[Hemoglobin-based oxygen carriers in sepsis].
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Animals↗
Biomedical subjects
H G Bone
Publications and source records attributed to H G Bone.
Alanyl-glutamine dipeptide does not affect hemodynamics despite a greater increase in myocardial heat shock protein 72 immunoreactivity in endotoxemic sheep.
The possible beneficial effect of supplemental glutamine (Gln) in critically ill patients has been suggested to be mediated by the induction of the cytoprotective heat shock proteins (HSP)32 and HSP72. There is evidence that HSP72 and HSP32 have opposite effects on the hemodynamic situation during endotoxemia. Therefore, the effect of Gln supplementation on the cardiovascular system is not clear. We investigated the effect of alanyl-Gln (Ala-Gln) dipeptide on cardiovascular function in healthy and endotoxemic sheep. Ten sheep catheterized for chronic studies received Ala-Gln 700 mg/(kg x d) [equal to 470 mg/(kg x d)Gln] on 4 consecutive days, and 10 sheep received NaCl (9 g/L) as the control solution. On d 4, four sheep of each group were killed and myocardial samples were taken for immunohistochemistry. The remaining sheep received a continuous infusion of endotoxin [Salmonella typhosa, 10 ng/(kg x min)]. Hemodynamic parameters were measured before application of Ala-Gln or the control solution, and during endotoxemia. Myocardial HSP72 immunoreactivity was determined by immunohistochemistry. After 24 h of endotoxemia, the sheep exhibited a hyperdynamic circulation. No difference was found in the hemodynamic parameters between treatment and control group. Ala-Gln treated sheep had a greater increase in myocardial HSP72 immunoreactivity compared with controls after (P < 0.05) but not before endotoxemia. In summary, Ala-Gln increased HSP72 immunoreactivity after endotoxemia, but did not alter hemodynamic parameters. Thus, Ala-Gln supplementation does not seem to aggravate the hyperdynamic circulation in endotoxemic shock.
Animals↗
Thoracic, but not lumbar, epidural anesthesia improves cardiopulmonary function in ovine pulmonary embolism.
UNLABELLED: We hypothesized that sympathetic stimulation is the main mechanism contributing to hemodynamic failure in pulmonary embolism. We investigated the effects of epidural anesthesia-induced sympathetic blockade, restricted to thoracic and lumbar levels, during pulmonary embolism. Two experiments were performed in chronically instrumented ewes. In the first experiment, six sheep received 6 mL bupivacaine 0.175% (Thoracic Epidural Anesthesia [TEA] group), and six sheep received 6 mL saline 0.9% (TEA-Control group), respectively, via an epidural catheter (T3 level). In the second experiment, six sheep received 2.8 mL bupivacaine 0.375% (Lumbar Epidural Anesthesia [LEA] group), and six sheep received 2.8 mL saline 0.9% (LEA-Control group) epidurally (L4 level). Embolization was performed by IV injection of autologous blood clots (Experiment 1, 0.75 mL/kg; Experiment 2, 0.625 mL/kg). TEA was associated with significantly slower heart rates, decreased mean pulmonary artery pressures and central venous pressures, and significantly higher stroke volume index and oxygenation in comparison with the TEA-Control group. By contrast, LEA was associated with significantly faster heart rates and increased central venous pressures and with a significantly lower stroke volume index in comparison with the LEA-Control group. TEA significantly reduced, and LEA significantly increased, hemodynamic deterioration, suggesting beneficial effects of TEA on cardiopulmonary function during pulmonary thromboembolism. IMPLICATIONS: Thoracic (but not lumbar) epidural anesthesia was associated with beneficial cardiopulmonary effects during experimental pulmonary thromboembolism in sheep.
Anesthesia, Epidural↗
Hemodynamic effects of terlipressin (a synthetic analog of vasopressin) in healthy and endotoxemic sheep.
OBJECTIVE: Hypotension, vasodilation, and vasoplegia are characteristic signs of septic shock. The vasoconstrictive response to catecholamines typically is reduced. A decreased vasopressive effect of catecholamines can be observed in the late phase of hemorrhagic shock. Interestingly, an unaltered vasopressive response to vasopressin can be demonstrated in hemorrhagic shock. In this study, we investigated the vasoconstrictive response to an agonist of the vasopressin receptor, terlipressin, in healthy sheep as well as in ovine hyperdynamic endotoxemia. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: Six female adult sheep. INTERVENTIONS: Healthy sheep, instrumented for chronic study, received terlipressin (15 microg/kg) as a bolus; 30 mins later, norepinephrine was continuously given for 30 mins. Three hours later, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng x kg(-1) x min(-1)) was started in the same sheep and given for the next 23 hrs. After 20 hrs of endotoxemia, terlipressin and norepinephrine were given as described previously. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were measured before and 30 mins after application of terlipressin and after 30 mins of continuous infusion of norepinephrine. Terlipressin significantly increased systemic vascular resistance index in healthy and endotoxemic sheep (p <.05). The increase was higher in endotoxemic compared with healthy animals (p <.05). Only during endotoxemia, terlipressin increased pulmonary vascular resistance index. This was accompanied by a significant decrease in cardiac index, whereas mean pulmonary arterial pressure did not change after application of terlipressin. Additional treatment with norepinephrine did not further increase systemic vascular resistance index or pulmonary vascular resistance index. CONCLUSIONS: Terlipressin reversed the hemodynamic changes in ovine endotoxemia. However, its pulmonary vasopressive effect might limit its therapeutic use in septic shock.
Animals↗
Increased carbon monoxide in exhaled air of critically ill patients.
Heme oxygenase produces carbon monoxide (CO) during breakdown of heme molecules primarily in liver and spleen. Recent data suggest that CO is also produced in the lungs. CO is excreted by exhalation via the lungs. A number of inflammatory agents induce the expression of heme oxygenase, possibly leading to increased CO production. To investigate whether critical illness results in increased CO production we measured the CO concentration in exhaled air in 30 critically ill patients and in healthy controls (n = 6). Critically ill patients showed a significantly higher CO concentration in exhaled air (median 2.4 ppm, 95% CI 1.0-7.0 ppm vs median 1.55 ppm, 95% CI 1.2-1.7 ppm, P = 0.01) as well as total CO production (median 20 ml/min, 95% CI 8 to 90 ml/min vs median 13.5 ml/min, 95% CI 11 to 19 ml/min, P = 0.026) compared to healthy controls. No correlation was found between CO concentration in exhaled air and carboxyhemoglobin concentration in arterial and central venous blood (P > 0.05). The increase of CO concentration in exhaled air in critical illness suggests an induction of inducible heme oxygenase (HO-1) and might reflect the severity of illness.
Adult↗
Weekly administration of alendronate: rationale and plan for clinical assessment.
OBJECTIVE: This paper describes the rationale and supporting data for once-weekly dosing of alendronate. BACKGROUND: Alendronate sodium, a bisphosphonate that potently inhibits bone resorption, has been shown to increase bone mass and substantially reduce the incidence of osteoporotic fractures, including fractures of the hip. The standard regimen of daily administration has generally been well tolerated. However, weekly administration may provide greater convenience to patients without compromising efficacy or tolerability. The pharmacokinetics of alendronate and bone remodeling theory predict similar efficacy for weekly and daily administration if the cumulative dose is the same. Bone resorption in individual remodeling units normally proceeds for approximately 2 weeks; alendronate inhibits the rate and extent of resorption. Because the half-life of residence on bone surfaces is several weeks, weekly administration of alendronate should inhibit bone resorption to an overall extent similar to that of daily dosing, thereby producing similar effects on bone mass and strength. Animal studies demonstrate that both weekly and daily parenteral administration of alendronate effectively increase bone mass and strength, but confirmation of efficacy is needed for weekly oral dosing in humans. Although daily bisphosphonates (alendronate and risedronate) elicited esophageal irritation in a canine model of gastroesophageal reflux, weekly dosing with alendronate at a higher unit dose did not. Thus, the lower frequency of weekly dosing with a higher unit dose may actually reduce the risk of upper gastrointestinal irritation compared with daily administration of a lower dose. CONCLUSIONS: Current safety and efficacy data justify further investigation of once-weekly dosing of alendronate. Two positive-control, double-blind, randomized trials of osteoporosis treatment and prevention are currently being performed to assess the comparability of weekly, biweekly, and daily dosing of alendronate with regard to effects on bone density, safety, and tolerability.
Alendronate↗
Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey.
BACKGROUND: The treatment of patients with asymptomatic primary hyperparathyroidism remains controversial despite a National Institutes of Health consensus statement. This statement also recommended a randomized clinical trial because none exists to address this issue. METHODS: Informed consent was obtained from 53 asymptomatic patients with confirmed asymptomatic primary hyperparathyroidism who participated in this randomized trial of parathyroidectomy versus observation. Patients completed the SF-36 Health Survey, an instrument that measures wellness, every 6 months for 2 years. Average annual changes were compared. RESULTS: Fifty-three patients (42 female, 11 male) with asymptomatic, mild (serum calcium level, 10.1-11.5 mg/dL) asymptomatic primary hyperparathyroidism who agreed to participate were randomized into either a surgical group or an observation group. The mean calcium level was 10.31 mg/dL. The only demographic difference between groups was age, with the operative group being older (66.7 vs 62.6 years; P <.03). The scores on 2 of the 9 domains of the SF-36 were significantly different (P <.007 and <.012, respectively); both favored the operative group. CONCLUSIONS: Improved function is seen after parathyroidectomy when compared with patients who did not undergo operation. This study supports surgical management of mild primary hyperparathyroidism at the time of diagnosis because many patients have reversible nonclassic symptoms of the disease.
Aged↗
Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group.
The bisphosphonate alendronate and conjugated equine estrogens are both widely used for the treatment of postmenopausal osteoporosis. Acting by different mechanisms, these two agents decrease bone resorption and thereby increase or preserve bone mineral density (BMD). The comparative and combined effects of these medications have not been rigorously studied. This prospective, double blind, placebo-controlled, randomized clinical trial examined the effects of oral alendronate and conjugated estrogen, in combination and separately, on BMD, biochemical markers of bone turnover, safety, and tolerability in 425 hysterectomized postmenopausal women with low bone mass. In addition, bone biopsy with histomorphometry was performed in a subset of subjects. Treatment included placebo, alendronate (10 mg daily), conjugated equine estrogen (CEE; 0.625 mg daily), or alendronate (10 mg daily) plus CEE (0.625 mg daily) for 2 yr. All of the women received a supplement of 500 mg calcium daily. At 2 yr, placebo-treated patients showed a mean 0.6% loss in lumbar spine BMD, compared with mean increases in women receiving alendronate, CEE, and alendronate plus CEE of 6.0% (P < 0.001 vs. placebo), 6.0% (P < 0.001 vs. placebo), and 8.3% (P < 0.001 vs. placebo and CEE; P = 0.022 vs. alendronate), respectively. The corresponding changes in total proximal femur bone mineral density were +4.0%, +3.4%, +4.7%, and +0.3% for the alendronate, estrogen, alendronate plus estrogen, and placebo groups, respectively. Both alendronate and CEE significantly decreased biochemical markers of bone turnover, specifically urinary N-telopeptide of type I collagen and serum bone-specific alkaline phosphatase. The alendronate plus CEE combination produced slightly greater decreases in these markers than either treatment alone, but the mean absolute values remained within the normal premenopausal range. Alendronate, alone or in combination with CEE, was well tolerated. In the subset of patients who underwent bone biopsies, histomorphometry showed normal bone histology with the expected decrease in bone turnover, which was somewhat more pronounced in the combination group. Thus, alendronate and estrogen produced favorable effects on BMD. Combined use of alendronate and estrogen produced somewhat larger increases in BMD than either agent alone and was well tolerated.
Adult↗
Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group.
We report here the second 2-yr extension of a clinical trial among postmenopausal women; 235 women continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 yr were switched to blinded placebo. Continuous treatment with alendronate (10 mg daily) for 7 yr increased lumbar spine bone mineral density (BMD) by 11.4% compared to baseline. After the initial 18 months, each additional year of treatment through yr 7 increased spine BMD by 0.8% for the 10-mg dose and 0.6% for the 5-mg dose, with significant increases during yr 6-7. Previously reported increases in BMD at other skeletal sites and decreases in biochemical markers of bone turnover remained stable during yr 6-7. Among women previously taking alendronate for 5 yr who were switched to placebo, there was no significant decline in BMD at the spine or hip, whereas small, but significant, decreases in BMD at the forearm and total body and small increases in biochemical markers were observed. The safety and tolerability profiles were similar to those of placebo. This is the largest published long-term study of antiresorptive therapy. Our findings indicate that long-term alendronate treatment is well tolerated and effective for 7 yr. Increases in spinal BMD continue for at least 7 yr, and other skeletal benefits are maintained. Discontinuation does not lead to accelerated bone loss, but continuous treatment yields better skeletal benefits than shorter treatment.
Absorptiometry, Photon↗
Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone.
Activating missense mutations of the GNAS1 gene, encoding the alpha subunit of the stimulatory G protein (Gs), have been identified in patients with the McCune-Albright syndrome (MAS; characterized by polyostotic fibrous dysplasia, café au lait skin pigmentation, and endocrine disorders). Because fibrous dysplasia (FD) of bone also commonly occurs outside of the context of typical MAS, we asked whether the same mutations could be identified routinely in non-MAS FD lesions. We analyzed a series of 8 randomly obtained, consecutive cases of non-MAS FD and identified R201 mutations in the GNAS1 gene in all of them by sequencing cDNA generated by amplification of genomic DNA using a standard primer set and by using a novel, highly sensitive method that uses a protein nucleic acid (PNA) primer to block amplification of the normal allele. Histologic findings were not distinguishable from those observed in MAS-related FD and included subtle changes in cell shape and collagen texture putatively ascribed to excess endogenous cyclic adenosine monophosphate (cAMP). Osteomalacic changes (unmineralized osteoid) were prominent in lesional FD bone. In an in vivo transplantation assay, stromal cells isolated from FD failed to recapitulate a normal ossicle; instead, they generated a miniature replica of fibrous dysplasia. These data provide evidence that occurrence of GNAS1 mutations, previously noted in individual cases of FD, is a common and perhaps constant finding in non-MAS FD. These findings support the view that FD, MAS, and nonskeletal isolated endocrine lesions associated with GNAS1 mutations represent a spectrum of phenotypic expressions (likely reflecting different patterns of somatic mosaicism) of the same basic disorder. We conclude that mechanisms underlying the development of the FD lesions, and hopefully mechanism-targeted therapeutic approaches to be developed, must also be the same in MAS and non-MAS FD.
Adolescent↗
Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group.
Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may be substantially reduced with once-weekly dosing. This dosing regimen would provide patients with increased convenience and would be likely to enhance patient compliance. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double-blind, multicenter study of postmenopausal women (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primary efficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-defined equivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied the equivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were: 5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weekly group, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group. These data are consistent with preclinical animal models, and suggest that once-weekly dosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverse experiences, were similar among the groups. We conclude that the alendronate 70 mg once-weekly dosing regimen will provide patients with a more convenient, therapeutically equivalent alternative to daily dosing, and may enhance compliance and long-term persistence with therapy.
Administration, Oral↗
Hearing loss as a complication of Paget's disease of bone.
Hearing loss has long been known to be a complication of Paget's disease of bone. Older ideas about the mechanisms of hearing loss are being replaced by a new view based on experimental evidence from patients. Studies reviewed show no evidence of auditory nerve dysfunction and confirm a cochlear site of lesion. A loss of bone mineral density in the cochlear capsule is associated with both a high-tone hearing loss and a low-tone air-bone gap.
Aged↗
[Oxygen delivery in sepsis. After 10 years more questions than answers].
Object of this review is to present the physiological principles, diagnostic techniques and therapeutic options that are related to modifications of oxygen delivery in sepsis. Despite intense research activities in this area, many topics regarding oxygen transport and oxygen consumption in sepsis are still not clear. For example, the often discussed shift of the critical value of oxygen delivery to higher values in sepsis has not been proven, yet. Beside an impaired regional perfusion also disturbances in the cellular oxygen utilization may be responsible for organ failure in sepsis. Until now, it was not shown, whether the increase of oxygen delivery to supranormal levels reduces mortality in septic patients. It is also unknown, which catecholamine and which infusion solution is suitable for the treatment of septic patients. In future further research is necessary to solve the problems associated with sepsis therapy.
Fluid Therapy↗
[Venous paradoxical air embolism].
Paradoxical air embolism may occur with any venous air embolism. Air may either enter the systemic circulation through a patent foramen ovale or through transpulmonary passage of air. While small venous air emboli are mostly well tolerated, even the smallest paradoxical air emboli can have fatal consequences in the systemic circulation. Therapy and prophylaxis of paradoxical air embolism equal those of venous air embolism. This is especially true, since paradoxical air embolism may not become obvious under general anesthesia. More specific therapeutic regiments, such as hyperbaric oxygenation and the infusion of perfluorocarbons, are still in an experimental stage.
Embolism, Air↗
An open-label extension study of alendronate treatment in elderly women with osteoporosis.
We have recently reported the results of a 24-month, double-blind, placebo-controlled study in 359 elderly osteoporotic women who were treated with daily oral alendronate (ALN) 1, 2.5, or 5 mg or placebo (PBO). We report the results of a 12-month, open-label, extension study during which 246 patients from the original study were treated with ALN 10 mg/day. Significant increases in lumbar spine bone mineral density (BMD) were observed in patients who had previously received PBO or ALN 1 and 2.5 mg/day for 24 months. Significant gains in trochanter BMD were seen in all treatment groups. Small changes were observed in femoral neck, total body, and forearm BMD during the course of this extension study. In general, the greatest increases in BMD during the open-label extension year occurred in patients who received either PBO or the lower doses of ALN during the previous 2-year blinded study. The frequencies of all categories of upper gastrointestinal adverse experiences (AEs) were less during months 25-36 (open-label extension) than during months 0-24 (original study). In conclusion, treatment with ALN 10 mg/day for 12 months in elderly women with osteoporosis who were previously treated for 24 months with PBO or ALN 1, 2.5, or 5 mg/day increased or maintained BMD of the spine, trochanter, and forearm, and was generally safe and well tolerated, especially in the upper gastrointestinal tract.
Absorptiometry, Photon↗
Intraoperative autotransfusion in small children: an in vitro investigation to study its feasibility.
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Blood Transfusion, Autologous↗
Therapeutic controversies in primary hyperparathyroidism.
There is little debate about the primacy of surgery in the management of classical PHPT. Rather, the question has been what to do about the many patients with nonclassical disease. A 1990 NIH consensus conference (55) clearly recommended surgery for patients with significant adverse effects of PHPT, for patients with complicating coexistent illnesses, for younger patients, and for those in whom consistent long-term follow-up could not be assured. It allowed that conscientious surveillance may be justified in patients with minimal hypercalcemia and no adverse effects, but it recognized that for many patients, the time and expense involved in rigorous follow-up would outweigh the burden of surgery. Nine years later, the demonstrated prevalence of nonclassical symptoms and their reversibility, the evidence of "asymptomatic" but harmful effects reversible by surgery, and the accumulating evidence for surgical reduction of increased long-term mortality risk substantially strengthen the argument for surgery in such patients. For these reasons, parathyroidectomy should generally be recommended for patients with a secure diagnosis of PHPT, even in the absence of classical symptoms.
Calcium↗