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STUDY DESIGN: Systematic review. OBJECTIVE: To study the morbidity and the potential benefits of using intraoperative skeletal traction as an adjunct method for correcting scoliosis. SUMMARY OF BACKGROUND DATA: Cotrel et al., used intraoperative skeletal traction in all patients in their original series of segmental spinal instrumentation for scoliosis correction (Cotrel et al., Clin Orthop Relat Res 1988;227:10-23). However, the use of intraoperative traction may introduce other forms of surgical morbidity, which has not been systematically studied. METHODS: Two independent reviewers searched MEDLINE (1948-current) and EMBASE (1980-current) using the keywords scoliosis, intraoperative, and traction in all fields, combined with AND. Studies were subject to full-text assessment against specific inclusion and exclusion criteria; discrepancies between the reviewers were resolved by a third independent reviewer. Data were extracted into standardized extraction tables and papers were critically appraised papers with regards to their relative strengths and weaknesses, with particular attention to the study objective. RESULTS: Nine papers were included: case report (n = 1), retrospective case series (n = 2), retrospective case-control (n = 6), and studies included both adolescent idiopathic scoliosis (AIS) and neuromuscular scoliosis. Seven studies reported positive effects of intraoperative skeletal traction on diverse outcome measures, such as correction of pelvic obliquity, Cobb angle, and axial plane deformity, as well as precluding the need for an anterior release preceding posterior instrumentation for large curves. Overall, there was only one reported postoperative traction-related complication (anterosuperior iliac spine pressure sore). One paper reported that intraoperative traction may evoke neuromonitoring signal changes in a large proportion of patients undergoing AIS surgery. These changes were responded to intraoperatively by decreasing or removing weight and none of the patients had postoperative neurologic deficits. CONCLUSION: Isolated intraoperative skeletal traction may be a low-morbidity adjunct to facilitate scoliosis surgery. Further studies are needed to compare outcomes of scoliosis surgery with or without intraoperative skeletal traction.

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Phenylbutazone (PBZ) is a nonsteroidal anti-inflammatory drug used in the treatment of chronic pain and arthritis. Topical and transdermal administration of PBZ would be beneficial in large animals in terms of minimizing gastro-intestinal ulcerations and other side effects, easy administration to legs and joints and minimizing the dose to reduce systemic toxicity of the drug. A topical liposomal preparation with different concentrations of a mono-substituted alkyl amide (MSA) and PBZ was formulated. The formulations were evaluated by in vitro skin-permeation kinetics through deer skin using Franz diffusion cells. By increasing drug loading from 1% to 5% w/w, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Similarly, by increasing the MSA concentration from 0% to 4%, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Overall, by increasing the drug load and the use of an appropriate amount of the penetration enhancer, the steady-state flux of PBZ through skin was increased fourfold (P < 0.001). MSA at both 2% and 4% w/w concentrations significantly increased the skin levels of PBZ as compared with control (P < 0.05). In conclusion, MSA served as an effective skin-penetration enhancer in the liposomal gel of PBZ for deer.

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The binding of tamoxifen (an HSA site IV ligand) to human serum albumin (HSA) in the presence of a perfluorochemical (PFC) erythrocyte substitute has been examined. Standard centrifugation followed by supernatant ultrafiltration was used to study the binding of 0.1 and 0.5 microgram mL-1 tamoxifen at ambient conditions. Tamoxifen was extensively bound (greater than 99%) to the PFC emulsion through an association with the emulsifiers of the droplets. Tamoxifen was also extensively bound (greater than 99%) to HSA. The percent free tamoxifen increased upon HSA dilution. Tamoxifen was extensively bound by various mixtures of HSA and the PFC emulsion and the percent free drug was similar to those obtained with HSA alone. However, the position of drug binding (PFC emulsion vs HSA) varied significantly with changes in the ratio of PFC emulsion to HSA. This could be important in terms of the different distribution of HSA and PFC emulsion in the body. Studies with PFC emulsion components indicated that any displacement of HSA-bound tamoxifen by the PFC emulsion was due to the oleic acid and, to a much smaller degree, Pluronic F-68 components. Other HSA site IV ligands are expected to be similarly displaced.

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At 37 degrees C, valproic acid was weakly bound by a PFCE through an interaction with the emulsifiers that was independent of both buffer and PFCE concentration. The binding by PFCE was dependent on valproic acid concentration in 0.1 M buffer, but not in 0.2 M buffer. The addition of PFCE to 4% HSA increased the percent free valproic acid due to both HSA dilution and displacement of HSA bound drug. This displacement was apparently due to an interaction with the PFC liquids and/or intact PFCE droplets, and with the oleic acid component of the PFCE.

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The binding of 43 and 216 micrograms/ml sodium salicylate by a perfluorochemical emulsion, by human albumin, and by their mixtures, has been examined at ambient room temperature. Sodium salicylate was chosen as a model drug since it is bound by both sites I and II on human albumin. The concentration of free salicylate was determined through standard centrifugation followed by supernatant ultrafiltration. Sodium salicylate was weakly bound by the perfluorochemical emulsion droplets through an interaction with the emulsifiers. This binding was independent of salicylate concentration. Sodium salicylate was also bound by human albumin and the per cent free salicylate was dependent on both drug and albumin concentration. Relative to salicylate binding by 4% human albumin, addition of the emulsion to 4% human albumin resulted in an increase in the per cent free salicylate in all mixtures examined. The addition of equal or greater volumes of the emulsion to 4% human albumin resulted in the direct and/or indirect displacement of albumin bound salicylate in addition to the protein dilution effect. This displacement of albumin bound salicylate was due to the oleic acid component of the emulsion.

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As a result of their ability to transport oxygen, PFC emulsions are being investigated for possible use in a wide variety of conditions. The recent FDA approval of F-DA to diminish myocardial ischemia during angioplasty is the first marketing approval for such a product in the world. The many potential uses of such products may result in their common application in the future, especially as new and better products are developed. The elimination, distribution, and tissue retention of PFC emulsions as well as the physiological changes that occur upon their administration have been the subject of many investigations. The results indicate that these agents may influence the pharmacokinetic properties of other drugs by a wide variety of mechanisms. Several studies have shown significant, but not necessarily consistent, changes in drug elimination and distribution following PFC emulsion infusion. Changes appear dependent on the drug examined, emulsion utilized, degree of blood exchange, species utilized, and the controls chosen for comparison. Often, the changes are time dependent indicating the importance of conducting long-term studies. While PFC emulsions do not appear to alter renal elimination of drugs, several studies have demonstrated that these agents have the potential to induce drug metabolism from several days to possibly months after exposure. Observed changes in drug volumes of distribution, which are often time dependent, may be due to changes in normal drug transport throughout the circulation and/or changes in membrane permeability and cell transport mechanisms. Changes in drug transport may result from depletion of plasma proteins or increases in alpha 1-acid glycoprotein levels due to trauma or PFC emulsion effects. The binding of drugs by PFC emulsion droplets varies greatly and PFC emulsion components displace some plasma protein bound drugs. The wide variability in the results and conclusions of the pharmacokinetic studies conducted to date emphasize the importance of utilizing adequate controls to identify which alterations are PFC emulsion specific.

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The effect of a perfluorochemical emulsion on ligand binding by human albumin was studied using a site specific approach. L-tryptophan was used as a marker for binding to site II on human albumin. Centrifugation, followed by supernatant ultrafiltration at ambient room temperature, was employed to determine the per cent tryptophan free. The partitioning of tryptophan from pH 7.4 phosphate buffer into the pure perfluorochemical liquids was insignificant. Tryptophan was not significantly bound by the perfluorochemical emulsion droplets. Binding of tryptophan by buffer dilutions of human albumin demonstrated that, at the tryptophan concentrations examined, human albumin concentration had little effect on the per cent tryptophan free. Tryptophan binding by mixtures of the perfluorochemical emulsion and human albumin showed that, at sufficiently high concentrations of the perfluorochemical emulsion, one or more of the emulsion components is responsible for the direct and/or indirect displacement of human albumin-bound tryptophan. The individual perfluorochemical emulsion components were studied for their effects on the binding of tryptophan by human albumin. Results showed that oleic acid and, to a very small degree, Pluronic F-68, were responsible for the displacement of human albumin-bound tryptophan.

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Propranolol binding to human albumin (HSA) and to mixtures of alpha 1-acid glycoprotein (AGP) and HSA was examined in the presence of a perfluorochemical (PFC) blood substitute. The per cent free propranolol was determined using a dialysis exchange method at 37 degrees C. In 4% HSA solutions the per cent free propranolol was 51.9% and 53.6% at propranolol concentrations of 100 and 500 ng/ml, respectively. Buffer dilutions of 4% HSA solutions resulted in an increase in free propranolol. However, dilution of the HSA solutions with the PFC emulsion resulted in a significant decrease in free propranolol. In solutions containing 4% HSA with 0.067% AGP, the per cent free propranolol was 22.6% and 23.5% for 100 and 500 ng/ml propranolol, respectively. Again, the per cent free propranolol increased upon plasma protein dilution with buffer solution and decreased upon dilution with the blood substitute. A centrifugation method was utilized to determine the per cent bound propranolol associated with the PFC emulsion droplets in the presence of the proteins. Propranolol was significantly bound by the PFC emulsion even in the presence of a mixture of AGP and HSA. These results indicate that the overall affinity of the PFC blood substitute for propranolol is very substantial. Thus, administration of this PFC blood substitute may not result in the significant increase in per cent free propranolol normally associated with plasma protein dilution.

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The binding of 0.4 microgram mL-1 diazepam and 0.75 mol diazepam mol-1 of albumin by a perfluorochemical (PFC) emulsion, Fluosol-DA, 20%, by human serum albumin (HSA), and by their mixtures, has been examined at ambient temperature. The concentration of free diazepam was determined by standard centrifugation followed by supernatant ultrafiltration. Non-specific loss of diazepam occurred to the ultrafiltration device. This loss was independent of drug concentration and a correction factor was employed to calculate the true free diazepam concentration. Diazepam was extensively bound by the PFC emulsion. The percent free diazepam increased as the emulsion concentration decreased, while the binding of diazepam appeared to be independent of drug concentration. Diazepam did not partition into the pure PFC liquids, indicating that emulsion-bound diazepam is only associated with the emulsifiers of the droplets. Diazepam was extensively bound by HSA and the percent free diazepam increased as drug concentration increased or as HSA concentration decreased. The PFC emulsion significantly displaced HSA bound diazepam in all mixtures examined. Studies with the individual and combined components of the emulsion indicated that this displacement is largely attributed to the oleic acid component and, to a much smaller degree, the Pluronic F-68 component of the emulsion.

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Propranolol binding to isolated human alpha-1-acid glycoprotein (AGP) and human albumin (HSA) was studied by equilibrium dialysis at 37 degrees C. With AGP (0.067%) and HSA (4%), total propranolol concentration was varied from 0.7 to 93,000 ng mL-1. Over this concentration range the percentage drug bound to HSA declined from 49 to 39% while that to AGP declined from 68 to 4%. Two classes of sites were identified on AGP with n1k1 = 8.50 X 10(4) M-1 and n2k2 = 3.12 X 10(4) M-1. With a pH 7.4 phosphate buffer, propranolol binding to AGP was greatest when the protein was initially dissolved in pH 7.4 water compared with pH 7.2 water or the phosphate buffer. Thus, the method of AGP solution preparation affected propranolol binding by this protein. For both AGP and HSA, greater drug binding was noted with phosphate buffers in comparison with a physiological buffer. With phosphate buffers, decreasing pH from 7.4 to 7.0 decreased propranolol binding by AGP, while decreasing pH from 7.7 to 7.4 had little effect. With HSA, the percent propranolol bound consistently decreased on lowering pH from 7.7 to 7.0.

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Warfarin binding by human albumin (HSA) is altered in the presence of a perfluorochemical (PFC) emulsion. To determine which PFC emulsion component(s) was responsible for these changes, the effects of the components on this interaction were determined. Fluorescence titrations and ultrafiltration were used to monitor the effects of the components on HSA binding of 2 and 10 micrograms/ml warfarin at room temperature. Component concentrations ranged up to that present in the emulsion except for yolk phospholipids which have limited buffer solubility. For solubility reasons, oleic acid and phospholipids were studied in the presence of pluronic F-68. At 0.5% HSA pluronic F-68 caused a significant displacement of bound warfarin, while glycerol had little effect on warfarin binding. At concentrations of 20% of that in the PFC emulsion oleic acid with pluronic F-68 caused a significant increase in warfarin binding. This was followed by a very large displacement of bound warfarin at the emulsion concentrations of oleic acid and pluronic F-68. The phospholipid component had no specific effect on warfarin binding. A combination of the 4 components had an effect very similar to that of only oleic acid with pluronic F-68. At 2% HSA the combined components caused an increase in warfarin binding while at 4% HSA the combined components had little, if any, effect on warfarin binding. Thus, changes in HSA binding of warfarin in the presence of a PFC emulsion can be attributed to the oleic acid and, to a smaller degree, pluronic F-68 components of the emulsion.

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A previous study demonstrated that a relatively large concentration of a perfluorochemical (PFC) emulsion caused significant displacement of bound warfarin from fatty acid free human albumin. To determine whether this displacement would occur when fatty acids were associated with albumin, the effect of the emulsion on warfarin binding by fraction V human albumin was examined. Binding of 2 and 10 micrograms/ml warfarin at room temperature by 4 per cent albumin solutions diluted with the emulsion was determined by centrifugation followed by supernatant ultrafiltration. Warfarin binding by identical buffer dilutions of albumin solutions served as controls. The emulsion had no effect on warfarin binding other than dilution when albumin solutions were diluted to 75 and 50% v/v. Further dilution of albumin solutions to 40, 25 and 10% v/v with blood substitute resulted in significant increases in the per cent free warfarin even though warfarin is weakly bound by the emulsion droplets. These increases in per cent free warfarin were apparently due to the displacement of albumin bound warfarin by a component(s) of the emulsion, possibly the potassium oleate component. The ability of 2 and 10 micrograms/ml warfarin to partition from pH 7.4 buffer into the purified PFC liquids was also determined at room temperature. Warfarin did not partition into the PFC liquids indicating that emulsion bound warfarin is only associated with the emulsifiers of the droplets.

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A commercial ultrafiltration device was examined for propranolol plasma protein binding studies. A nonspecific loss of free drug resulted in a low recovery in the ultrafiltrate. Use of a rinse filtrate did not completely compensate for this loss. Use of different centrifugal forces indicated the loss was not due to significant membrane rejection of drug. Equilibrating the device with sample for four hours slightly improved the recovery while use of a higher ionic strength buffer had no effect. Propranolol was bound by the membrane, but there was a larger, continuous loss to the o-ring. Results with an alternate commercial device were also unsatisfactory.

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The effect of a perfluorochemical blood substitute on ligand binding by human albumin was examined using warfarin as a model drug. Binding of warfarin by four per cent human albumin solutions diluted with either buffer or blood substitute, and by blood substitute diluted with buffer was examined. Solutions containing 2 or 10 micrograms/ml warfarin were quantitated by liquid scintillation counting using 14C-warfarin. The per cent warfarin free at room temperature was determined by centrifugation followed by supernatant ultrafiltration. Warfarin was weakly bound by the blood substitute and the overall effect of albumin dilution with the blood substitute was an increase in per cent warfarin free. Blood substitute binding of warfarin may explain the decrease of per cent warfarin free observed when albumin solutions were diluted to 50 and 75% v/v with blood substitute rather than buffer. However, the per cent warfarin free increased when albumin solutions were diluted to 25% v/v with blood substitute rather than buffer. The fraction free increased by 39.0% and 30.4% at total warfarin concentrations of 2 and 10 micrograms/ml, respectively. This relative increase in per cent warfarin free may be the result of a direct and/or indirect displacement of albumin bound warfarin by a component(s) of the blood substitute.

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Disagreement exists over the primary-site binding constant for the interaction of furosemide with human albumin. Disagreement also exists over which experimental methods are accurate in this particular interaction. Therefore, furosemide binding by human albumin was examined using albumin fluorescence quenching by both the method of Levine and the method of Steiner et al. The binding constants obtained by each method differed greatly, with the results of the latter method being similar to those of other experimental methods. It was concluded that the method of Levine overestimates the binding constant for this drug-protein interaction.

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