Faster Detection of Ischemia in Free Muscle Transfer When Using Microdialysis.

BACKGROUND: Microdialysis is a clinical method used to detect ischemia after microvascular surgery. Microdialysis is easy to use and reliable, but its value in most clinical settings is hampered by a 1- to 2-h delay in the delivery of patient data. This study evaluated the effectiveness of an increase in the microdialysis perfusion rate from 0.3 to 1.0 µL/min on the diagnostic delay in the detection of ischemia. METHODS: In eight pigs, two symmetric pure muscle transfers were dissected based on one vascular pedicle each. In each muscle, two microdialysis catheters were placed. The two microdialysis catheters were randomized to a perfusion rate of 0.3 or 1.0 µL/min, and the two muscle transfers were randomized to arterial or venous ischemia, respectively. After baseline monitoring, arterial and venous ischemia was introduced by the application of vessel clamps. Microdialysis sampling was performed throughout the experiment. The ischemic cutoff values were based on clinical experience set as follows: CGlucose < 0.2 mmol/L, CLactate > 7 mmol/L, and the lactate/pyruvate ratio > 50. RESULTS: The delay for the detection of 50% of arterial ischemia was reduced from 60 to 25 minutes, and for the detection of all cases of arterial ischemia, the delay was reduced from 75 to 40 minutes when the perfusion rate was increased from 0.3 to 1.0 µL/min. After the same increase in perfusion, the detection of 50% of venous ischemia was reduced from 75 to 40 minutes, and for all cases of venous ischemia, a reduction from 135 to 95 minutes was found. CONCLUSION: When using microdialysis for the detection of ischemia in pure muscle transfers, an increase in the perfusion rate from 0.3 to 1.0 µL/min can reduce the detection delay of ischemia.

Bone and subcutaneous adipose tissue pharmacokinetics of vancomycin in total knee replacement patients.

Background and purpose - The incidence of orthopedic methicillin-resistant Staphylococcus aureus (MRSA) infections is increasing. Vancomycin may therefore play an increasingly important role in orthopedic perioperative antimicrobial prophylaxis. Studies investigating perioperative bone and soft tissue concentrations of vancomycin are sparse and challenged by a lack of appropriate methods. We assessed single-dose plasma, subcutaneous adipose tissue (SCT) and bone concentrations of vancomycin using microdialysis in male patients undergoing total knee replacement. Methods - 1,000 mg of vancomycin was administered postoperatively intravenously over 100 minutes to 10 male patients undergoing primary total knee replacement. Vancomycin concentrations in plasma, SCT, cancellous, and cortical bone were measured over the following 8 hours. Microdialysis was applied for sampling in solid tissues. Results - For all solid tissues, tissue penetration of vancomycin was significantly impaired. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 2 mg/L was 3, 36, 27, and 110 min for plasma, SCT, cancellous, and cortical bone, respectively. As opposed to the other compartments, a mean MIC of 4 mg/L could not be reached in cortical bone. The area under the concentration-time curve from 0 to the last measured value and peak drug concentrations (Cmax) for SCT, cancellous, and cortical bone was lower than that of free plasma. The time to Cmax was higher for all tissues compared with free plasma. Interpretation - Postoperative penetration of vancomycin to bone and SCT was impaired and delayed in male patients undergoing total knee replacement surgery. Adequate perioperative vancomycin concentrations may not be reached using standard prophylactic dosage.

Vancomycin concentrations in the cervical spine after intravenous administration: results from an experimental pig study.

Background and purpose - Vancomycin may be an important drug for intravenous perioperative antimicrobial prophylaxis in spine surgery. We assessed single-dose vancomycin intervertebral disc, vertebral cancellous bone, and subcutaneous adipose tissue concentrations using microdialysis in a pig model. Material and methods - 8 female pigs received 1,000 mg of vancomycin intravenously as a single dose over 100 minutes. Microdialysis probes were placed in the C3-C4 intervertebral disc, C3 vertebral cancellous bone, and subcutaneous adipose tissue, and vancomycin concentrations were obtained over 8 hours. Venous blood samples were obtained as reference. Results - Ranging from 0.24 to 0.60, vancomycin tissue penetration, expressed as the ratio of tissue to plasma area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments. The lowest penetration was found in the intervertebral disc. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 4 µg/mL was 3, 17, 25, and 156 min for plasma, subcutaneous adipose tissue, vertebral cancellous bone, and the intervertebral disc, respectively. In contrast to the other compartments, a mean MIC of 8 µg/mL was not reached in the intervertebral disc. An approximately 3-times longer elimination rate was observed in the intervertebral disc in comparison with all the other compartments (p < 0.001), and the time to peak drug concentration was higher for all tissues compared with plasma Interpretation - Preoperative administration of 1,000 mg of vancomycin may provide adequate vancomycin tissue concentrations with a considerable delay, though tissue penetration was incomplete. However, in order also to achieve adequate intervertebral disc concentrations in all individuals and accommodating a potentially higher MIC target, supplemental application of vancomycin may be necessary.

Continuous versus short-term infusion of cefuroxime: assessment of concept based on plasma, subcutaneous tissue, and bone pharmacokinetics in an animal model.

The relatively short half-lives of most ß-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. For short-term infusion, the tissue penetration ratios were 0.97 (95% confidence interval [CI], 0.67 to 1.39), 0.61 (95% CI, 0.51 to 0.73), and 0.45 (95% CI, 0.36 to 0.56) for subcutaneous tissue, cancellous bone, and cortical bone, respectively. For continuous infusion, they were 0.53 (95% CI, 0.33 to 0.84), 0.38 (95% CI, 0.23 to 0.57), and 0.27 (95% CI, 0.13 to 0.48) for the same tissues, respectively. The absolute areas under the concentration-time curve were also lower in the continuous infusion group. Nevertheless, a significantly longer time with concentrations above the MIC was found for continuous infusion up until MICs of 4, 2, 2, and 0.5 µg/ml for plasma and the same three tissues mentioned above, respectively. For drugs with a short half-life, like cefuroxime, continuous infusion seems to be favorable compared to short-term infusion; however, incomplete tissue penetration and high MIC strains may jeopardize the continuous infusion approach.

Pharmacokinetics of cefuroxime in porcine cortical and cancellous bone determined by microdialysis.

Traditionally, the pharmacokinetics of antimicrobials in bone have been investigated using bone biopsy specimens, but this approach suffers from considerable methodological limitations. Consequently, new methods are needed. The objectives of this study were to assess the feasibility of microdialysis (MD) for measuring cefuroxime in bone and to obtain pharmacokinetic profiles for the same drug in porcine cortical and cancellous bone. The measurements were conducted in bone wax sealed and unsealed drill holes in cortical bone and in drill holes in cancellous bone and in subcutaneous tissue. As a reference, the free and total plasma concentrations were also measured. The animals received a bolus of 1,500 mg cefuroxime over 30 min. No significant differences were found between the key pharmacokinetic parameters for sealed and unsealed drill holes in cortical bone. The mean ± standard error of the mean area under the concentration-time curve (AUC) values from 0 to 5 h were 6,013 ± 1,339, 3,222 ± 1086, 2,232 ± 635, and 952 ± 290 min · µg/ml for free plasma, subcutaneous tissue, cancellous bone, and cortical bone, respectively (P < 0.01, analysis of variance). The AUC for cortical bone was also significantly different from that for cancellous bone (P = 0.04). This heterogeneous tissue distribution was also reflected in other key pharmacokinetic parameters. This study validates MD as a suitable method for measuring cefuroxime in bone. Cefuroxime penetration was impaired for all tissues, and bone may not be considered one distinct compartment.

Acute kidney injury in rats with or without pre-existing chronic kidney disease: cytokine/chemokine response.

AIM: Evidence suggests the possibility that pre-existing chronic kidney (CKD) disease may result in a more severe outcome of acute kidney injury (AKI). The aim of this study was to examine whether CKD enhances the inflammatory response in the kidney, as well as other organs, in response to AKI in rats. METHODS: CKD was induced by 5/6 nephrectomy (Nx) and AKI by intestinal ischaemia and reperfusion (IIR). RESULTS: For 6 weeks following Nx there was a progressive increase in serum creatinine with associated development of albuminuria. The increment in creatinine above baseline determination 90 min following IIR was comparable in 5/6 Nx and in the sham 5/6 Nx. Similarly, increased levels of serum alanine transaminase and histomorphological changes in the lungs were observed in the rats exposed to IIR compared with those exposed to sham IIR, with no additional significant impact of 5/6 Nx. In kidney tissue the levels of cytokines/chemokines were equally elevated regardless of exposure to sham IIR or IIR. In lung and liver tissue the levels of cytokines/chemokines were equally elevated in the rats that were exposed to IIR, regardless of exposure to sham Nx or Nx. CONCLUSION: We conclude that the immediate severity of AKI induced by IIR in rats with CKD is similar to that induced in rats without CKD. However, the impact of Nx on the cytokine/chemokine response after AKI is not uniform in kidney, lung or liver tissue.

Increased post-operative ischemia in the femoral head found by microdialysis by the posterior surgical approach: a randomized clinical trial comparing surgical approaches in hip resurfacing arthroplasty.

BACKGROUND: Hip resurfacing arthroplasty (HRA) is associated with osteonecrosis of the femoral head and femoral neck fracture, which may be caused by a decrease in the perfusion of the bone initiated at surgery. Several studies have demonstrated a decreased blood flow during surgery depending on the choice of surgical approach. We investigated the effect of the surgical approach on the blood flow and metabolism in the femoral head and neck in HRA by Laser Doppler flowmetry (LDF) and microdialysis. MATERIALS AND METHODS: We conducted a randomized clinical trial on 38 patients, allocated to HRA by either the posterior (Post) or the antero-lateral (AntLat) surgical approach. LDF was performed during surgery and microdialysis after surgery to assess the concentration of the following metabolic markers: glucose, lactate, pyruvate and glycerol. RESULTS: At 44-50 h after surgery, the mean lactate/pyruvate (L/P) and lactate/glucose (L/G) ratio was higher in the Post group compared to the AntLat group; L/P 195.3 (SEM 123) in Post and 128.5 (108.0) in AntLat; L/G 16.9 (6.5) in Post and 8.9 (3.7) in AntLat (p L/P = 0.02 and p L/G = 0.03). There was no difference in the LDF measurements (p = 0.74). INTERPRETATION: HRA in the posterior approach results in increased post-operative ischemia in the femoral head and neck although during surgery, no difference in the blood flow was found. Still, the antero-lateral approach also causes considerable ischemia and other possible explanations, such as damage to the retinacular vessels during surgery or altered microcirculation because of heating from the cementation process, needs to be investigated.

Monitored extended secondary arterial ischemia in a free muscle transfer.

In reconstructive microsurgery, flap failure can be catastrophic to the patient. Different monitoring methods have been implemented in an attempt to recognize secondary ischemia during its early stages. However, the exact onset of secondary ischemia can be difficult to determine because there are no well-documented and reliable monitoring techniques that offer true continuous monitoring in a clinical setting. Because of the uncertain time in terms of the onset of secondary ischemia, the exact length of ischemia before revascularization, the secondary ischemia time, cannot be obtained. This is probably part of the reason why not much has been published regarding the effect of secondary ischemia time in reference to flap survival. We present a case of a free gracilis muscle flap that was salvaged despite more than 11 hours of arterial ischemia. The flap was monitored using microdialysis and at no time was the ischemia clearly demonstrated by clinical inspection. We conclude that clinical monitoring in some cases can be an unreliable method for monitoring free muscle transfers suffering from arterial ischemia and that further studies are needed for more specific guidelines regarding the critical secondary ischemia time in muscle flaps.

Reduction in waiting time for diagnosis and treatment of head and neck cancer - a fast track study.

UNLABELLED: Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organization and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient flow. MATERIAL AND METHODS: Initiatives were implemented throughout the year 2007. Focus was on optimizing logistics for all patients referred to the center with suspected head and neck cancer. Initiatives included a full-time case manager, pre-booked slots for clinical work-up and weekly tumor-boards. Key-dates were registered and relevant intervals were quantitatively evaluated and compared to a reference-group from 2006. RESULTS: We registered 446 patients. Waiting times for first clinical examination on ENT department were reduced from median eight to median two days through 2007 (p < 0.0001). Time from first clinical examination and until referral for treatment was reduced from median 21 to median nine days (p < 0.0001). Time from referral to treatment and until initiation of treatment was reduced from median 26 to median 15 days (p < 0.001). The net result of these reductions was a reduced overall time from median 57 days ultimo 2006 to median 29 days ultimo 2007 (p < 0.0001). CONCLUSION: The current project has shown that it is possible to reduce waiting times in head and neck cancer. Through logistic changes, employment of a full-time case manager, strengthening the multidisciplinary tumor board and giving higher priority for head and neck cancer patients, the overall time from first suspicion of cancer until treatment start was reduced from 57 calendar days to 29 calendar days.

Metabolic markers obtained by microdialysis can detect secondary intestinal ischemia: an experimental study of ischemia in porcine intestinal segments.

BACKGROUND: The free intestinal flap has become a recognized part of the surgical armamentarium for the reconstruction of the cervical esophagus and in the treatment of severe short bowel syndrome. However, the intestinal flap is difficult to monitor postoperatively and is susceptible to ischemia. Entire avoidance of neglected ischemia and false alarms require a monitoring system with sensitivity and specificity of 100%. The aim of this study was to investigate the value of microdialysis (MD) as a monitoring method for detecting ischemia in intestinal transplants. METHODS: In 12 pigs the entire small intestine was divided into three segments, each isolated on a vascular pedicle consisting of one artery and one vein. For metabolic monitoring of the intestinal segments, one CMA 63 MD catheter was placed in each segment in the mesentery just at the border of the intestinal wall. After 1 h of arterial ischemia followed by 2 h of reperfusion, the three intestinal segments in each pig were allocated to arterial ischemia, venous ischemia, or no ischemia. A total of 10 control segments, 10 segments with arterial ischemia, and nine segments with venous ischemia were provided for evaluation of metabolic changes. RESULTS: One hour of secondary ischemia induced considerable metabolic changes, with a decrease in the concentration of glucose (C (Glucose)) followed by an increase in the concentration of lactate (C (Lactate)) as well as in the lactate:pyruvate (L/P) and lactate:glucose (L/G) ratios. The changes became even more pronounced after 1(1/2) h when the L/P and L/G ratios had increased 9 and 30 times, respectively, in the ischemic segments and without overlap in values between the ischemic and the nonischemic segments. When using C (Glucose) < 0.2 mmol/l or L/G > 50 as cutoff levels for detection of ischemia, a sensitivity and a specificity of 100% could be achieved. An increase in C (Glucose) of more than 2 mmol/l, after the infusion of glucose, could be used as a challenge test to exclude ischemia. CONCLUSIONS: A monitoring system based on the determination of the C (Glucose) and C (Lactate) by using microdialysis can be used for positive differentiation between ischemic and nonischemic intestinal segments.

Pure muscle transfers can be monitored by use of microdialysis.

Most of the methods available for postoperative monitoring of free transfers depend on an accessible skin island. Monitoring of muscle transfers without skin islands represents a challenge. The aim of this study was to describe the experiences after clinical monitoring of free muscle transfers by the use of microdialysis. The charts of 75 free muscle transfers monitored with microdialysis were evaluated with special emphasis on whether or not complications were predicted by the monitoring system. In 16 of the 75 cases, an ischemic trend was seen. In five of these cases, the ischemic trend was reversed without surgical revascularization. In the remaining 11 cases (14.7%), further ischemic trends were seen, and surgical revision with revascularization was needed for transfer salvage. Six of the 11 transfers were subsequently saved. None of the remaining five transfers were lost due to neglected ischemia. The microdialysis system did not exhibit any negative or positive false alarms. No damage to the muscle flap was experienced while performing the monitoring procedures. Microdialysis is a reliable and safe monitoring method for surveillance of free muscle transfers.

Postoperative monitoring of free flaps in autologous breast reconstruction: a multicenter comparison of 398 flaps using clinical monitoring, microdialysis, and the implantable Doppler probe.

Many techniques for flap monitoring following free tissue transfer have been described; however, there is little evidence that any of these techniques allow for greater rates of flap salvage over clinical monitoring alone. We sought to compare three established monitoring techniques across three experienced microsurgical centers in a comparable cohort of patients. A retrospective, matched cohort study of 398 consecutive free flaps in 347 patients undergoing autologous breast reconstruction was undertaken across three institutions during the same 3-year period, with a single form of postoperative monitoring used at each institution: clinical monitoring alone, the Cook-Swartz implantable Doppler probe, or microdialysis. Both objective and subjective measures of efficacy were assessed. Clinical monitoring alone, the implantable Doppler probe, and microdialysis showed statistically similar rates of flap salvage. False-negative rates were also statistically similar (only seen in the clinically monitored group). However, there was a statistically significant increase in false-positive alarms causing needless take-backs to theater in the microdialysis and implantable Doppler arms, P < 0.001. This study did not find any technique superior to clinical monitoring alone. New monitoring technologies should be compared objectively with clinical monitoring as the current standard in postoperative flap monitoring.

Microdialysis for the Assessment of Intervertebral Disc and Vertebral Cancellous Bone Metabolism in a Large Porcine Model.

BACKGROUND/AIM: It remains challenging to evaluate the in vivo pathophysiological biochemical characteristics in spine tissue, due to lack of an applicable model and feasible methods. The aim of this study was to apply microdialysis for the assessment of basic metabolites from the C3-C4 intervertebral disc, C3 vertebral cancellous bone and subcutaneous adipose tissue in a large porcine model. MATERIALS AND METHODS: In 7 pigs, glucose, pyruvate, lactate and glycerol concentrations were evaluated in an 8-hour sampling period. RESULTS: The mean lactate/pyruvate (L/P) ratios for the intervertebral disc and vertebral cancellous bone were comparable and exceeded the ischemic cut-off value of 25 for the entire sampling interval. For subcutaneous adipose tissue, the L/P ratio was below the ischemic cut-off. CONCLUSION: This exploratory study confirms previous findings of ischemia in bone and the intervertebral disc. This encourages new microdialysis study designs in spine tissue employing large porcine models to create new knowledge and a greater understanding of the metabolism and pathogenesis in spine tissue.

Bone, subcutaneous tissue and plasma pharmacokinetics of cefuroxime in total knee replacement patients - a randomized controlled trial comparing continuous and short-term infusion.

Cefuroxime is widely used as antibiotic prophylaxis for orthopaedic procedures. We evaluated bone, subcutaneous tissue (SCT) and plasma pharmacokinetics of cefuroxime in male patients undergoing total knee replacement (TKR) after both traditional short-term infusion (STI) and continuous infusion (CI). Eighteen male patients undergoing TKR were randomly assigned to STI or CI of 1.5 g of cefuroxime. Measurements were obtained in plasma, SCT, cancellous and cortical bone every 30 min for 8 h following surgery. For sampling in solid tissues, microdialysis was applied. Population pharmacokinetic modelling was performed in order to estimate pharmacokinetic parameters, and to assess the probability of attaining cefuroxime concentrations above clinically relevant minimal inhibitory concentrations (MICs) for 65% and 90% of the 8 h dosing interval. Low SCT and cortical bone penetration were found in both the STI and the CI group, but the findings were only significant in the STI group. Irrespective of MIC, tissue and target, CI leads to improved probability of attaining relevant pharmacokinetic targets compared with STI. For the Staphylococcus aureus MIC breakpoint (4 µg/mL), STI leads to inadequate probability of target attainment. CI of 1.5 g of cefuroxime leads to improved probability of attaining relevant pharmacokinetic targets in male TKR patients compared with traditional STI. These findings suggest that application of CI may improve antibiotic prophylaxis for male TKR patients.

Cerebral Effects of Targeted Temperature Management Methods Assessed by Diffusion-Weighted Magnetic Resonance Imaging.

The aim of this randomized porcine study was to compare surface targeted temperature management (TTM) to endovascular TTM evaluated by cerebral diffusion-weighted magnetic resonance imaging (MRI): apparent diffusion coefficient (ADC), and by intracerebral/intramuscular microdialysis. It is well known that alteration in the temperature affects ADC, but the relationship between cerebral ADC values and the cooling method per se has not been established. Eighteen anesthetized 60-kg female swine were hemodynamically and intracerebrally monitored and subsequently subjected to a baseline MRI. The animals were then randomized into three groups: (1) surface cooling (n = 6) at 33.5°C using EMCOOLSpad®, (2) endovascular cooling (n = 6) at 33.5°C using an Icy® cooling catheter with the CoolGard 3000®, or (3) control (n = 6) at 38.5°C using a Bair Hugger™. The swine were treated with TTM for 6 hours followed by a second MRI examination, including ADC. Blood and microdialysate were sampled regularly throughout the experiment, and glucose, lactate, pyruvate, glycerol, and the lactate/pyruvate ratio did not differ among groups, neither intracerebrally nor intramuscularly. Surface cooling yielded a significantly lower median ADC than endovascular cooling: 714 (634; 804) × 10-6 mm2/s versus 866 (828; 927) × 10-6 mm2/s, (p < 0.05). The surface cooling ADC was lowered to a range usually attributed to cytotoxic edema and these low values could not be explained solely by the temperature effect per se. To what extent the ADC is fully reversible at rewarming is unknown and the clinical implications should be further investigated in clinical studies.

Pharmacokinetics of single-dose cefuroxime in porcine intervertebral disc and vertebral cancellous bone determined by microdialysis.

BACKGROUND: Pyogenic spondylodiscitis is associated with prolonged antimicrobial therapy and high relapse rates. Nevertheless, tissue pharmacokinetic studies of relevant antimicrobials in both prophylactic and therapeutic situations are still sparse. Previous approaches based on bone biopsy and discectomy exhibit important methodological limitations. PURPOSE: The objective of this study was to assess the C3-C4 intervertebral disc (IVD), C3 vertebral body cancellous bone, and subcutaneous adipose tissue (SCT) pharmacokinetics of cefuroxime by use of microdialysis in a large animal model. STUDY DESIGN: This was a single-dose, dense sampling large animal study of cefuroxime spine penetration. METHODS: Ten female pigs were assigned to receive 1,500 mg of cefuroxime intravenously over 15 minutes. Measurements of cefuroxime were obtained from plasma, SCT, vertebral cancellous bone, and IVD for 8 hours thereafter. Microdialysis was applied for sampling in solid tissues. RESULTS: For both IVD and vertebral cancellous bone, the area under the concentration curve from zero to the last measured value (AUC(0-last)) was significantly lower than that of free plasma. As estimated by the ratio of tissue AUC(0-last) to plasma AUC(0-last), tissue penetration (95% confidence interval) of cefuroxime was significantly incomplete for the IVD 0.78 (0.57; 0.99), whereas for vertebral cancellous bone 0.78 (0.51; 1.04) and SCT 0.94 (0.73; 1.15) it was not. The penetration of cefuroxime from plasma to the IVD was delayed, and the maximal concentration and the elimination of cefuroxime were also reduced compared with both SCT and vertebral cancellous bone. Because of this delay in elimination of cefuroxime, the time with concentrations above the minimal inhibitory concentration (T(>MIC)) was significantly longer in the IVD compared with the remaining compartments up to MICs of 6 µg/mL. CONCLUSIONS: Microdialysis was successfully applied for serial assessment of the concentration of cefuroxime in the IVD and the vertebral cancellous bone. Penetration of cefuroxime from plasma to IVD was found to be incomplete and delayed, but because of a prolonged elimination, superior T(>MIC) was found in the IVD up to MICs of 6 µg/mL.

Single-dose pharmacokinetics of vancomycin in porcine cancellous and cortical bone determined by microdialysis.

High treatment failure rates and the need for prolonged antimicrobial therapy for osteomyelitis and implant-associated infections suggest that antimicrobial bone penetration may be incomplete. Assessment of the bone pharmacokinetics of antimicrobials is challenged by a lack of validated methods. In this study, 1000 mg of vancomycin was administered as a single dose over 100 min to eight female pigs. Plasma, subcutaneous adipose tissue (SCAT) and bone pharmacokinetics were investigated over 12 h. Microdialysis was applied for collection of samples in bone and SCAT. The vancomycin concentration in microdialysates was determined using ultra-high performance liquid chromatography, whilst the free plasma concentration was determined using Cobas c501. The mean (95% CI) area under the concentration-time curve (AUC(0-last); minµg/mL) was 9375 (7445-11304), 9304 (7374-11233), 5998 (3955-8040) and 3451 (1522-5381) for plasma, SCAT, and cancellous and cortical bone, respectively (ANOVA P-value < 0.001). Both cortical and cancellous bone AUC0-last were lower than that of free plasma (P < 0.01). Peak drug concentrations (C(max)) in cortical and cancellous bone were also significantly lower than that of free plasma (P < 0.001). Moreover, both AUC(0-last) and C(max) were significantly lower in cortical bone than in cancellous bone (P < 0.025). Bone penetration of vancomycin was found to be incomplete and delayed. Significant differences in pharmacokinetics between cancellous and cortical bone suggest that bone may not be considered as one compartment. Future studies should focus on validating the applicability of microdialysis for assessment of antimicrobial bone pharmacokinetics.

Development of intestinal ischemia/reperfusion-induced acute kidney injury in rats with or without chronic kidney disease: Cytokine/chemokine response and effect of α-melanocyte-stimulating hormone.

BACKGROUND: The primary aim of the study was to investigate the cytokine/chemokine response in the kidney, lung, and liver following acute kidney injury (AKI). The secondary aim was to test whether α-melanocyte-stimulating hormone (α-MSH) could prevent a reduction in organ function, and attenuate the inflammatory cytokine/chemokine response within the kidney, lung, and liver following AKI in rats with or without preexisting chronic kidney disease (CKD). METHODS: A two-stage animal model, in which AKI was induced in rats with preexisting CKD, induced by 5/6 nephrectomy (Nx), was used. Six weeks later, AKI was induced by intestinal ischemia and reperfusion (IIR). Sham procedures [S(Nx) and S(IIR)] were also performed. RESULTS: Increasing levels of serum creatinine (sCr) demonstrated progressive development of CKD in response to Nx, and following IIR sCr levels increased further significantly, except in the S(Nx) group treated with α-MSH. However, no significant differences in the fractional increase in sCr were observed between any of the groups exposed to IIR. In kidney, lung, and liver tissue the levels of interleukin (IL)-1ß were significantly higher in rats undergoing IIR when compared to the S(IIR) and control rats. The same pattern was observed for the chemokine monocyte chemoattractant protein (MCP)-1 in lung and liver tissue. Furthermore, kidney IL-1ß and RANTES levels were significantly increased after IIR in the Nx rats compared to the S(Nx) rats. CONCLUSION: Both the functional parameters and the cytokine/chemokine response are as dramatic when AKI is superimposed onto CKD as onto non-CKD. No convincing protective effect of α-MSH was detected.

Microdialysis: characterisation of haematomas in myocutaneous flaps by use of biochemical agents.

Metabolic markers are measured by microdialysis to detect postoperative ischaemia after reconstructive surgery with myocutaneous flaps. If a haematoma develops around the microdialysis catheter, it can result in misinterpretation of the measurements. The aim of the present study was to investigate whether a haematoma in a flap can be identified and dissociated from ischaemia, or a well-perfused flap, by a characteristic chemical profile. In 7 pigs, the pedicled rectus abdominal muscle flap was mobilised on both sides. A haematoma was made in each flap and two microdialysis catheters were placed, one in the haematoma, and the other in normal tissue. One flap was made ischaemic by ligation of the pedicle. For 6 hours, the metabolism was monitored by measurement every half-an-hour of the concentrations of glucose, lactate, pyruvate, and glycerol from all 4 catheters. After 3 hours of monitoring, intravenous glucose was given as a challenge test to identify ischaemia. The non-ischaemic flap could be differentiated from the ischaemic flap by low glucose, and high lactate, concentrations. It was possible to identify a catheter surrounded by a haematoma in ischaemic as well as non-ischaemic muscle from a low or decreasing concentration of glucose together with a low concentration of lactate. All four sites could be completely dissociated when the concentrations of glucose and lactate were evaluated and combined with the lactate:glucose ratio and a flow chart. The challenge test was useful for differentiating between haematomas in ischaemic and non-ischaemic tissue.