The effect of prolonged euglycemic hyperinsulinemia on lean body mass after severe burn.

BACKGROUND: The hypermetabolic response to burn increases protein catabolism. Euglycemic hyperinsu-linemia with exogenous insulin maintains muscle protein by continued stimulation of net protein synthesis. Our aim was to determine the effect of euglycemic hyperinsulinemia over the entire hospitalization on muscle anabolism by investigating lean body mass (LBM) as the primary endpoint. METHODS: Eighteen subjects between the ages of 2 and 18 with burns of more than 40% were prospectively randomized into 2 groups, a control (n = 9) and a treatment group (n = 9). The treatment group was given continuous intravenous insulin at a rate of at least 1.5 microU/kg/min to maintain serum glucose levels between 100 to 140 mg/dL. Treatment was instituted 24 to 48 hours after arrival and continued until the patient's injury was 95% healed. All patients received continuous enteral feeding. Patients underwent body composition studies by dual-energy x-ray absorptiometry (DEXA) scan on postoperative day 6 after initial burn excision and when 95% healed. RESULTS: Nutritional intakes were not different between groups. In the control, subjects continued catabolism resulted in peripheral muscle wasting and centripetal obesity with diminished truncal LBM. The treatment group had improvement in lean body mass (P =.004) and bone mass (P =.025). The treatment group also had less peripheral muscle wasting with overall increases in upper/lower extremity LBM (P =.005). Hospital length of stay in days per percent of total body surface area burned was decreased in the insulin group (control = 1.03 +/- 0.1 vs 0.7 +/- 0.9 for insulin patients; P <.05). CONCLUSIONS: Euglycemic hyperinsulinemia throughout the hospital course mitigates muscle catabolism and preserves lean body mass.

Ciprofloxacin as a therapeutic modality in pediatric burn wound infections: efficacious or contraindicated?

BACKGROUND: Food and Drug Administration regulations state that ciprofloxacin hydrochloride may cause arthropathies. For this reason, such therapy is contraindicated in the pediatric population. However, several studies in children with cystic fibrosis have found the drug to be efficacious. Our hypothesis was that ciprofloxacin treatment is justified in the case of multiresistant organisms in burn populations. DESIGN: During a 4-year period (January 1, 1993, to December 31, 1997) we treated 56 of our pediatric burn patients with ciprofloxacin when cultures proved resistant to other antibiotics. The burn area was 65% of the total body surface area. The average patient age was 8.4 years. Of the 56 patients who received ciprofloxacin, 50 received the recommended dose. Biopsy specimens were assessed for quantitative bacteriology and antibiotic sensitivity. Radiologic review was conducted to examine for arthropathy. RESULTS: All patients showed unequivocal reduction in quantitative bacterial counts, and susceptibility to ciprofloxacin remained stable without the development of resistance. Of the 56 patients treated, 42 had a major reduction in their quantitative wound biopsies from 10(6) to less than 100 colonies per gram of tissue, while the remaining 14 were observed to have a 2- to 3-log decrease. No arthropathy was detected in any of the 56 patients receiving ciprofloxacin. Review of the patients' charts showed no documented adverse events associated with the use of ciprofloxacin. All patients survived their thermal injury and the complications associated with it without any untoward problems or complications of arthropathy. CONCLUSION: On the basis of these data, ciprofloxacin therapy in the treatment of immunosuppressed pediatric burn patients is efficacious and does not cause arthropathy.

Metabolic bone disease of total parenteral nutrition.

Parenteral nutrition-associated metabolic bone disease in children is manifested primarily as osteopenia and, on occasion, fractures. The etiology is likely multifactorial, with calcium and phosphate deficiency playing a major role in the preterm infant and with the role of aluminum toxicity yet to be clearly defined in this population. Lack of normal values of bone histomorphometry in the premature infant as well as lack of normal data for biochemical markers of bone turnover in these patients contribute to the uncertainty. Other factors that may play a role in the pathogenesis include lack of periodic enteral feeding; underlying intestinal disease, including malabsorption and inflammation; the presence of neoplasms; and drug-induced alterations in calcium and bone metabolism. The true incidence and prevalence of parenteral nutrition-associated bone abnormalities in pediatric patients remain unknown.

Dysregulation of calcium homeostasis after severe burn injury in children: possible role of magnesium depletion.

OBJECTIVE: To determine the cause and extent of hypocalcemia observed in children after severe burns. DESIGN: We studied 10 children with burns covering 57% +/- 17% (SD) body surface area, ages 9.6 +/- 4.7 years, who were admitted consecutively during a 6-month period. Diet supplied a minimum of 2.7 gm/m2 of calcium, 0.3 gm/m2 of magnesium, and 2.2 gm/m2 phosphate. Blood specimens were obtained daily for 10 +/- 5 days for the following tests: (1) simultaneous analysis for ionized calcium, magnesium, and intact parathyroid hormone (group A); (2) two of these children, randomly selected, had serial 2-hour determinations on a single day (group B); (3) a modified Ellsworth-Howard test, consisting of a 10-minute infusion of synthetic parathyroid hormone 18 +/- 10 days post-burn and associated changes in urinary cyclic adenosine monophosphate excretion and renal threshold phosphate concentration (group C). Three of these children, when normomagnesemic, also received a standard magnesium infusion to determine magnesium retention (group D). Data were analyzed with chi-square, regression analysis, and non-parametric testing as appropriate. RESULTS: All patients showed sustained hypocalcemia and hypomagnesemia; intact parathyroid hormone response was inappropriately low and response to synthetic parathyroid hormone infusion was blunted. Lowest ionized calcium levels were associated with hypomagnesemia. CONCLUSION: Hypoparathyroidism and blunted renal response to parathyroid hormone suggest that magnesium depletion may contribute to their pathogenesis. Magnesium repletion and monitoring are recommended.

Histomorphometric and biochemical characterization of bone following acute severe burns in children.

Severe burns in adults is associated with an uncoupling of normal remodeling, low bone formation without reduced resorption. The risk of osteopenia that may occur under such circumstances is heightened by our detection in a cross-sectional study of low bone mass in severely burned children. We report here the acute histomorphometric and biochemical response of bone to severe burn injury, as well as bone mass in severely burned children. We enrolled 24 patients ages 5.8 to 17.5 years following burns of 63 +/- 16% (SD) body surface area. Serum and urine were collected weekly until iliac crest bone biopsy was obtained 26 +/- 10 days postburn. Seventeen of 18 patients, including 5 patients receiving growth hormone treatment to accelerate wound healing, failed to take up doxycycline in trabecular bone, and had no detectable osteoblasts at the osteoid seam, while eroded surface was normal and osteoblasts were documented by staining. Thus, bone formation was virtually absent. There was an eightfold elevation in urinary free cortisol excretion and high serum levels of acute phase reactants and interleukin-1 beta and -6. Biochemical markers of bone formation, osteocalcin, and type I procollagen propeptide were low, as were resorptive markers urinary pyridinoline and deoxypyridinoline. However, there was no correlation with resorptive surface. Mean age-related z-score for bone mass was -1.06 +/- 1.05, 40 days postburn. Immobilization and endogenous corticosteroid production may be the main factors responsible for acutely reduced bone formation while inflammatory cytokines may mediate resorption.

Aluminum in parenteral solutions revisited--again.

It has been a dozen years since aluminum was first shown to contaminate parenteral nutrition solutions and to be a contributing factor in the pathogenesis of metabolic bone disease in parenteral nutrition patients as well as in uremic patients. However, there are no regulations in place to effectively reduce aluminum contamination of various parenterally administered nutrients, drugs, and biologic products. The purpose of this review is fourfold: 1) to summarize our knowledge of the adverse effects of aluminum on bone formation and mineralization in parenteral nutrition patients; 2) to discuss the possible role of aluminum in the osteopenic bone disease of preterm infants; 3) to show how lack of regulations covering aluminum content of parenteral solutions can lead to vulnerability of new groups of patients to aluminum toxicity, the example being given here is that of burn patients; and 4) to trace the development of efforts at regulating the aluminum contamination of large- and small-volume parenteral drug products and to point out what still needs to be done in this regard.

Rat tail suspension reduces messenger RNA level for growth factors and osteopontin and decreases the osteoblastic differentiation of bone marrow stromal cells.

We previously reported that bone marrow stromal cells produce insulin-like growth factors (IGF-I and -II), and that medium conditioned by marrow stromal cells stimulates osteoblast proliferation in vitro. The present study employed the rat tail-suspension model to unload the hindlimbs. It was designed to test the hypothesis that the development of osteopenia or osteoporosis could be due to a deficit in the osteogenic function of marrow stromal cells. Although tail suspension suppressed body weight during the first 3 days of an 11-day pair-fed study, the overall weight gain recorded by these animals was normal. Nevertheless, bone growth was inhibited by suspension. Similarly, the total adherent marrow stromal cell population harvested from the femurs and tibias was decreased by tail suspension, and only half the normal number of fibroblastic stromal cell colonies grew when they were cultured. The proliferation of alkaline-phosphatase-positive cells in the stroma was also inhibited. Northern hybridization revealed that the messenger RNA level for transforming growth factor-beta 2 and IGF-II in stromal cell was reduced by tail suspension. The production of IGF-II by marrow stromal cells was also decreased. The steady-state level of five different transcript sizes of IGF-I mRNA was altered differentially by tail suspension. Osteopontin mRNA was also reduced in marrow stromal cells from tail-suspended rats compared with the normal rats. These data suggest that skeletal unloading not only alters the mRNA level for growth factors and peptide production, but also affects the proliferation and osteogenic differentiation of marrow stromal cells. These changes may be responsible for the reduced bone formation in osteopenia and osteoporosis.

Risk of aluminum accumulation in patients with burns and ways to reduce it.

Severely burned patients experience a bone lesion consisting of markedly reduced bone formation and evidence of decreased resportion. The cause of the lesion may be multifactorial, but aluminum loading, which also occurs in patients with burns, has been documented to produce this type of injury in both humans and animals. To assess the risk of aluminum loading with patients with burns, we analyzed fluids, creams, and medication used in the management of acute burn injury for aluminum content. These substances were classified according to route of administration: cutaneous, enteral, or parenteral, to assess the risk of aluminum loading. Cutaneous exposure to aluminum is greatest from baths, which may provide up to 8 mg aluminum. However, the dynamics of aluminum entry into the blood via a damaged skin barrier are unclear. Enteral exposure to aluminum is no greater than daily dietary exposure. Parenteral sources of aluminum, especially 25% human serum albumin and calcium gluconate, provide the most significant risk of loading because of direct introduction of aluminum into the circulation. Substitution with a different brand of albumin and calcium chloride can reduce the parenteral aluminum load by as much as 95% and minimize any role aluminum may play in the pathogenesis of this bone lesion.

Effects of aluminum on rat bone cell populations.

Aluminum (Al) loading is associated with reduced bone formation and osteomalacia in human and certain animal models. However, uncertainty exists as to the cellular effect(s) of Al as both inhibition and stimulation of osteoblast proliferation have been reported. Furthermore, the extent to which Al affects osteoprogenitor cell populations is unknown. To determine the cellular effects of Al in the rat, an animal model in which Al bone disease has been produced, we compared the in vitro effect of 10-50 microns Al on the proliferation and hydroxyproline collagen formation of marrow osteoprogenitor stromal cell populations and perinatal rat calvarial osteoblasts. In subconfluent cultures, Al suppressed proliferation of both marrow fibroblast-like stromal cells and calvarial osteoblasts. In confluent cultures, however, Al selectively stimulated periosteal fibroblast and osteoblast DNA synthesis and collagen (hydroxyproline) production, both in the presence or absence of 1,25-dihydroxyvitamin D. Osteocalcin was not detected in osteoblast-conditioned media or extracellular matrix. These observations suggest that the bone formation defect associated with Al toxicity in growing rats may be a function of impaired patterns of osteoprogenitor/osteoblast proliferation. Furthermore, the Al-stimulated increase in collagen formation is consistent with the development of osteomalacia in Al-toxic humans and animals. The mechanism by which Al stimulated DNA synthesis and collagen production in more mature cultures awaits further study.

Bone disease in burn patients.

Burn patients are at risk for bone disease due to aluminum (Al) exposure from use of antacids and albumin, partial immobilization, and increased production of endogenous glucocorticoids. Moreover, severely burned children are growth impaired up to 3 years after the burn. To determine the extent of bone disease, we studied nine men and three women, ages 18-41 years, with greater than 50% body surface area burn. Seven patients underwent iliac crest bone biopsy following double tetracycline labeling, one additional patient expired after a single label, and three others had postmortem specimens obtained for quantitative Al only. Serial serum and urine samples were obtained weekly until biopsy or death. All biopsied patients had reduced bone formation and osteoid area, surface, and width, with mineral apposition rate, osteoblast surface, and osteoclast number with normal eroded surfaces compared to age- and sex-matched normal ambulatory volunteers. Burn patients also had reduced bone formation, mineral apposition rate, osteoid area, and surface compared to age-matched volunteers at short-term bed rest. Serum levels of osteocalcin were low. Most patients had mild hypercalcemia but only a third had hypercalciuria. All patients had elevated Al in blood or urine; urine Al correlated inversely with serum osteocalcin. In 60% significant bone Al was detectable by stain or quantitation. Our data are compatible with burn patients having markedly reduced bone turnover. Al loading, partial immobilization, endogenous corticosteroids, and cytokine production may be among the etiologic factors.

Partial characterization of rat marrow stromal cells.

Fibroblast-like rat marrow stromal cell (CFU-F) cultures have been characterized in terms of their responsiveness to calciotropic hormones, metal ions, the nonsteroidal antiinflammatory drug, and by their putative paracrine role in the maintenance of active populations of osteoblasts at the marrow-bone interface. These studies indicate that CFU-Fs lack a complete osteoblast signature. Subconfluent CFU-Fs grown in the presence or absence of 10(-7) M dexamethasone lack receptors for PTH and calcitonin, and fail to show enhanced cAMP or cGMP responses to 10(-7) M 1-34 PTH (rat), or any evidence of osteocalcin production [+/- 10(-9) M 1,25-(OH)2D3]. Low concentrations of fluoride [10(-12) and 10(-9) M] stimulated CFU-F grown in vitro in serum-free media, though higher levels (10(-7) and 10(-6) M), inhibited growth in vivo and in vitro. Aluminum (10(-12)-10(-7) M) and ibuprofen (10(-7) M) did not alter normal growth patterns, indicating an action on bone cells more differentiated than CFU-Fs. Serum-free conditioned medium (CM) from control and ovariectomized (OVX)/OVX+ dihydrotachysterol-Rx rat CFU-F cultures was mitogenic for neonatal rat calvarial osteoblasts in vitro, but not for ROS 17/2.8 cells. The studies affirm the mesenchymal-like character of CFU-Fs and project their significant role in sustaining functional endosteal osteogenic cell populations.

The aluminum content of parenteral solutions: current status.

Aluminum contaminates several chemical compounds that are administered intravenously to patients. The most highly contaminated are calcium and phosphate salts, followed by albumin and heparin. Parenteral administration of aluminum bypasses the gastrointestinal tract, which serves as a protective barrier to aluminum entry into the blood. In the past, parenteral administration of aluminum as a contaminant of water used in hemodialysis and of casein hydrolysate, the former source of protein in parenteral nutrition solutions, was associated with a low-turnover osteomalacic bone disease and, in the case of uremic patients, encephalopathy. Groups currently at risk for aluminum accumulation in tissue resulting from parenteral administration include premature infants receiving long-term parenteral nutrition and patients receiving plasmapheresis therapy with albumin. Both groups may develop metabolic bone disease; the pathogenesis may involve aluminum. The Food and Drug Administration is currently considering regulation of aluminum in fluids used for parenteral nutrition. No changes are presently proposed with regard to albumin.

Elevated serum aluminum levels in severely burned patients who are receiving large quantities of albumin.

Aluminum contaminates various fluids that are used in intravenous therapy, and it is associated with bone disease and encephalopathy. Albumin is highly contaminated with aluminum, which is eliminated primarily by renal excretion. Patients with burns receive large quantities of albumin and have impaired renal function, which puts them at hypothetical risk for aluminum loading. To assess the risk of aluminum loading we analyzed sera from 12 patients with burns for aluminum concentrations. Serum aluminum concentration was elevated in 8 of the 12 patients, and levels were at or near toxicity in 3 of the 8. Serum aluminum and serum creatinine levels directly correlated, r = 0.71 and p less than 0.005. No relation was found between serum aluminum and amount of albumin received. However, patients with the highest serum aluminum levels were the most severely burned and none survived. Thus patients with burns who are receiving albumin are at risk for aluminum loading. Impaired renal function contributes to aluminum retention.

A simplified screening test for the diagnosis of allergy.

The Quidel allergy screen is a relatively rapid (less than 2 hours) multiallergen dipstick method for detecting specific immunoglobin E antibodies in serum. It was developed to answer the need of primary physician nonspecialists in allergy for a convenient in-office screening test for diagnosing allergy. The new test was evaluated against the benchmark diagnostic skin tests and the radioallergosorbent serologic tests for sensitivity, specificity, accuracy, and technical feasibility in an office setting. It was found that while the Quidel allergy screen lacks the specificity of the standard tests, its overall sensitivity, as defined by the percentage of patients with positive skin reactions who also tested positive with the Quidel screen (68%), its ease of use, and its rapidity warrant its consideration as a screening tool for confirming a possible case of allergy.

Hypocalcemia complicating deferoxamine therapy in an infant with parenteral nutrition-associated aluminum overload: evidence for a role of aluminum in the bone disease of infants.

Aluminum (Al) contaminates total parenteral nutrition (TPN) solutions given to infants, and high levels of Al have been demonstrated in their bone, serum, and urine. However, it is uncertain whether Al at current levels of contamination of TPN solutions is harmful to bone. We report an 8-month-old infant who developed osteopenic bone disease while receiving TPN, which did not respond to large amounts of calcium, phosphate, and vitamin D2. Serum and urine Al levels were greatly elevated and fell after a short course of deferoxamine. However, shortly after treatment began, serum calcium levels fell in the absence of hypercalciuria. We postulate that chelation of Al from this patient's bone permitted increased bone calcium uptake. This would suggest that Al at current levels of contamination of TPN solutions may impair bone calcium uptake and thus contribute to the pathogenesis or exacerbation of TPN-related osteopenia.