Henk J. Th. M. Haarman

Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma

BACKGROUND Infections are an important cause of morbidity and mortality in patients with multiple trauma. Studies in both animals and human beings have suggested that glutamine-enriched nutrition decreases the number of infections. METHODS Patients with multiple trauma with an expected survival of more than 48 h, and who had an Injury Severity Score of 20 or more, were randomly allocated glutamine supplemented enteral nutrition or a balanced, isonitrogenous, isocaloric enteral-feeding regimen along with usual care. Each patient was assessed every 8 h for infection, the primary endpoint. Data were analysed both per protocol, which included enteral feeding for at least 5 days, and by intention to treat. FINDINGS 72 patients were enrolled and 60 received enteral feeding (29 glutamine-supplemented) for at least 5 days. Five (17%) of 29 patients in the glutamine-supplemented group had pneumonia compared with 14 (45%) of 31 patients in the control group (p<0.02). Bacteraemia occurred in two (7%) patients in glutamine group and 13 (42%) in the control group (p<0.005). One patient in the glutamine group had sepsis compared with eight (26%) patients in the control group (p<0.02). INTERPRETATION There was a low frequency of pneumonia, sepsis, and bacteraemia in patients with multiple trauma who received glutamine-supplemented enteral nutrition. Larger studies are needed to investigate whether glutamine-supplemented enteral nutrition reduces mortality.

The Accuracy of Diagnostic Imaging for the Assessment of Chronic Osteomyelitis: A Systematic Review and Meta-Analysis

BACKGROUND A variety of diagnostic imaging techniques is available for excluding or confirming chronic osteomyelitis. Until now, an evidence-based algorithmic model for choosing the most suitable imaging technique has been lacking. The objective of this study was to determine the accuracy of current imaging modalities in the diagnosis of chronic osteomyelitis. METHODS A systematic review and meta-analysis of the literature was conducted with a comprehensive search of the MEDLINE, EMBASE, and Current Contents databases to identify clinical studies on chronic osteomyelitis that evaluated diagnostic imaging modalities. The value of each imaging technique was studied by determining its sensitivity and specificity compared with the results of histological analysis, findings on culture, and clinical follow-up of more than six months. RESULTS A total of twenty-three clinical studies in which the accuracy was described for radiography (two studies), magnetic resonance imaging (five), computed tomography (one), bone scintigraphy (seven), leukocyte scintigraphy (thirteen), gallium scintigraphy (one), combined bone and leukocyte scintigraphy (six), combined bone and gallium scintigraphy (three), and fluorodeoxyglucose positron emission tomography (four) were included in the review. No meta-analysis was performed with respect to computed tomography, gallium scintigraphy, and radiography. Pooled sensitivity demonstrated that fluorodeoxyglucose positron emission tomography was the most sensitive technique, with a sensitivity of 96% (95% confidence interval, 88% to 99%) compared with 82% (95% confidence interval, 70% to 89%) for bone scintigraphy, 61% (95% confidence interval, 43% to 76%) for leukocyte scintigraphy, 78% (95% confidence interval, 72% to 83%) for combined bone and leukocyte scintigraphy, and 84% (95% confidence interval, 69% to 92%) for magnetic resonance imaging. Pooled specificity demonstrated that bone scintigraphy had the lowest specificity, with a specificity of 25% (95% confidence interval, 16% to 36%) compared with 60% (95% confidence interval, 38% to 78%) for magnetic resonance imaging, 77% (95% confidence interval, 63% to 87%) for leukocyte scintigraphy, 84% (95% confidence interval, 75% to 90%) for combined bone and leukocyte scintigraphy, and 91% (95% confidence interval, 81% to 95%) for fluorodeoxyglucose positron emission tomography. The sensitivity of leukocyte scintigraphy in detecting chronic osteomyelitis in the peripheral skeleton was 84% (95% confidence interval, 72% to 91%) compared with 21% (95% confidence interval, 11% to 38%) for its detection of chronic osteomyelitis in the axial skeleton. The specificity of leukocyte scintigraphy in the axial skeleton was 60% (95% confidence interval, 39% to 78%) compared with 80% (95% confidence interval, 61% to 91%) for the peripheral skeleton. CONCLUSIONS Fluorodeoxyglucose positron emission tomography has the highest diagnostic accuracy for confirming or excluding the diagnosis of chronic osteomyelitis. Leukocyte scintigraphy has an appropriate diagnostic accuracy in the peripheral skeleton, but fluorodeoxyglucose positron emission tomography is superior for detecting chronic osteomyelitis in the axial skeleton.

Treatment of traumatic thoracolumbar spine fractures: a multicenter prospective randomized study of operative versus nonsurgical treatment.

Study Design. Multicenter prospective randomized trial. Objective. To test the hypotheses that thoracolumbar AO Type A spine fractures without neurologic deficit, managed with short-segment posterior stabilization will show an improved radiographic outcome and at least the same functional outcome as compared with nonsurgically treated thoracolumbar fractures. Summary of Background Data. There are various opinions regarding the ideal management of thoracolumbar Type A spine fractures without neurologic deficit. Both operative and nonsurgical approaches are advocated. Methods. Patients were randomized for operative or nonsurgical treatment. Data sampling involved demographics, fracture classifications, radiographic evaluation, and functional outcome. Results. Sixteen patients received nonsurgical therapy, and 18 received surgical treatment. Follow-up was completed for 32 (94%) of the patients after a mean of 4.3 years. At the end of follow-up, both local and regional kyphotic deformity was significantly less in the operatively treated group. All functional outcome scores (VAS Pain, VAS Spine Score, and RMDQ-24) showed significantly better results in the operative group. The percentage of patients returning to their original jobs was found to be significantly higher in the operative treated group. Conclusions. Patients with a Type A3 thoracolumbar spine fracture without neurologic deficit should be treated by short-segment posterior stabilization.

Properties of calcium phosphate ceramics in relation to their in vivo behavior.

B one replacement has been under investigation for many centuries. The first report on bone replacement comes from the bronze age, when a skull defect was treated by implantation of a bone autograft. However, the first successful treatment of a bone defect with a bone graft was performed by the Dutch surgeon Job van Meek’ren in 1668. After that, it took many centuries before the first large series of bone transplants was reported. Since that time, the advantages and disadvantages of bone transplantation have become clearly understood. The need for bone replacement is evident in traumatology and orthopedics. Loss of bone caused by trauma, infection, or tumor resection poses great problems on both the treating surgeon and the patient. Treatment of these conditions often includes the implantation of autogenous bone transplant material, but this method leads to significant consequences for the patient. Harvesting autogenous bone grafts causes comorbidity in 6 to 20% of patients, such as persistent pain, hypersensitivity, or anesthesia, and 3 to 9% have more serious problems. Artificial bone replacement materials can avoid these consequences. Since the first use of plaster of paris as an artificial bone replacement material in 1894, different groups of artificial bone replacement materials have been developed over the years. Glass ceramics, metal ceramics, polymers, and calcium phosphate ceramics, such as hydroxyapatite (HA) and tricalciumphosphate (TCP) have been investigated extensively. These materials have different properties and, therefore, display different interactions with the host tissue. Factors such as porosity, osteoconductivity, and biocompatibility seem to become increasingly important in the development of new artificial bone replacement materials. This paper focuses on the relation between the properties of bone replacement materials, especially calcium phosphate ceramics, and the host tissue, to provide some clarity in the processes involved in the incorporation of these materials in bone tissue. Developments in the combination of osteogenic or osteoinductive substances and calcium phosphate ceramics will be discussed as well. POROSITY

Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow

Hydroxyapatite is a synthetic bone graft, which is used for the treatment of bone defects and nonunions. However, it is a rather inert material with no or little intrinsic osteoinductive activity. Recombinant human osteogenic protein‐1 (rhOP‐1) is a very potent biological agent, that enhances osteogenesis during bone repair. Bone marrow contains mesenchymal stem cells, which are capable of new bone formation. Biosynthetic bone grafts were created by the addition of rhOP‐1 or bone marrow to granular porous hydroxyapatite. The performance of these grafts was tested in a sheep model and compared to the results of autograft, which is clinically the standard treatment of bone defects and nonunions. A 3 cm segmental bone defect was made in the tibia and fixed with an interlocking intramedullary nail. There were five treatment groups: no implant (n = 6), autograft (n = 8), hydroxyapatite alone (n = 8), hydroxyapatite loaded with rhOP‐1 (n = 8), and hydroxyapatite loaded with autologous bone marrow (n = 8). At 12 weeks, healing of the defect was evaluated with radiographs, a torsional test to failure, and histological examination of longitudinal sections through the defect. Torsional strength and stiffness of the healing tibiae were about two to three times higher for autograft and hydroxyapatite plus rhOP‐1 or bone marrow compared to hydroxyapatite alone and empty defects. The mean values of both combination groups were comparable to those of autograft. There were more unions in defects with hydroxyapatite plus rhOP‐1 than in defects with hydroxyapatite alone. Although the differences were not significant, histological examination revealed that there was more often bony bridging of the defect in both combination groups and the autograft group than in the group with hydroxyapatite alone. Healing of bone defects, treated with porous hydroxyapatite, can be enhanced by the addition of rhOP‐1 or autologous bone marrow. The results of these composite biosynthetic grafts are equivalent to those of autograft.

Quantification of fracture healing with three-dimensional computed tomography

Abstract Quantitative methods are necessary for an objective evaluation of fracture healing. Three-dimensional computed tomography (CT) for the measurement of callus volume and density could be such a method and was investigated in an animal model. In 23 goats a closed tibial fracture was created and stabilized with a cast. The animals were killed at 2, 4 and 6 weeks for radiographical, CT and biomechanical analysis. From the CT scans a three-dimensional reconstruction of the callus was made to measure its volume and mean density. At 2 weeks the callus volume had already reached its maximum. In contrast, callus density, torsional strength and torsional stiffness increased over time (P < 0.0001, analysis of variance, ANOVA). Multiple regression analysis showed that the callus volume was not related to the torsional properties. However, callus density was a significant explanatory variable for both torsional strength (R2 = 0.72, P < 0.0001) and torsional stiffness (R2 = 0.82, P < 0.0001). Therefore, callus density as measured by three-dimensional CT is a predictor of the extent of fracture consolidation. CT with three-dimensional reconstruction of the callus seems a valid technique for the quantification of fracture healing.

Effect of recombinant human osteogenic protein-1 on the healing of a freshly closed diaphyseal fracture

Osteogenic protein-1 (OP-1), or bone morphogenetic protein-7, is an osteoinductive morphogen that is involved in embryonic skeletogenesis and in bone repair. In bone defect models without spontaneous healing, local administration of recombinant human OP-1 (rhOP-1) induces complete healing. To investigate the ability of rhOP-1 to accelerate normal physiologic fracture healing, an experimental study was performed. In 40 adult female goats a closed tibial fracture was made, stabilized with an external fixator, and treated as follows: (1) no injection; (2) injection of 1 mg rhOP-1 dissolved in aqueous buffer; (3) injection of collagen matrix; and (4) injection of 1 mg rhOP-1 bound to collagen matrix. The test substances were injected in the fracture gap under fluoroscopic control. At 2 and 4 weeks, fracture healing was evaluated with radiographs, three-dimensional computed tomography (CT), dual-energy X-ray absorptiometry, biomechanical tests, and histology. At 2 weeks, callus diameter, callus volume, and bone mineral content at the fracture site were significantly increased in both rhOP-1 groups compared with the no-injection group. As signs of accelerated callus maturation, bending and torsional stiffness were higher and bony bridging of the fracture gap was observed more often in the group with rhOP-1 dissolved in aqueous buffer than in uninjected fractures. Treatment with rhOP-1 plus collagen matrix did not result in improved biomechanical properties or bony bridging of the fracture gap at 2 weeks. At 4 weeks there were no differences between groups, except for a larger callus volume in the rhOP-1 plus collagen matrix group compared with the control groups. All fractures showed an advanced stage of healing at 4 weeks. In conclusion, the healing of a closed fracture in a goat model can be accelerated by a single local administration of rhOP-1. The use of a carrier material does not seem to be crucial in this application of rhOP-1.

Reaming debris in osteotomized sheep tibiae.

BACKGROUND Reamed nailing gives better fracture healing than unreamed nailing in operative treatment of fractures and nonunions. This study investigates the effect of isolated reaming debris on fracture healing in an animal model. METHODS Thirty sheep were treated with an osteotomy of the tibia with 5-mm distraction. In one group, the osteotomy gap was left empty; in the second group, the gap was packed with reaming debris from the ipsilateral femur; and in the third group, the gap was packed with cancellous bone from the iliac crest. At follow-up, callus volume was measured on standard radiographs. RESULTS After 3 weeks, callus volume from the reaming debris group as well as the iliac crest group had increased significantly compared with the empty group. CONCLUSION This study shows that isolated reaming debris supports callus building as much as conventional bone grafting, which might explain why fractures heal with more callus formation when treated with reamed nailing compared with unreamed nailing.

Resorbable calcium phosphate particles as a carrier material for bone marrow in an ovine segmental defect

Resorbable calcium phosphate ceramics are only osteoconductive; therefore, their combination with osteogenic substances may lead to stimulation of bone healing. In the present study this combination, using autologous bone marrow, was investigated. In 31 sheep, a 3-cm tibial segmental defect was created and stabilized with an intramedullary nail. The animals were divided into four groups: empty defects (group 1, n = 7), and defects filled with 10-mL dense resorbable calcium phosphate particles (group 2, n = 8), with 10-mL particles soaked in bone marrow (group 3, n = 8), or with 10-mL autologous bone (group 4, n = 8). On evaluation after 12 weeks, significantly higher values were seen in group 3 than in group 2 for callus volume (p = .016), bone mineral density ratio (p = .03), bone mineral content ratio (p = .04), torsional strength (p = .005), and torsional stiffness (p = .01). For all end points, the outcome of group 3 was lower than that of group 4. In the histology, there was direct contact between newly formed bone and remnants of the particles. There were no signs of inflammatory reactions. Although a stimulatory effect of bone marrow was seen, the combination of resorbable calcium phosphate particles with bone marrow does not provide an alternative for autologous bone grafting.

Effect of (poly)-L-lactic acid on the proliferation and differentiation of primary bone cells in vitro

A previous study has shown bone formation around poly-L-lactic acid (PLLA) wire in vivo. However, it is still unknown how bone cells are stimulated to form bone around PLLA wire. The effect of PLLA on primary bone cells in vitro is the subject of this study. Osteoprogenitor and osteoblastic cells derived from neonatal mouse calvaria were cultured after addition of PLLA wire or L-lactide to the culture medium. Alkaline phosphatase (AP) activity, as a parameter of bone cell differentiation, and DNA content, to assess cell growth were measured. In osteoblast-enriched cell cultures PLLA wire did not affect DNA content, but AP activity was increased by 28%. In osteoprogenitor-enriched cell cultures PLLA wire decreased DNA content by 10%, but AP activity of the cells was not affected. L-Lactide enhanced the DNA content of osteoblastic cell cultures at 0.1 mM by 19%, but not at higher concentrations, and did not affect cell differentiation. In osteoprogenitor cell cultures, L-lactide had no effect at all. These results indicate that the proliferation and differentiation of bone cells in vitro can be modulated by PLLA, dependent on their stage of differentiation. L-Lactide at concentrations up to 10 mM did not adversely affect cell growth or differentiation, while PLLA wire upregulated the expression of the osteoblastic phenotype. These data support the observation of newly formed bone around poly-lactic acid wire in vivo in other the studies.