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1.  Evaluation of a Continuous Blood Glucose Monitoring System Using Central Venous Microdialysis 
Glycemic control in critically ill patients has been shown to be beneficial. In this prospective study, we evaluated the accuracy and technical feasibility of a continuous glucose monitoring system using intravascular microdialysis.
Fifty patients undergoing cardiac surgery were monitored using a 4 Fr intravenous microdialysis catheter (Eirus SLC™, Dipylon Medical AB, Solna, Sweden) percutaneously placed with the tip of the catheter positioned in the superior vena cava. The catheter was connected to the Eirus™ monitoring system, and the patients were monitored for up to 48 h postoperatively in the intensive care unit (ICU). As reference, arterial blood samples were taken every hour and analyzed in a blood gas analyzer.
Data were available from 48 patients. A total of 994 paired (arterial blood gas microdialysis) samples were obtained. Glucose correlation coefficient (R2) was 0.85. Using Clarke error grid analysis, 100% of the paired samples were in region AB, and 99% were in region A. Mean glucose level was 8.3 mmol/liter (149 mg/dl), mean relative difference was 0.2%, and mean absolute relative difference was 5%. A total of 99.2% of the paired samples were correct according to International Organization for Standardization (ISO) criteria. Bland-Altman analysis showed that bias ± limits of agreement were 0.02 ± 1.1 mmol/liter (0.36 ± 20 mg/dl).
Central venous microdialysis using the Eirus monitoring system is a highly accurate and reliable method for continuous blood glucose monitoring up to 48 h in ICU patients undergoing cardiac surgery. The system may thus be useful in critically ill ICU patients.
PMCID: PMC3570876  PMID: 23294781
critically ill patients; glucose monitoring; glycemic control; microdialysis
2.  Moderate intra-abdominal hypertension is associated with an increased lactate-pyruvate ratio in the rectus abdominis muscle tissue: a pilot study during laparoscopic surgery 
Annals of Intensive Care  2012;2(Suppl 1):S14.
The development of intra-abdominal hypertension [IAH] in critically ill patients admitted to the ICU is an independent predictor of mortality. In an attempt to find an early, clinically relevant metabolic signal of modest IAH, we investigated abdominal wall metabolite concentrations in a small group of patients undergoing laparoscopic surgery. We hypothesized that elevated intra-abdominal pressure [IAP] due to pneumoperitoneum leads to an increased lactate/pyruvate [L/P] ratio in the rectus abdominis muscle [RAM], indicating anaerobic metabolism.
Six patients scheduled for elective laparoscopic gastric fundoplication were studied. Two hours before surgery, a microdialysis catheter (CMA 60, CMA Small Systems AB, Solna, Sweden) was inserted into the RAM under local anaesthesia. Catheter placement was confirmed by ultrasound. The microdialysis perfusion rate was set at 0.3 μL/min. Dialysate was collected hourly prior to pneumoperitoneum, during pneumoperitoneum, and for 2 h after pneumoperitoneum resolution. IAP was maintained at 12 to 13 mmHg during the surgery. The glucose, glycerol, pyruvate and lactate contents of the dialysate were measured.
The median (interquartile range) L/P ratio was 10.3 (7.1 to 15.5) mmol/L at baseline. One hour of pneumoperitoneum increased the L/P ratio to 16.0 (13.6 to 35.3) mmol/L (p = 0.03). The median pneumoperitoneum duration was 86 (77 to 111) min. The L/P ratio at 2 h post-pneumoperitoneum was not different from that at baseline (p = 1.0). No changes in glycerol or glucose levels were observed.
IAH of 12 to 13 mmHg, even for a relatively short duration, is associated with metabolic changes in the abdominal wall muscle tissue of patients undergoing laparoscopic surgery. We suggest that tissue hypoperfusion occurs even during a modest increase in IAP, and intramuscular metabolic monitoring could therefore serve as an early warning sign of deteriorating tissue perfusion.
PMCID: PMC3390303  PMID: 22873415
microdialysis; intra-abdominal pressure; intra-abdominal hypertension; lactate-to-pyruvate ratio; muscle ischemia; early clinical sign
3.  Endovascular Revascularization for Patients with Critical Limb Ischemia: Impact on Wound Healing and Long Term Clinical Results in 189 Limbs 
Korean Journal of Radiology  2013;14(3):430-438.
To evaluate the impact on wound healing and long-term clinical outcomes of endovascular revascularization in patients with critical limb ischemia (CLI).
Materials and Methods
This is a retrospective study on 189 limbs with CLI treated with endovascular revascularization between 2008 and 2010 and followed for a mean 21 months. Angiographic outcome was graded to technical success (TS), partial failure (PF) and complete technical failure. The impact on wound healing of revascularization was assessed with univariate analysis and multivariate logistic regression models. Analysis of long-term event-free limb survival, and limb salvage rate (LSR) was performed by Kaplan-Meier method.
TS was achieved in 89% of treated limbs, whereas PF and CF were achieved in 9% and 2% of the limbs, respectively. Major complications occurred in 6% of treated limbs. The 30-day mortality was 2%. Wound healing was successful in 85% and failed in 15%. Impact of angiographic outcome on wound healing was statistically significant. The event-free limb survival was 79.3% and 69.5% at 1- and 3-years, respectively. The LSR was 94.8% and 92.0% at 1- and 3-years, respectively.
Endovascular revascularization improve wound healing rate and provide good long-term LSRs in CLI.
PMCID: PMC3655296  PMID: 23690709
Critical limb ischemia; Infrapopliteal angioplasty; Diabetic foot
4.  Results of Infrapopliteal Endovascular Procedures Performed in Diabetic Patients with Critical Limb Ischemia and Tissue Loss from the Perspective of an Angiosome-Oriented Revascularization Strategy 
Our aim was to describe our experience with infrapopliteal endovascular procedures performed in diabetic patients with ischemic ulcers and critical ischemia (CLI). A retrospective study of 101 procedures was performed. Our cohort was divided into groups according to the number of tibial vessels attempted and the number of patent tibial vessels achieved to the foot. An angiosome anatomical classification of ulcers were used to describe the local perfusion obtained after revascularization. Ischemic ulcer healing and limb salvage rates were measured. Ischemic ulcer healing at 12 months and limb salvage at 24 months was similar between a single revascularization and multiple revascularization attempts. The group in whom none patent tibial vessel to the foot was obtained presented lower healing and limb salvage rates. No differences were observed between obtaining a single patent tibial vessel versus more than one tibial vessel. Indirect revascularization of the ulcer through arterial-arterial connections provided similar results than those obtained after direct revascularization via its specific angiosome tibial artery. Our results suggest that, in CLI diabetic patients with ischemic ulcers that undergo infrapopliteal endovascular procedures, better results are expected if at least one patent vessel is obtained and flow is restored to the local ischemic area of the foot.
PMCID: PMC3914461  PMID: 24527215
5.  Endovascular Techniques In Limb Salvage: Infrapopliteal Angioplasty 
Critical limb ischemia (CLI) results from inadequate blood flow to supply and sustain the metabolic needs of resting muscle and tissue. Infragenicular atherosclerosis is the most common cause of CLI, and it is more likely to develop when multilevel or diffuse arterial disease coincides with compromised run-off to the foot. Reports of good technical and clinical outcomes have advanced the endovascular treatment options, which have gained a growing acceptance as the primary therapeutic strategy for CLI, especially in patients with significant risk factors for open surgical bypass. In fact, endovascular recanalization of below-the-knee arteries has proven to be feasible and safe, reduce the need for amputation, and improve wound healing. The distribution of various vascular territories or angiosomes in the foot has been recognized, and it appears advantageous to revascularize the artery supplying the territory directly associated with tissue loss. In addition, the targeted application and local delivery of drugs using drug-coated balloons (DCB) during angioplasty has the potential to improve patency rates compared to balloon angioplasty alone.
PMCID: PMC3693525  PMID: 23805344
balloon angioplasty; infrapopliteal artery disease; drug coated balloon; critical limb ischemia; chronic limb ischemia; angiosome; diabetes
6.  Axillofemoral bypass with local anesthesia: a way forward to enable limb salvage in high-risk patients 
For an active, ambulant patient with critical, lower limb ischemia, amputation can lead to a poor quality of life. A small group of older people with critical limb ischemia are considered at high risk for revascularization under conventional anesthesia owing to their comorbid conditions. In these cases, when endovascular therapy is not an option, the decision to amputate or revascularize presents a dilemma, especially in ambulant patients. In this article, we present 2 cases in which the individuals had diabetic foot gangrene, rest pain, and multiple comorbidities, and were unfit to undergo conventional anesthesia. In addition, they had severe aortoiliac occlusive disease, which cannot be managed by endovascular methods. Both patients were living independently and were ambulant before their foot ulcer and ischemia. They underwent an axillofemoral bypass under local anesthesia. The postoperative course was uneventful. After a 3-year follow-up, both patients continue to be ambulant and have no complaints. With selective use of local anesthetic techniques, surgical teamwork to shorten the procedure time, and close meticulous postoperative care, an axillofemoral bypass can enable limb salvage for ambulant patients who are considered unfit for conventional anesthesia.
PMCID: PMC3417959  PMID: 22915880
limb salvage; axillofemoral bypass; local anesthesia; high-risk patients
7.  The influence of preconditioning on metabolic changes in the pig liver before, during, and after warm liver ischemia measured by microdialysis 
Hepatology International  2008;3(1):310-315.
Ischemia-reperfusion injury induced by the Pringle maneuver is a well-known problem after liver surgery. The aim of this study was to monitor metabolic changes in the pig liver during warm ischemia and the following reperfusion preceded by ischemic preconditioning (IPC).
Eight Landrace pigs underwent laparotomy. Two microdialysis catheters were inserted in the liver, one in the left lobe and another in the right lobe. A reference catheter was inserted in the right biceps femoris muscle. Microdialysis samples were collected every 30 min during the study. After 2 h of baseline measurement, IPC was performed by subjecting pigs to 10 min of ischemia, followed by 10 min of reperfusion. Total ischemia for 60 min was followed by 3 h of reperfusion. The samples were analyzed for glucose, lactate, pyruvate, and glycerol. Blood samples were drawn three times to determine standard liver parameters.
All parameters remained stable during baseline. Glycerol and glucose levels increased significantly during ischemia, followed by a decrease from the start of reperfusion. During the ischemic period, lactate levels increased significantly and decreased during reperfusion. The lactate–pyruvate ratio increased significantly during ischemia and decreased rapidly during reperfusion. Only minor changes were observed in standard liver parameters.
The present study demonstrated profound metabolic changes before, during, and after warm liver ischemia under the influence of IPC. Compared with a similar study without IPC, the metabolic changes seem to be unaffected by preconditioning.
PMCID: PMC2712317  PMID: 19669382
Warm liver ischemia; Portal triad clamping; Preconditioning; Metabolic changes; Microdialysis
8.  Tibial Intervention for Critical Limb Ischemia 
Diagnosis and treatment of critical limb ischemia (CLI) is increasingly important as the average age of the world population and the incidence of diabetes and metabolic syndrome increases. Fortunately, most patients will not progress to this stage of peripheral arterial disease, yet if left untreated, there is a high risk of future cardiovascular events. At the point of ischemic rest pain or tissue loss, there are significant implications for morbidity and mortality. There is a high prevalence of multisegment occlusive disease in the CLI patient with the infrapopliteal vessels frequently involved. Revascularization of the affected limb is of utmost importance as the prospects of wound healing and relief of ischemic rest pain are poor without reestablishing continuous flow to the distal extremity. With the advent of endovascular devices designed to treat this vexing problem, the ability to successfully treat this difficult patient population with less procedural morbidity has been greatly enhanced.
PMCID: PMC3036465  PMID: 21326541
Peripheral arterial disease; angioplasty; endovascular therapy; ischemic rest pain
9.  Our Treatment Strategy for Critical Limb Ischemia 
For the treatment of critical limb ischemia, collaboration with wound specialists and cardiologists performing revascularization is important. The foot care unit affiliated with related departments opened at our hospital in July 2010 for limb salvage, mainly under the leadership of the departments of cardiovascular internal medicineand plastic surgery. We have treated 194 patients up until October 2012. The primary diseases included 81 cases (87 limbs) of foot ulcer and gangrene, with complications of peripheral arterial diseases (PADs) in all cases. Intravascular treatment was conducted for 69 limbs with PAD complications, and the initial success rate was 85.5%, of which surgical debridement or minor amputation was performed on 32 limbs. Regarding open wounds following operation and chronic ulcer, platelet-rich plasma therapy was conducted in 29 limbs and negative pressure wound therapy in 15 limbs. Among all of the patients treated, 58 limbs healed, 10 cases died, and the others are currently receiving ongoing treatment. Cardiovascular internal medicine specialists and plastic surgeons examine patients together at the outpatient clinic and prepare and implement a multidisciplinary treatment plan including vascular reconstructions and operation. We cooperate with physicians in each related department and efforts in team medicine have been made for the purpose of limb salvage.
PMCID: PMC3872428  PMID: 24386568
10.  Elevated Monocytes in Patients with Critical Limb Ischemia Diminish after Bypass Surgery 
The Journal of surgical research  2009;167(1):140-150.
Mononuclear cells (MNC) increase neovascularization and ulcer healing after injection into an ischemic extremity. Circulating MNC are composed of lymphocytes (85%), monocytes (15%) and endothelial progenitor cells (EPC; 0.03%). We hypothesized that ischemic limbs secrete paracrine signals to recruit bone marrow-derived monocytes and EPC into the circulation, such that patients with critical limb ischemia (CLI) have increased circulating monocytes compared to control patients. We also hypothesized that circulating monocytes and EPC recruitment decrease after resolution of ischemia with successful revascularization.
We reviewed the records of all patients at the VA Connecticut Healthcare System undergoing lower extremity peripheral bypass surgery between 2002 and 2007, only including patients with both preoperative and postoperative complete blood counts with differentials.
Patients with CLI (n=24) had elevated preoperative monocyte counts compared to control patients (n=8) (0.753±0.04 vs. 0.516±0.05; p=0.0046), whereas the preoperative lymphocyte counts were not significantly different. After revascularization, ischemic patients had decreased monocyte counts compared to control patients (-20% vs. +55%; p=.0003), although lymphocyte counts were unchanged in both groups. Diabetic patients also had reduced postoperative monocyte counts (-32% vs. +13%; p=0.035). Multivariable logistic regression demonstrated that the only factor that independently predicted reduced postoperative monocyte count was preoperative CLI (p=0.038).
Patients with CLI have increased numbers of circulating monocytes, and the monocyte number decreases with resolution of ischemia after successful revascularization. Circulating monocytes may be a clinically useful perioperative marker in patients with CLI undergoing vascular surgery.
PMCID: PMC2895962  PMID: 19854451
Blood Cells; Ischemia; Claudication; Monocyte; Peripheral Vascular Disease
11.  A Phase II Trial of Autologous Transplantation of Bone Marrow Stem Cells for Critical Limb Ischemia: Results of the Naples and Pietra Ligure Evaluation of Stem Cells Study 
In a multicenter, prospective phase II study without controls, no-option critical limb ischemia (CLI) patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment. Patients showed improvement in objective and subjective measures of perfusion and improved amputation-free survival rates at 12 months after the treatment. This study provides evidence that autologous bone marrow transplantation is well tolerated by CLI patients without adverse effects, confirming the feasibility and safety of the procedure.
Critical limb ischemia (CLI) is a vascular disease affecting lower limbs, which is going to become a demanding challenge because of the aging of the population. Despite advances in endovascular therapies, CLI is associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. To date, 25%–40% of CLI patients are not candidates for surgical or endovascular approaches, ultimately facing the possibility of a major amputation. This study aimed to assess the safety and efficacy of autologous bone marrow (BM) transplantation performed in “no-option” patients, in terms of restoring blood perfusion by collateral flow and limb salvage. A multicenter, prospective, not-controlled phase II study for no-option CLI patients was performed. Patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment. Variation of blood perfusion parameters, evaluated by laser Doppler flowmetry or transcutaneous oximetry, was set as the primary endpoint at 12 months after treatment and amputation-free survival as the secondary endpoint. Sixty patients were enrolled and treated with BM transplantation, showing improvement in objective and subjective measures of perfusion. Furthermore, survival analysis demonstrated improved amputation-free survival rates (75.2%) at 12 months after the treatment. This study provides further evidence that autologous bone marrow transplantation is well tolerated by CLI patients without adverse effects, demonstrating trends toward improvement in perfusion and reduced amputation rate, confirming the feasibility and safety of the procedure.
PMCID: PMC3659723  PMID: 23197862
Adult human bone marrow; Adult stem cells; Angiogenesis; Autologous stem cell transplantation; Bone marrow transplant; Stem/progenitor cell; Transplantation; Vascular development
12.  Disparity in Outcomes of Surgical Revascularization for Limb Salvage 
Circulation  2008;119(1):123-130.
Vein bypass surgery is an effective therapy for atherosclerotic occlusive disease in the coronary and peripheral circulations; however, long-term results are limited by progressive attrition of graft patency. Failure of vein bypass grafts in patients with critical limb ischemia results in morbidity, limb loss, and additional resource use. Although technical factors are known to be critical to the success of surgical revascularization, patient-specific risk factors are not well defined. In particular, the relationship of race/ethnicity and gender to the outcomes of peripheral bypass surgery has been controversial.
Methods and Results
We analyzed the Project of Ex Vivo Vein Graft Engineering via Transfection III (PREVENT III) randomized trial database, which included 1404 lower extremity vein graft operations performed exclusively for critical limb ischemia at 83 North American centers. Trial design included intensive ultrasound surveillance of the bypass graft and clinical follow-up to 1 year. Multivariable modeling (Cox proportional hazards and propensity score) was used to examine the relationships of demographic variables to clinical end points, including perioperative (30-day) events and 1-year outcomes (vein graft patency, limb salvage, and patient survival). Final propensity score models adjusted for 16 covariates (including type of institution, technical factors, selected comorbidities, and adjunctive medications) to examine the associations between race, gender, and outcomes. Among the 249 black patients enrolled in PREVENT III, 118 were women and 131 were men. Black men were at increased risk for early graft failure (hazard ratio [HR], 2.832 for 30-day failure; 95% confidence interval [CI], 1.393 to 5.759; P=0.0004), even when the analysis was restricted to exclude high-risk venous conduits. Black patients experienced reduced secondary patency (HR, 1.49; 95% CI, 1.08 to 2.06; P=0.016) and limb salvage (HR, 2.02; 95% CI, 1.27 to 3.20; P=0.003) at 1 year. Propensity score models demonstrate that black women were the most disadvantaged, with an increased risk for loss of graft patency (HR, 2.02 for secondary patency; 95% CI, 1.27 to 3.20; P=0.003) and major amputation (HR, 2.38; 95% CI, 1.18 to 4.83; P=0.016) at 1 year. Perioperative mortality and 1-year mortality were similar across race/gender groups.
Black race and female gender are risk factors for adverse outcomes after vein bypass surgery for limb salvage. Graft failure and limb loss are more common events in black patients, with black women being a particularly high-risk group. These data suggest the possibility of an altered biological response to vein grafting in this population; however, further studies are needed to determine the mechanisms underlying these observed disparities in outcome.
PMCID: PMC2901839  PMID: 19103988
bypass; grafts; peripheral artery disease; race; women
13.  Karyotype analysis of four jewel-beetle species (Coleoptera, Buprestidae) detected by standard staining, C-banding, AgNOR-banding and CMA3/DAPI staining 
Comparative Cytogenetics  2012;6(2):183-197.
The male karyotypes of Acmaeodera pilosellae persica Mannerheim, 1837 with 2n=20 (18+neoXY), Sphenoptera scovitzii Faldermann, 1835 (2n=38–46), Dicerca aenea validiuscula Semenov, 1895 – 2n=20 (18+Xyp) and Sphaerobothris aghababiani Volkovitsh et Kalashian, 1998 – 2n=16 (14+Xyp) were studied using conventional staining and different chromosome banding techniques: C-banding, AgNOR-banding, as well as fluorochrome Chromomycin A3 (CMA3) and DAPI. It is shown that C-positive segments are weakly visible in all four species which indicates a small amount of constitutive heterochromatin (CH). There were no signals after DAPI staining and some positive signals were discovered using CMA3 staining demonstrating absence of AT-rich DNA and presence of GC-rich clusters of CH. Nucleolus organizing regions (NORs) were revealed using Ag-NOR technique; argentophilic material mostly coincides with positive signals obtained using CMA3 staining.
PMCID: PMC3833796  PMID: 24260661
Coleoptera; Buprestidae; karyotypes; Ag-banding; C-banding; CMA3-staining; DAPI-staining
14.  Critical Limb Ischemia 
Opinion statement
Critical limb ischemia (CLI), defined as chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease, is the most advanced form of peripheral arterial disease. Traditionally, open surgical bypass was the only effective treatment strategy for limb revascularization in this patient population. However, during the past decade, the introduction and evolution of endovascular procedures have significantly increased treatment options. In a certain subset of patients for whom either surgical or endovascular revascularization may not be appropriate, primary amputation remains a third treatment option. Definitive high-level evidence on which to base treatment decisions, with an emphasis on clinical and cost effectiveness, is still lacking. Treatment decisions in CLI are individualized, based on life expectancy, functional status, anatomy of the arterial occlusive disease, and surgical risk. For patients with aortoiliac disease, endovascular therapy has become first-line therapy for all but the most severe patterns of occlusion, and aortofemoral bypass surgery is a highly effective and durable treatment for the latter group. For infrainguinal disease, the available data suggest that surgical bypass with vein is the preferred therapy for CLI patients likely to survive 2 years or more, and for those with long segment occlusions or severe infrapopliteal disease who have an acceptable surgical risk. Endovascular therapy may be preferred in patients with reduced life expectancy, those who lack usable vein for bypass or who are at elevated risk for operation, and those with less severe arterial occlusions. Patients with unreconstructable disease, extensive necrosis involving weight-bearing areas, nonambulatory status, or other severe comorbidities may be considered for primary amputation or palliative measures.
PMCID: PMC2860564  PMID: 20461120
15.  Prognostic Significance of Circulating and Endothelial Progenitor Cell Markers in Type 2 Diabetic Foot 
Objective. We studied circulating precursor cells (CPC) in type 2 diabetes mellitus (T2DM) with neuropathic foot lesions with or without critical limb ischemia and relationships between endothelial precursor cells (EPC) and peripheral neuropathy. Methods and Subjects. We measured peripheral blood CD34, CD133, and CD45 markers for CPC and KDR, CD31 markers for EPC by citofluorimetry and systemic neural nociceptor CGRP (calcitonin gene related protein) by ELISA in 8 healthy controls (C) and 62 T2DM patients: 14 with neuropathy (N), 20 with neuropathic foot lesions (N1), and 28 with neuroischemic recent revascularized (N2) foot lesions. Timing of lesions was: acute (until 6 weeks), healed, and not healed. Results. CD34+ and CD133+ were reduced in N, N1, and N2 versus C, and CD34+ were lower in N2 versus N1 (P = 0.03). In N2 CD34+KDR+ remain elevated in healed versus chronic lesions and, in N1 CD133+31+ were elevated in acute lesions. CGRP was reduced in N2 and N1 versus C (P < 0.04 versus C 26 ± 2 pg/mL). CD34+KDR+ correlated in N2 with oximetry and negatively in N1 with CGRP. Conclusions. CD34+ CPC are reduced in diabetes with advanced complications and diabetic foot. CD34+KDR+ and CD31+133+ EPC differentiation could have a prognostic and therapeutic significance in the healing process of neuropathic and neuroischemic lesions.
PMCID: PMC3929532  PMID: 24624298
16.  Noninvasive management of the diabetic foot with critical limb ischemia: current options and future perspectives 
Foot ulcers are a major complication in patients with diabetes mellitus and involve dramatic restrictions to quality of life and also lead to enormous socio-economical loss due to the high amputation rate. The poor and slow wound healing is often aggravated by the frequent comorbidity of foot ulcers with peripheral arterial disease, making the treatment of this condition even more complicated. While the local treatment of foot ulcers is mainly based on mechanical relief and prevention or treatment of infection, improving perfusion of the impaired tissue remains the major challenge in peripheral arterial disease. While focal arterial stenosis is the domain of interventional angioplasty or vascular surgery, patients with critical limb ischemia and lacking options for revascularization have a much worse prognosis, because current treatment options avoiding amputation are scarce. However, based on recent research efforts, there is rising hope for promising and more-effective therapeutic approaches for these patients. Here, we discuss the current improvements of established therapies aimed at an improvement of limb perfusion, as well as the development of novel cutting-edge therapies based on stem-cell technology. The experiences of a ‘high-volume center’ for treatment of diabetic foot syndrome with a current major amputation rate of 4% are discussed.
PMCID: PMC3474643  PMID: 23148189
autologous bone marrow transplantation; critical limb ischemia; diabetic foot; prostaglandins; therapy; urokinase
17.  IN.PACT Amphirion paclitaxel eluting balloon versus standard percutaneous transluminal angioplasty for infrapopliteal revascularization of critical limb ischemia: rationale and protocol for an ongoing randomized controlled trial 
Trials  2014;15:63.
The effectiveness and durability of endovascular revascularization therapies for chronic critical limb ischemia (CLI) are challenged by the extensive burden of infrapopliteal arterial disease and lesion-related characteristics (e.g., severe calcification, chronic total occlusions), which frequently result in poor clinical outcomes. While infrapopliteal vessel patency directly affects pain relief and wound healing, sustained patency and extravascular care both contribute to the ultimate “patient-centric” outcomes of functional limb preservation, mobility and quality of life (QoL).
IN.PACT DEEP is a 2:1 randomized controlled trial designed to assess the efficacy and safety of infrapopliteal arterial revascularization between the IN.PACT Amphirion™ paclitaxel drug-eluting balloon (IA-DEB) and standard balloon angioplasty (PTA) in patients with Rutherford Class 4-5-6 CLI.
This multicenter trial has enrolled 358 patients at 13 European centers with independent angiographic core lab adjudication of the primary efficacy endpoint of target lesion late luminal loss (LLL) and clinically driven target lesion revascularization (TLR) in major amputation-free surviving patients through 12-months. An independent wound core lab will evaluate all ischemic wounds to assess the extent of healing and time to healing at 1, 6, and 12 months. A QoL questionnaire including a pain scale will assess changes from baseline scores through 12 months. A Clinical Events Committee and Data Safety Monitoring Board will adjudicate the composite primary safety endpoints of all-cause death, major amputation, and clinically driven TLR at 6 months and other trial endpoints and supervise patient safety throughout the study. All patients will be followed for 5 years. A literature review is presented of the current status of endovascular treatment of CLI with drug-eluting balloon and standard PTA. The rationale and design of the IN.PACT DEEP Trial are discussed. IN.PACT DEEP is a milestone, prospective, randomized, robust, independent core lab-adjudicated CLI trial that will evaluate the role of a new infrapopliteal revascularization technology, the IA-DEB, compared to PTA. It will assess the overall impact on infrapopliteal artery patency, limb salvage, wound healing, pain control, QoL, and patient mobility. The 1-year results of the adjudicated co-primary and secondary endpoints will be available in 2014.
Trial registration
PMCID: PMC3936931  PMID: 24552184
Peripheral vascular disease; Critical limb ischemia; Infrapopliteal; Drug-eluting balloon
18.  Always Contact a Vascular Interventional Specialist Before Amputating a Patient with Critical Limb Ischemia 
Patients with severe critical limb ischemia (CLI) due to long tibial artery occlusions are often poor candidates for surgical revascularization and frequently end up with a lower limb amputation. Subintimal angioplasty (SA) offers a minimally invasive alternative for limb salvage in this severely compromised patient population. The objective of this study was to evaluate the results of SA in patients with CLI caused by long tibial occlusions who have no surgical options for revascularization and are facing amputation. We retrospectively reviewed all consecutive patients with CLI due to long tibial occlusions who were scheduled for amputation because they had no surgical options for revascularization and who were treated by SA. A total of 26 procedures in 25 patients (14 males; mean age, 70 ± 15 [SD] years) were evaluated. Technical success rate was 88% (23/26). There were four complications, which were treated conservatively. Finally, in 10 of 26 limbs, no amputation was needed. A major amputation was needed in 10 limbs (7 below-knee amputations and 3 above-knee amputations). Half of the major amputations took place within 3 months after the procedure. Cumulative freedom of major amputation after 12 months was 59% (SE = 11%). In six limbs, amputation was limited to a minor amputation. Seven patients (28%) died during follow-up. In conclusion, SA of the tibial arteries seem to be a valuable treatment option to prevent major amputation in patients with CLI who are facing amputation due to lack of surgical options.
PMCID: PMC2868169  PMID: 19688364
Subintimal angioplasty; Tibial arteries; Critical limb ischemia
19.  Intravascular Microdialysis as a Method for Measuring Glucose and Lactate during and after Cardiac Surgery 
The aim was to evaluate intravascular microdialysis as a method for measuring blood glucose and lactate in a clinical setting during and after cardiac surgery.
Ten patients undergoing cardiac surgery were included. A microdialysis catheter was percutaneously placed in the superior vena cava or right atrium. Glucose and lactate values measured by the microdialysis technique were analyzed and compared with reference methods, i.e., arterial and venous blood gas values, once every hour up to 24 hours postoperatively. Laboratory plasma glucose was additionally analyzed every 4 hours for reference value.
Mean absolute differences were low between microdialysis and reference methods for both glucose and lactate values. All microdialysis glucose values were in the clinically acceptable zone of error grid analysis when compared with plasma glucose values. Accuracy of glucose values was 92% according to International Organization for Standardization criteria.
Intravascular microdialysis is a novel and promising technique for real-time and accurate measurement of glucose and lactate during and after open heart surgery. Development of sensor technology may allow for continuous measurement of blood glucose and lactate using intravascular microdialysis.
PMCID: PMC3208865  PMID: 22027302
glucose; heart surgery; lactate; microdialysis
20.  Simultaneous hybrid revascularization for symptomatic lower extremity arterial occlusive disease 
Multilevel revascularization, using a combination of endovascular and open (hybrid) surgery, is increasingly being used. Hybrid surgery allows complex anatomy to be treated by minimally invasive procedures in medically high risk patients. The aim of the present study was to report a novel hybrid surgery for lesions in the multilevel lower extremity arteries and to evaluate the clinical outcomes. Consecutive patients who presented at a single institution between March 2009 and Feburary 2012 were selected for inclusion in the study. The patients had disabling claudication or critical limb ischemia and underwent treatment for revascularization by open surgery or by a combination of open surgery and endovascular procedure. Retrospective analysis was conducted from a prospectively collected database. All procedures were performed by a vascular surgeon in an operating room. Postoperative surveillance in outpatient clinics was conducted at 3 and 6 months and every 6 months thereafter. A total of 76 patients were included in the study with a mean age of 67.1±11.3 years (range, 42–94 years) and the male to female ratio was 67:9. The most common indication for revascularization was Rutherford category IV (resting pain). The immediate technical success rate of hybrid surgery was 90.5%, with an overall limb salvage rate of 97.4%. The primary patency rates of the hybrid and open groups were 100 and 90.9%, respectively (P=0.441). Therefore, the results of the present study indicate that hybrid surgery is a feasible option for the treatment of multilevel peripheral arterial occlusive disease, showing favorable patency and limb salvage rates. These observations indicate that femoral endarterectomy plays a vital role in hybrid surgery.
PMCID: PMC3961109  PMID: 24669236
hybrid; endovascular procedures; revascularization; lower extremity; artery
21.  Microdialysis in the femoral head of the minipig and in a blood cloth of human blood 
Acta Orthopaedica  2011;82(2):241-245.
Microdialysis can detect ischemia in soft tissue. In a previous study, we have shown the development of ischemia in the femoral head removed from patients undergoing total hip replacement. That study also raised some methodological questions that this study tries to answer: what is happening in the dead space around the catheter in the drill canal, and is there an equilibrium period after the insertion of the catheter?
Material and methods
In an ex-vivo study using 5 syringes with 5 mL human blood, a microdialysis catheter was inserted and microdialysis was performed over 3 h. In an in-vivo study, a drill hole was made in the proximal part of the femur in 6 mature Göttingen minipigs and microdialysis was performed over 3 h. The pigs were kept normoventilated during the experiment.
The ex-vivo microdialysis results showed that lactate kept a steady level and glucose and glycerol both fell; pyruvate fell but leveled out. The mean lactate/pyruvate ratio increased from 13 (SD 4) to 32 (SD 6) (p < 0.001). In vivo, relative recovery was 57% (SD 11). Lactate increased, pyruvate stayed constant, and glucose and glycerol levels fell. The lactate/pyruvate ratio increased from 30 (8) initially to 37 (8) after 1 h (p = 0.007) but no statistically significant change from 1 to 2 h was observed.
The ex-vivo study showed a clear washout pattern, and was different from what we see in bone. The in-vivo study indicated that an equilibrium period is necessary or that a reference measurement in healthy bone must be used when performing short measurements in bone.
PMCID: PMC3235298  PMID: 21428845
22.  Long-term outcome of infrapopliteal catheter-based intervention for critical limb ischemia 
Percutaneous treatment of tibioperoneal occlusive disease is associated with decreased morbidity compared with bypass surgery. The long-term patency and limb salvage rates are not well documented.
To evaluate the long-term outcome of endoluminal interventions for tibioperoneal lesions.
A retrospective study was performed to determine the outcomes of patients undergoing infrapopliteal catheter-based intervention for critical limb ischemia. Collected data included demographics, comorbidities, clinical presentation, pre- and postintervention noninvasive vascular measurements (segmental pressure and waveforms, and ankle-brachial index [ABI]), type of intervention, limb loss rate, patient follow-up and need for surgical revascularization. Statistical analysis was performed with the two-tailed t test. P<0.05 was considered significant; results were reported as mean ± SD. Cox regression analysis and Kaplan-Meier limb survival analysis were performed to demonstrate freedom from amputation over time.
Thirty-five patients underwent intervention from 2003 to 2008; technical success was achieved in 26 patients (75%). Arterial segmental pressure studies revealed a significant increase in ABI – preprocedure ABI was 0.62±0.24 versus a postintervention ABI of 0.81±0.29 (P=0.02). The limb salvage rate was 63% during the follow-up period. Limb salvage was better for patients who underwent isolated infrapopliteal intervention versus combined above and below the knee intervention.
Percutaneous interventions for tibioperoneal occlusive disease offer an acceptable limb salvage rate and may be the preferred initial treatment for critical limb ischemia.
PMCID: PMC2903018  PMID: 22477512
Atherectomy; Critical limb ischemia; Tibioperoneal angioplasty
23.  CoCMA: Energy-Efficient Coverage Control in Cluster-Based Wireless Sensor Networks Using a Memetic Algorithm 
Sensors (Basel, Switzerland)  2009;9(6):4918-4940.
Deployment of wireless sensor networks (WSNs) has drawn much attention in recent years. Given the limited energy for sensor nodes, it is critical to implement WSNs with energy efficiency designs. Sensing coverage in networks, on the other hand, may degrade gradually over time after WSNs are activated. For mission-critical applications, therefore, energy-efficient coverage control should be taken into consideration to support the quality of service (QoS) of WSNs. Usually, coverage-controlling strategies present some challenging problems: (1) resolving the conflicts while determining which nodes should be turned off to conserve energy; (2) designing an optimal wake-up scheme that avoids awakening more nodes than necessary. In this paper, we implement an energy-efficient coverage control in cluster-based WSNs using a Memetic Algorithm (MA)-based approach, entitled CoCMA, to resolve the challenging problems. The CoCMA contains two optimization strategies: a MA-based schedule for sensor nodes and a wake-up scheme, which are responsible to prolong the network lifetime while maintaining coverage preservation. The MA-based schedule is applied to a given WSN to avoid unnecessary energy consumption caused by the redundant nodes. During the network operation, the wake-up scheme awakens sleeping sensor nodes to recover coverage hole caused by dead nodes. The performance evaluation of the proposed CoCMA was conducted on a cluster-based WSN (CWSN) under either a random or a uniform deployment of sensor nodes. Simulation results show that the performance yielded by the combination of MA and wake-up scheme is better than that in some existing approaches. Furthermore, CoCMA is able to activate fewer sensor nodes to monitor the required sensing area.
PMCID: PMC3291946  PMID: 22408561
wireless sensor network; sensing coverage; energy efficiency; memetic algorithm
24.  List of Organizations Approved for Courses Qualifying for Category I Credits in CMA Certification Program 
California Medicine  1972;117(4):81-83.
The following organizations, societies and institutions have been approved for Category I (formerly Group A) credit towards the California Medical Association's certificate in continuing medical education program. The credit hours are based on the number of hours of the course. Only those courses which are directly related to medical education and applied to patient care are acceptable. Courses put on by approved institutions, in subject matter not directly related to patient care and medical education, are not eligible for Category I credit in the program.
This listing is not all-inclusive, as new programs are continuously being accredited, but it is up to date of as August 1, 1972. Physicians should refer to this listing when completing their annual reporting form.
PMCID: PMC1518721  PMID: 4561707
25.  Contemporary Evaluation and Management of the Diabetic Foot 
Scientifica  2012;2012:435487.
Foot problems in patients with diabetes remain a major public health issue and are the commonest reason for hospitalization of patients with diabetes with prevalence as high as 25%. Ulcers are breaks in the dermal barrier with subsequent erosion of underlying subcutaneous tissue that may extend to muscle and bone, and superimposed infection is a frequent and costly complication. The pathophysiology of diabetic foot disease is multifactorial and includes neuropathy, infection, ischemia, and abnormal foot structure and biomechanics. Early recognition of the etiology of these foot lesions is essential for good functional outcome. Managing the diabetic foot is a complex clinical problem requiring a multidisciplinary collaboration of health care workers to achieve limb salvage. Adequate off-loading, frequent debridement, moist wound care, treatment of infection, and revascularization of ischemic limbs are the mainstays of therapy. Even when properly managed, some of the foot ulcers do not heal and are arrested in a state of chronic inflammation. These wounds can frequently benefit from various adjuvants, such as aggressive debridement, growth factors, bioactive skin equivalents, and negative pressure wound therapy. While these, increasingly expensive, therapies have shown promising results in clinical trials, the results have yet to be translated into widespread clinical practice leaving a huge scope for further research in this field.
PMCID: PMC3820495  PMID: 24278695

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