Complications With the Use of BMP-2 in Scaphoid Nonunion Surgery.

PURPOSE: In an effort to improve fracture healing and decrease the need for autologous bone graft, products such as recombinant human bone morphogenetic protein (rhBMP-2) have been developed and used in both spine and nonspine surgery. There is a paucity of literature regarding the use of rhBMP-2 in scaphoid nonunion surgery with very little reporting on the complications associated with its use. The objective of this study was to retrospectively review the complications documented for a case series of patients treated with revision fixation, bone graft, and rhBMP-2 in revision scaphoid nonunion surgery. METHODS: We retrospectively reviewed 6 cases of scaphoid nonunion revision surgery comprising open reduction and internal fixation (ORIF). All cases were performed for persistent nonunion after a previous scaphoid ORIF. All patients were treated with revision screw fixation, bone graft, and rhBMP-2. Union was determined by computed tomography in all cases. Complications of nonunion, heterotopic bone formation, delayed wound healing, functional loss of motion, and need for revision surgery are reported. RESULTS: Between 2011 and 2014, 6 cases in which rhBMP-2 was used in revision scaphoid nonunion surgery were identified. All patients had failed an initial attempt at ORIF after delayed union or nonunion. The time from injury to index ORIF ranged from 3 months to 4 years (mean, 24 months). Revision surgery with rhBMP-2 was performed at an average of 6 months from the index ORIF. Of the 6 cases, 2 had resultant persistent nonunion. Both underwent scaphoid excision and midcarpal arthrodesis. Four cases developed notable heterotopic ossification (one of which required revision surgery). One patient had a loss of functional motion after the revision surgery. There were no cases of delayed wound healing. Only one of the 6 patients healed without complications. CONCLUSIONS: In this case series, the use of rhBMP-2 in scaphoid nonunions was associated with a higher complication rate than reported in previous studies. Surgeons performing off-label use of rhBMP-2 should be aware of the potential for complications including heterotopic ossification. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Reduced variability of neoral pharmacokinetic studies in pediatric renal transplantation.

In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra-individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved.

A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients.

The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 x C0 + 1.77 x C2 + 4. 1 x C4 (mean prediction error +/- SD = 0.3 +/- 6.4%, 95% confidence interval=-1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period.

A limited sampling strategy for the estimation of eight-hour neoral areas under the curve in renal transplantation.

Neoral, the microemulsion formulation of cyclosporine (CsA), demonstrates more consistent bioavailability than the corn oil formulation Sandimmune. Because of Neoral's rapid peak and metabolism, 8-hour dosing has to be used in many pediatric and some adult patients to maintain adequate CsA peak-to-trough ratios. Although the area under the curve (AUC) is considered the best estimate of total drug exposure, it requires repeated blood sampling. Abbreviated AUC profiles yielding excellent estimates of Neoral AUC with twice daily dosing have been described, but no such abbreviated strategy exists for 8-hour dosing. One hundred fifty-two pharmacokinetic profiles in 23 patients were used to derive and prospectively test a limited two-sample strategy to predict Neoral AUCs in pediatric and adult patients on 8-hour dosing regimens of Neoral. The formula was derived from 69 full 8-hour CsA pharmacokinetic profiles in nine children who underwent renal transplantation. Stepwise forward linear and multiple-curve regression techniques assessed the relative importance of single and combination concentration time points to predict AUC. The abbreviated profiles were validated by comparing the mean prediction error for each regression equation. The abbreviated profile calculated by second (C2)- and fourth (C4)-hour levels (AUC = 129 + 1.84 x C2 + 4.39 x C4) correlated well with the full AUC (r2 = 0.96; p < 0001). Mean prediction error was -0.4% +/- 5.48%, and no values fell outside the clinically acceptable 15% prediction error limit. Prospectively applying the formula to 83 AUCs of 14 adults who underwent renal transplantation and were taking Neoral three times a day demonstrated an excellent fit (r2 = 0.93; p < 0.001), with 94% of predicted values falling inside the +/-15% limit. The authors describe the development of a clinically acceptable, limited sampling strategy to predict 8-hour Neoral AUCs in children and adults who underwent renal transplantation.

Selecting and educating perioperative nurses for an ambulatory surgery setting.

A decision was made that review of technical skills for the perioperative and postanesthesia nurses hired from within the hospital was not necessary because they all had experience in their specialty areas. Those hired from other areas of the hospital will spend one month with a preceptor in the postanesthesia care area, one month in our short stay unit with a preceptor, and one month either in class or OR observation. All will have formal classes on anesthesia, fluid and electrolytes, and the philosophy of ambulatory surgery. These employees were released from their previous positions three months before the projected opening date of the new unit to allow them to learn the new skills. The patient care manager assigned responsibilities to the perioperative nurses hired from the main OR. They were asked to research needed equipment and supplies for various procedures in the different specialty areas. The patient care manager felt this would help them make a smooth transition to the new unit by making them feel like members of the team. My original hypothesis that perioperative nurses will not only rise to the occasion, but will far exceed our expectations will be tested when we move to the new ambulatory surgery unit. Although our opening date has been delayed, I am confident that our forethought and preparation will result in a smooth transition and an efficient staff.

Selective jejunal hyperabsorption of calcium in absorptive hypercalciuria.

Calcium absorption in the jejunum and ileum of patients with absorptive hypercalciuria was studied by in vivo intestinal perfusion. Net calcium absorption in the jejunum was markedly increased at four luminal calcium concentrations (1 to 20 mM) in the patients with absorptive hypercalciuria when compared to that in normal subjects. In the ileum, net calcium absorption was only slightly increased in the patients with absorptive hypercalciuria. Experiments with radioactive calcium (47Ca) revealed increased unidirectional flux out of the jejunal lumen in the patients but no difference in the unidirectional flux into the lumen, when compared to that in normal control subjects. Net magnesium absorption was normal in the patients. These results suggest that hyperabsorption of calcium in patients with absorptive hypercalciuria is mainly due to enhanced calcium transport in the jejunum and that the defect is specific for calcium since magnesium is absorbed normally.

Ion transport changes during calcitonin-induced intestinal secretion in man.

Previous studies have shown that synthetic salmon calcitonin (SCT) infused intravenously causes secretion of water and electrolytes in the jejunum of normal human subjects. The present experiments were carried out to learn more about the nature of this intestinal secretory process. During SCT- or synthetic human calcitonin (HCT)-induced intestinal secretion, the following observations were made: (1) There was no change in potential difference; (2) Cl was secreted against an electrochemical gradient; (3) unidirectional Na flux out of the lumen was decreased while the opposite flux was normal; (4) luminal pCO2 fell; (5) addition of glucose to the jejunal contents stimulated Na abdsorption, and this in turn counteracted the secretory effect of calcitonin. These findings suggest that calcitonin induces active Cl secretion and inhibits active Na absorption, and that HCO3 absorption is reduced by virtue of OH secretion; furthermore, jejunal glucose absorption and glucose-stimulated Na absorption are intact during calcitonin-induced secretion. Intravenous infusion of HCT caused intestinal secretion only when blood levels were much higher than occur physiologically; therefore, calcitonin is probably not a mediator of spontaneous variations of intestinal transport in normal people. However, because calcitonin induces secretion in the ileum as well as in the jejunum, hypercalcitonemia (within the range commonly found in patients with medullary carcinoma of the thyroid) could be a cause of severe secretory diarrhea.

Magnesium absorption in the human small intestine. Results in normal subjects, patients with chronic renal disease, and patients with absorptive hypercalciuria.

Magnesium absorption was studied in the normal human jejunum and ileum by in vivo intestinal perfusion, using test solutions containing from 0 to 20 mM Mg (as MgCl2). As luminal Mg concentration was increased, the rate of absorption in the jejunum rose progressively with a tendency towards saturation at the higher concentrations. The kinetics and rates of Mg absorption in the ileum were comparable to those in the jejunum, with the exception that at higher luminal concentrations the ileal absorptive process was fully saturated. Using test solutions containing various combinations of Ca and Mg, we found that Ca had little or no influence on Mg absorption, even through Mg depressed Ca absorption to a modest extent. Patients with end-stage renal disease, who had a reduced rate of Ca absorption (presumably due to deficiency of 1,25-dihydroxycholecalciferol) were found to have a severe depression of Mg absorption. On the other hand, patients with absorptive hypercalciuria and nephrolithiasis, who had an increased rate of Ca absorption, were found to absorb Mg normally. These results suggest that Mg absorption in the human is mediated by a transport process different from that which facilitates Ca absorption, and that normal Mg absorption may be dependent on vitamin D. Our results do not establish whether or not the normal intestine can absorb Mg against an electrochemical gradient.

Use of mutant fibroblasts in the analysis of the regulation of cholesterol metabolism in human cells.

Analysis of mutant human fibroblasts deficient in a cell surface receptor for low density lipoproteins (LDL) has led to the delineation of an important, hitherto unrecognized, regulatory process for cholesterol metabolism. On normal cells, binding of LDL to this receptor regulates cholesterol metabolism by two mechanisms: (a) suppression of cholesterol synthesis and (b) facilitation of the rate of proteolytic degradation of the lipoprotein. In cells from homozygotes with the autosomal dominant disorder Familial Hypercholesterolemia, a nearly total reduction in LDL receptors results in two secondary abnormalities: (a) overproduction of cholesterol due to an inability of LDL to suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis, and (b) impairment in the rate of proteolytic degradation of LDL. Cells from heterozygotes possess about 50 per cent of the normal number of LDL recpetors; this leads to a concentration-dependent defect in regulation, so that attainment of rates of cholesterol synthesis and LDL degradation equal to that in normal cells requires a two to three-fold higher concentration of extracellular LDL in the heterozygote. The identification of this genetic regulatory defect in fibroblasts of heterozygotes with Familial Hypercholesterolemia makes available an in vitro system for studying the molecular mechanism by which a dominant mutation affects gene expression in mammalian cells.

3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human hair roots.

The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (1.1.1.34) was measured in isolated human hair roots. In growing scalp hair roots, the amount of enzyme activity per cell was surprisingly high and was of the same order of magnitude as has been reported for human liver cells and for human fibroblasts cultured in the absence of low density lipoproteins. Hair root enzyme activity showed no diurnal variation, was unaffected by cholestyramine feeding, and was similar in 14 normal subjects, one patient with abetalipoproteinemia, and one homozygote and three heterozygotes with familial hypercholesterolemia. The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human hair roots appears to be unrelated to the level of low density lipoproteins in the plasma.