Early β-lactam concentrations and infectious complications after lung transplantation

Antibiotic underdosing in prophylactic antibiotic regimes after lung transplantation (LTx) can increase the risk of infection. We aimed to study whether β-lactam concentrations achieved desirable pharmacodynamic targets in the early phase after LTx and the association between drug concentrations and the development of early infections or the acquisition of multidrug-resistant (MDR) strains. We reviewed patients in whom broad-spectrum β-lactam levels were measured after LTx during antibiotic prophylaxis. β-Lactam concentrations were considered “insufficient” if drug levels remained below four times the clinical breakpoint of the minimal inhibitory concentration for Pseudomonas aeruginosa. The primary outcome was the occurrence of an infection and/or acquisition of MDR pathogens in the first 14 days after transplantation. A total of 70 patients were included. “Insufficient” drug concentrations were found in 40% of patients. In 27% of patients, an early MDR pathogen was identified and 49% patients were diagnosed with an early posttransplant infection. Patients with “insufficient” drug concentrations acquired more frequently MDR bacteria and/or developed an infection than others (22/28, 79% vs. 20/42, 48% – p = .01). β-Lactam levels were often found to be below the desired drug targets in the early phase after transplantation and may be associated with the occurrence of early infectious complications.     

Why are angiotensin concentrations so high in the kidney?

PURPOSE OF REVIEW: Recent studies have reported that intrarenal angiotensin II content and angiotensin II concentrations in the proximal tubular fluid and renal interstitial fluid are much greater than the circulating angiotensin II levels. These high intrarenal angiotensin II levels are responsible for regulating renal hemodynamics and tubular transport. RECENT FINDINGS: Intrarenal angiotensin II levels have been assessed from total tissue contents as well as renal interstitial fluid and proximal tubular fluid concentrations. Total tissue contents expressed per gram of tissue weight are greater than plasma angiotensin II concentrations; tubular fluid concentrations and renal interstitial fluid concentrations are even greater in the range of 3-10 pmoles/ml. In hypertensive states, there is also an increased intracellular accumulation of angiotensin II mediated by angiotensin type 1 receptor-dependent endocytosis. The high intrarenal angiotensin II levels are also caused by the presence of angiotensinogen messenger RNA and protein in the proximal tubule cells. Furthermore, there is positive amplification by which increases in circulating angiotensin II stimulate increased production and secretion of angiotensinogen, which is also manifested as an increased urinary excretion rate. SUMMARY: The ability of the kidney to generate high intratubular and interstitial concentrations allows the kidney to regulate intrarenal levels in accord with the homeostatic needs for the regulation of renal hemodynamics and tubular reabsorption and the regulation of sodium balance. When inappropriately stimulated, high intrarenal angiotensin II levels contribute to excessive salt and water retention, the development of hypertension, and long-term proliferative effects leading to renal injury.     

High concentrations of β-hydroxybutyrate alter the kinetics of bovine spermatozoa

Postpartum cows, mainly with metabolic diseases, such as ketosis, usually experience an increased number of services per conception. During ketosis, high concentrations of β-hydroxybutyrate (BHBA) in follicular, uterine and oviductal fluid have been considered to cause subfertility in cows. However, the effect of sperm exposure to an environment with high BHBA concentration is not known. This study investigated the influence of high levels of BHBA on kinetics, oxidative status and morphology of bovine spermatozoa. To assess the effect of BHBA after sperm selection, bovine spermatozoa were incubated (180 min) with different BHBA concentrations: 0 (Control), 0.8, 2.4 or 5 mM. Sperm kinetics was evaluated after 30, 60, 120 and 180 min, and oxidative status and morphology were analysed at 180 min. Oxidative status was evaluated through the production of reactive oxidative species (ROS), total antioxidant capacity and lipid peroxidation. High concentrations of BHBA decreased the curvilinear velocity, straight line velocity, mean path velocity, linearity, straightness and hyperactivity of spermatozoa. However, there was no effect of BHBA on oxidative and antioxidant capacity as well as on sperm morphology. In conclusion, exposure of bovine spermatozoa to high levels of BHBA impairs sperm kinetics without altering oxidative and antioxidant mechanisms.     

Cigarette smoking decreases TGF-β1 serum concentrations after long bone fracture

TGF-β1 serum concentrations are considered to be one of the most promising markers of fracture healing. Previously, we demonstrated significant differences in the post-traumatic time courses of patients with timely and delayed fracture healing. The aim of this study was to evaluate possible differences in the serum concentrations of TGF-β1 in cigarette-smoking vs. non-smoking patients with timely and delayed fracture healing in order to understand pathophysiological pathways through which smoking impairs fracture healing.Serum samples were collected from 248 patients undergoing surgical treatment for long bone fractures within 1 year of surgery. Samples from 14 patients with atrophic-type delayed fracture healing were compared with 14 matched patients with normal bone healing. Each group included seven smokers and seven non-smokers. Post-operative serum concentrations were analysed at 1, 2, 4, 8, and 12 weeks as well as 1 year after surgery. The patients were monitored both clinically and radiologically for the entire duration of the study.All patients increased TGF-β1 serum concentrations after surgery. In patients with normal fracture healing, significantly higher TGF-β1 levels were observed in non-smokers (70 ng/ml) than in smokers (50 ng/ml) at the 4th week after surgery (p = 0.007). Also at the 4th week, in patients with delayed healing, significantly lower TGF-β1 levels were observed in smokers than in non-smokers (38 ng/ml vs. 47 ng/ml, p = 0.021). However, no significant differences between non-smokers with delayed healing and smokers with normal healing (p = 0.151) were observed at the 4th week after surgery. TGF-β1 serum concentrations reached a plateau in all groups from the 6th to the 12th week after surgery, with a slight decrease observed in the final measurement taken 1 year after surgery.This study demonstrates that, after fracture, TGF-β1 serum concentrations are reduced by smoking, and this reduction is statistically significant during the 4th week after surgery. Our findings may help reveal the mechanism by which smoking impairs fracture healing. Furthermore, these results may help to establish a serological marker that predicts impaired fracture healing soon after the injury. Surgeons will not only be able to monitor the bone healing, but they will also be able to monitor the success of additional treatments such as ultrasound and bone morphologic proteins (BMPs).     

Should we reconsider iron administration based on prevailing ferritin and hepcidin concentrations?

The results of recent randomized, controlled trials in patients with chronic kidney disease and anemia have suggested that hyporesponsiveness to erythropoiesis stimulating agents (ESA) is a significant predictor of poor patient outcomes. Functional iron deficiency (FID) is the most common cause of suboptimal ESA response, and intravenous iron administration (IVFe) efficiently raises hemoglobin (Hb) concentrations even under the condition of FID. Consequently, renal anemia correction has conceptually shifted from ??higher Hb values with high ESA doses?? to ??prevention of ESA hyporesponsiveness with IVFe??. The discovery of hepcidin has profoundly changed our understanding of the place of FID in renal anemia therapy. Hepcidin reduces the abundance of iron transport proteins which facilitate iron absorption from the gut and iron mobilization from macrophages. Serum hepcidin is mainly modulated by iron stores, as is serum ferritin. High hepcidin or ferritin levels block intestinal iron absorption and iron recycling in macrophages and decrease iron availability for erythropoiesis, leading to FID. Iron administration, especially IVFe, increases hepcidin levels and concomitantly inhibits iron supply to erythroid cells. This in turn could lead to a vicious circle, exacerbating FID and increasing iron demand. Therefore, physicians should be cautious with unrestricted IVFe to chronic kidney disease patients with FID.     

Alterations of leptin and ghrelin serum concentrations in renal disease: simple epiphenomena?

The hypothesis that alterations of serum concentrations of the anorexigenic adipose tissue-derived hormone leptin or the orexigenic peptide ghrelin might help to regain appetite and fight malnutrition in patients with chronic renal failure cannot be confirmed at present. For the future, however, strategies interfering with signal transduction of these peptides in the hypothalamus might be more promising and should be investigated and further developed.     

Plasma concentrations after high-dose (45 mg · kg−1) rectal acetaminophen in children

Although the recommended dose of rectal acetaminophen (25–30 mg · kg^?1) is twice that for oral administration (10–15 mg · kg^?1), the literature justifies the use of a higher dose when acetaminophen is administered via the rectal route. We measured’ venous plasma acetaminophen concentrations resulting from 45 mg · kg^?1 of rectal acetaminophen in ten ASA 1, 15 kg paediatric patients undergoing minor surgery with a standardized anaesthetic. After induction of anaesthesia, a single 650 mg suppository (Abenol®, SmithKline Beecham Pharma Inc.) was administered rectally. Plasma was sampled at t = 0, 15, 30, 45, 60, 90, 120, 180, 240 min in the first five patients and at t = 0, 30, 60, 90, 120, 180, 240, 300, 420 min in the subsequent five. Acetaminophen plasma concentrations were determined’ using a TDxFLx® fluorescence polarization immunoassay (Abbott Laboratories, Toronto, Ontario). The maximum plasma concentration was 88 ± 39 μmol · L^?1 (13 ± 6 μg · ml^?1) and the time of peak plasma concentration was 198 ± 70 min (mean ± SD). At 420 min, the mean plasma concentration was 46 ± 18 μmol · L^?1 (7.0 ± 0.9 μg · ml^?1). No plasma concentrations associated with toxicity (> 800 μmol · L^?1) were identified. A 45 mg · kg^?1 rectal dose of acetaminophen resulted in peak plasma concentrations comparable with those resulting from 10–15 mg · kg^?1 of oral acetaminophen at three hours after suppository insertion. It is concluded that the delayed and erratic absorption of acetaminophen after rectal administration leads to unpredictable plasma concentrations. Rectal acetaminophen will not be consistently effective for providing rapid onset of analgesia in children.     

Elevated concentrations of the β-subunit of S100 protein in renal cell tumors in rats

Concentrations of and -subunits of S100 protein (S100- and S100-) in rat kidney neoplasms, including renal cell and mesenchymal tumors, were determined using a highly sensitive enzyme immunoassay, and both types immunohistochemically localized in tissue sections. Concentration of S100- in each histological type of rat tumor were lower than in normal kidney, whereas levels of S100- (mean±SE: 29.7±14.2 ng/mg protein, n=15) in renal cell tumors were significantly higher than in normal kidneys (0.55±0.06 ng/mg protein, n=7), or mesenchymal tumors (1.21±0.43 ng/mg protein, n=9). In normal rat kidney tissues S100- was immunohistochemically positive in epithelial cells of the distal tubules, the thin limbs of loops of Henle, and the collecting ducts. No appreciable immunostaining for S100- was found in any nephron segment. Both S100- and S100- were positive for renal cell tumors, indicating new appearance of the latter during renal carcinogenesis in rats.     

Cefuroxime concentrations in the anterior and posterior column of the lumbar spine – an experimental porcine study

BACKGROUND CONTEXTSurgical site infection following spine surgery is associated with increased morbidity and mortality. Perioperative antibiotic prophylaxis is a key factor in lowering the risk of acquiring an infection. Previous studies have assessed perioperative cefuroxime concentrations in the anterior column of the cervical spine with an anterior surgical approach. However, the majority of surgeries are performed in the posterior column and many surgeries involve the lumbar spine.PURPOSEThe objective of this study was to compare the perioperative tissue concentrations of cefuroxime in the anterior and posterior column during lumbar spine surgery with a posterior surgical approach.STUDY DESIGNIn vivo experimental pharmacokinetic study of cefuroxime concentrations in an acute preclinical porcine model.METHODSThe lumbar vertebral column was exposed from L1 to L5 in 8 female pigs. Microdialysis catheters were placed for sampling in the anterior column (vertebral body) and posterior column (posterior arch) within the same vertebra (L5). Cefuroxime (1.5 g) was administered intravenously. Microdialysates and plasma samples were continuously obtained over 8 hours. Cefuroxime concentrations were quantified by Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry. The primary endpoint was the time above the cefuroxime clinical breakpoint minimal inhibitory concentration (T>MIC) for Staphylococcus aureus of 4 µg/mL. The secondary endpoint was tissue penetration (AUC_tissue/AUC_plasma).RESULTSMean T>MIC 4 µg/mL (95% confidence interval) was 123 min (105–141) in plasma, 97 min (79–115) in the anterior column and 93 min (75–111) in the posterior column. Tissue penetration (95% confidence interval) was incomplete for both the anterior column 0.48 (0.40–0.56) and posterior column 0.40 (0.33–0.48).CONCLUSIONST>MIC was comparable between the anterior and posterior column. Mean cefuroxime concentrations decreased below the clinical breakpoint minimal inhibitory concentration for S. aureus of 4 µg/mL after 123 minutes (plasma), 97 minutes (anterior column) and 93 minutes (posterior column). This is shorter than the duration of most lumbar spine surgeries, and therefore alternative dosing regimens should be considered in posterior open lumbar spine surgeries lasting more than 1.5 hours.CLINICAL SIGNIFICANCEOpen lumbar spine surgery often involves extensive soft tissue dissection, stripping and retraction of the paraspinal muscles which may impair the local blood flow exposing the lumbar vertebra to postoperative infections. A single intravenous administration of 1.5 g cefuroxime only provided sufficient prophylactic target tissue concentrations in the vertebra of the lumbar spine for up to 1.5 hours.     

Does lead interfere with hemoglobin-based oxygen carrier (HBOC) function? A pilot study of lead concentrations in three approved or tested HBOCs and oxyhemoglobin dissociation with HBOCs and/or bovine blood with varying lead concentrations

We measured lead concentrations in three hemoglobin-based oxygen carriers (HBOCs; Oxyglobin, Hemopure, and Hemolink) and compared them with lead concentrations from blood-bank blood. Oxyhemoglobin dissociation was measured with large concentrations of lead in bovine HBOC, with or without bovine blood, and in bovine blood. Samples of each were prepared by combining one with normal saline (control), the second with small lead concentrations (22 micro g/dL), and the third with toxic lead concentrations (70 micro g/dL). They were blended in 2 tonometers at oxygen concentrations (2.5%, 5%, 8%, 10%, 21%, and 95%) with 5% CO(2) and the remainder nitrogen for 5 min per sample after a 15-min wash-in with each level of oxygen and were measured with co-oximetry. Oxygen saturation was plotted against PO(2), fitting fourth-order polynomial nonlinear regression to the data. The lead concentrations of the three HBOCs were 0.51, 0.22, 0.40 micro g/dL. There were no clinically important differences of the oxyhemoglobin dissociation curves as a function of lead concentration. The lead concentrations of the three tested HBOCs were small and no larger than the average for blood-bank blood. The presence of increasing concentrations of lead in either concentrated solution of bovine HBOC or a 1:1 mixture of bovine HBOC and native bovine blood does not appear to affect hemoglobin oxygenation in an acute in vitro model of increased lead concentrations. IMPLICATIONS: Gunshot wounds rapidly increase circulating lead concentrations. Lead concentrations are small in three hemoglobin-based oxygen carriers (HBOCs), and HBOCs and/or bovine blood do not appear to be affected by lead concentrations in terms of immediate oxygen on-loading and off-loading. HBOCs may be useful in patients with gunshot wounds.     

Do intracellular, extracellular or urinary magnesium concentrations predict renal retention of magnesium in critically ill patients?

BACKGROUND AND OBJECTIVE: Magnesium disorders are common in hospitalized patients. In patients with low or normal magnesium, the intravenous magnesium loading test has been demonstrated to be a sensitive test to assess magnesium deficiency in critically ill patients. However, it is more time consuming and more difficult than the measurement of intracellular or extracellular magnesium concentrations. This study evaluated whether erythrocyte, plasma and urinary magnesium concentrations predict renal magnesium retention measured by th magnesium loading test. METHODS: One-hundred-and-three intensive care patients (36 females, 67 males) in a tertiary care centre and 41 healthy subjects (13 females, 28 males) took part in this prospective study. Intracellular, total plasma, ionize extracellular and urinary magnesium concentrations were measured and also magnesium retention by intravenous magnesium loading test. RESULTS: Total plasma magnesium concentration was poorly correlated with magnesium retention (r = 0.36 r2 = 0.13) and was the only parameter that significantly predicted magnesium retention in intensive care patients (P < 0.01). However, only 10% of the magnesium retention data were linked to the total plasma magnesium concentration. CONCLUSIONS: Total plasma magnesium concentration predicts magnesium retention in critically ill intensive care patients but not intracellular and urinary magnesium concentrations. Only a small proportion of the magnesium retention was due to the total plasma magnesium concentration.     

Normal serum concentrations of S-100 protein and changes in cerebrospinal fluid concentrations of S-100 protein during and after thoracoabdominal aortic aneurysm surgery: Is S-100 protein a biochemical marker of clinical value in detecting spinal cord ischemia?

Purpose: This study was performed to determine the concentration of S-100 protein in serum and in the cerebrospinal fluid (CSF) during and 24 hours after thoracoabdominal aortic aneurysm repair. Methods: This prospective study was performed at St. Antonius Hospital in Nieuwegein, The Netherlands. Eight patients who underwent elective thoracoabdominal aortic surgery participated in the study. Arterial blood and CSF samples for analysis of S-100 protein were drawn after induction of anesthesia, during the cross-clamp period of the critical segment, after 5 minutes of reperfusion, during the closure of the skin, and 24 hours after closure of the skin. Results: No increase in S-100 protein concentration could be detected in serum (<0.2 μg/L). The S-100 protein concentration in CSF increased during the procedure in all patients (4.2 ± 3.1 μg/L). However, in one patient, who became paraplegic, the S-100 protein concentration in CSF increased even further after 24 hours (10 μg/L). Conclusions: The preliminary results suggest that S-100 protein in CSF may be a marker of clinical value in evaluating the effects of measures to detect and reduce spinal cord ischemia. (J Vasc Surg 1998;27:344-6.)     

Elevated concentrations of γ-enolase in renal cell tumors in rats: similarity to renal cell carcinoma in man

Concentrations of enolase isozymes in normal kidney and renal cell tumors in rats were determined using a highly sensitive enzyme immunoassay, and the isozymes were immunohistochemically localized in tissue sections. Levels of -enolase in renal cell turnors were significantly lower than in normal kidney, whereas those of -enolase were significantly elevated (mean ±SD:211±129 ng/mg protein, n=15, as compared to 27.1±2.9 ng/mg protein, n=7). The proportion of -enolase in the total enolases in the tumor tissues (1.6±0.5%) was significantly higher than in normal kidney (0.15±0.005). Immunohistochemistry revealed epithelial cells of all nephron segments to be positive for the -isozyme, whereas -enolase staining was strongly positive only in the loops of Henle, being faint in the distal tubules and absent in the proximal tubules. Both - and -enolases demonstrated positive immunostaining in all of the seven renal cell tumors studied. These findings indicate that an isozyme switch from - to -enolase occurs during rat kidney carcinogenesis, taking into account the derivation from proximal tubules, consistent with the findings for renal cell carcinomas in man.