly related to delta Pmic. With one relation fitting all data of rabbits that were conscious, infused with hexamethonium, and anesthetized with pentobarbital sodium, we concluded that the two short-term volume redistributions are not direct neural control or local regulation, but the response of a passive, permeable microcirculation to delta Pmic. From the linear relations, we obtained 0.88 ml.mmHg-1.kg-1 as the compliance of the rabbit microcirculation and 0.21 ml.min-1.mmHg-1.kg-1 as its filtration coefficient.

Fluid restitution and shift of blood volume in anesthetized rabbits subject to cyclic hemorrhage.

We investigated the effect of a 10% cyclic blood volume change with a period of 2 or 4 min to study the short-term control of blood volume. In experiments with pentobarbital-anesthetized rabbits, the blood density variation over a 2-min cycle is 0.94 +/- 0.04 (SE) g/l, and the plasma density variation is 0.17 +/- 0.04 g/l. The plasma density variation could result from a fluid restitution from the extravascular space (with a density 1,005 g/l), with a volume equal to 14% of the withdrawn blood volume. This restitution cannot account, however, for the entire observed density change in arterial blood. Because of the Fahraeus effect in microvascular flow, a shift in blood volume from the microvasculature is another mechanism that could lead to a decrease in the density of arterial blood. An analysis of the blood and plasma density variations indicates that a blood volume (49% of the shed volume) is shifted from the micro- to macrocirculation. This volume compensation by fluid restitution and volume shift acts to minimize the effect of hemorrhage on the filling of the venous system. We found that the blood density waveform parallels the change in blood volume. When the blood volume change reverses its direction, the density change also reverses direction with a time delay less than 8 s. The blood density variations are not altered by bilateral vagotomy or its combination with hexamethonium (a sympathetic ganglionic blocker). These observations of anesthetized rabbits indicate that the short-term compensation is primarily due to the volume shift from the microcirculation and is not regulated by humoral or neural mechanisms but by local mechanisms such as autoregulation and the passive response due to changes in microvascular pressure.

Driving simulator performance in patients with sleep apnea.

Although previous studies have shown that patients with obstructive sleep apnea have a higher automobile crash rate than normal subjects, objective measurements of driving performance in patients with sleep apnea have not been reported. Therefore, we compared the driving performance of subjects with untreated, severe sleep apnea to that of control subjects on two driving simulators. Using a simulator with road films, six subjects with untreated, severe apnea performed worse than did a control group of seven normal subjects on both highway and city/rural driving (p less than 0.05). Using a personal computer program simulating a monotonous highway drive, 12 subjects with untreated sleep apnea performed worse than 12 control subjects. The patients with apnea hit a greater number of road obstacles during their 30-minute simulated drive than did the control subjects (44 +/- 52 in patients with apnea versus 9 +/- 7 in control subjects, p less than 0.05). Six patients with apnea hit fewer road obstacles after treatment with nasal continuous positive airway pressure (CPAP) than before treatment (29 +/- 19 before CPAP versus 13 +/- 8 after CPAP, p less than 0.05). We conclude that: (1) driving simulator performance of untreated subjects with severe obstructive sleep apnea is worse than that of control subjects; (2) driving simulator performance of subjects treated with nasal CPAP improves.