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1.  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
2.  Bone marrow aspirate injection for treatment of critical limb ischemia with comparison to patients undergoing high-risk bypass grafts 
Journal of vascular surgery  2014;61(1):134-137.
Bone marrow cell therapy (BMCT) for patients with critical limb ischemia (CLI) is a potential treatment in candidates with poor options for standard revascularization procedures. Whereas clinical trials are ongoing, there are few comparative data to assess its efficacy compared with bypass.
Patients with poor revascularization options underwent BMCT between 2011 and 2013. Outcomes were compared with those of a cohort of CLI patients undergoing infrainguinal bypass thought to be at high risk for graft failure (tissue loss, a tibial target, and a previous endovascular treatment or bypass). BMCT patients underwent harvest of bone marrow that was then concentrated and injected intramuscularly into the ischemic limb.
There were 20 BMCT patients and 35 high-risk bypass patients. All BMCT patients had either rest pain (80%) or tissue loss (80%). The majority (65%) had a prior intervention (bypass, 30%; endovascular, 58%) compared with high-risk bypass patients, all of whom had previous revascularization attempts (bypass, 43% [P = .35]; endovascular, 77% [P = .14]). Mean follow-up was 773 days after BMCT and 972 days after high-risk bypass. All patients tolerated BMCT without issues or complications. A second BMCT treatment was performed in 21% because of clinical deterioration. Wound healing occurred in 75% at 1.5 years, including patients receiving second injections, all of which resolved. Rest pain improved in 87.5% of patients. Pain completely resolved in 58% at 1.5 years. Ankle-brachial index improvement was 0.23 (±0.25). Three BMCT patients went on to amputation. One-year freedom from major amputation or death was 78% for BMCT vs 69% for high-risk bypass (P = .60).
BMCT is a potential option in CLI patients who are not candidates for bypass or endovascular intervention. Limb salvage is unexpectedly high in this population with few other options.
PMCID: PMC4283107  PMID: 25086735
3.  Racial Disparities in the Use of Revascularization Before Leg Amputation in Medicare Patients 
Black patients with peripheral arterial disease undergo amputation at two to four times the rate of white patients. In order to determine whether differences in attempts at limb salvage might contribute to this disparity, we studied the limb care received prior to amputation by black patients compared to whites.
Using inpatient Medicare data for years 2003-2006, we identified a retrospective sample of all beneficiaries who underwent major lower extremity amputation. ‘Limb salvage care’ was defined as limb-related admissions and procedures that occurred during the two years prior to amputation. We used multiple logistic regression to compare rates of revascularization and other limb care received by black versus white amputees, adjusting for individual patient characteristics. We then controlled for hospital referral region in order to assess whether differences in care might be attributable to the geographic regions in which black and white patients received care. Finally, we examined the timing of revascularization relative to amputation for both races.
Our sample included 24,600 black and 65,881 white amputees. Compared with whites, black amputees were more likely to be female and had lower socioeconomic status. Average age, rates of diabetes, and levels of comorbidity were similar between races. Black amputees were significantly less likely than whites to have undergone revascularization (23.6 vs. 31.6%, p<0.0001), any limb-related admission (39.6 vs. 44.7%, p<0.0001), toe amputation (12.9 vs. 13.8%, p<0.0005) or wound debridement (11.6 vs. 14.2%, p<0.0001) prior to amputation. After adjusting for differences in individual patient characteristics, black amputees remained significantly less likely than whites to undergo revascularization (OR 0.72 [95% confidence interval 0.68-0.76]), limb-related admission (OR 0.81 [0.78-0.84]), or wound debridement prior to amputation (OR 0.80 [0.75-0.85]). Timing of revascularization relative to amputation was similar between races. Observed differences in care were shown to exist within hospital referral regions, and were not accounted for by regional differences in where black and white patients received care.
Black patients are much less likely than whites to undergo attempts at limb salvage prior to amputation. Further studies should explore whether this disparity might be attributable to race-related differences in severity of arterial disease, patient preferences, or physician decision-making.
PMCID: PMC3152619  PMID: 21571495
4.  Collective Therapy and Therapeutic Strategy for Critical Limb Ischemia 
Annals of Vascular Diseases  2013;6(1):27-32.
Objective: To determine a treatment strategy based on the outcomes of various previous interventions for critical limb ischemia in arteriosclerosis obliterans (ASO).
Material and Methods: We examined outcomes of 292 ASO patients who had had critical limb ischemia between May 1995 and July 2009. Patients underwent the following procedures in 167 cases: aortofemoral bypass (n = 14), femorofemoral crossover bypass (n = 29), femoropopliteal bypass (n = 104) and femorotibial bypass (n = 40). Other procedures included bypass only (n = 147), bypass combined with thromboendarterectomy (n = 10), bypass combined with endovascular therapy (n = 6), bypass combined with lumbar sympathectomy (n = 2), endovascular therapy combined with thromboendarterectomy (n = 4), endovascular therapy (n = 19), lumbar sympathectomy (n = 6), conservative therapy (n = 65), and major amputation (n = 31). We also calculated P3 risk scores and measured transcutaneous oxygen pressure (tcPO2) and skin perfusion pressure (SPP) before and after therapy.
Results: The limb salvage rate was 87% at 2 years in the arterial reconstruction group. In the low-risk group (a P 3 risk score of 3), the 1-year amputation-free survival rate was 96%. In the medium-risk group (a P 3 risk score of 4–7), the 1-year amputation-free survival rate was 88%. In the high-risk group (a P 3 risk score of 8), the 1-year amputation-free survival rate was 66%. The hospital death rate in the arterial reconstruction group was 3.2%, all of whom were patients who underwent bypass. The survival rate at 5 years was 65% and 36% in the conservative therapy only group. Ulcers healed in 140 out of 144 patients. The 4 patients with unhealed infections had tcPO2 or SPP values of more than 30 mmHg after treatment. Major amputations were performed in 4 of 5 patients who had tcPO2 or SPP values from 20 to 30 mmHg after treatment. Major amputations were performed in all 6 patients who had tcPO2 or SPP values of less than 20 mmHg after treatment.
Conclusion: In cases with tcPO2 or SPP values of more than 30 mmHg, an ulcer will probably heal, except in infected cases. We suggest that, if these values are less than 30 mmHg, complete revascularization should be performed. The P3 risk score was useful in predicting limb salvage in the current series. Hybrid therapy in bypass and endovascular therapy must be performed in cases where patients are in a generally poor condition. It is important to attempt amelioration in limb salvage and to control the operative mortality rate with sufficient perioperative control. (English Translation of Jpn J Vasc Surg 2011;20:905–911)
PMCID: PMC3634996  PMID: 23641280
critical limb ischemia; hybrid therapy; transcutaneous oxygen pressure; skin perfusion pressure
5.  Stenting for Peripheral Artery Disease of the Lower Extremities 
Executive Summary
In January 2010, the Medical Advisory Secretariat received an application from University Health Network to provide an evidentiary platform on stenting as a treatment management for peripheral artery disease. The purpose of this health technology assessment is to examine the effectiveness of primary stenting as a treatment management for peripheral artery disease of the lower extremities.
Clinical Need: Condition and Target Population
Peripheral artery disease (PAD) is a progressive disease occurring as a result of plaque accumulation (atherosclerosis) in the arterial system that carries blood to the extremities (arms and legs) as well as vital organs. The vessels that are most affected by PAD are the arteries of the lower extremities, the aorta, the visceral arterial branches, the carotid arteries and the arteries of the upper limbs. In the lower extremities, PAD affects three major arterial segments i) aortic-iliac, ii) femoro-popliteal (FP) and iii) infra-popliteal (primarily tibial) arteries. The disease is commonly classified clinically as asymptomatic claudication, rest pain and critical ischemia.
Although the prevalence of PAD in Canada is not known, it is estimated that 800,000 Canadians have PAD. The 2007 Trans Atlantic Intersociety Consensus (TASC) II Working Group for the Management of Peripheral Disease estimated that the prevalence of PAD in Europe and North America to be 27 million, of whom 88,000 are hospitalizations involving lower extremities. A higher prevalence of PAD among elderly individuals has been reported to range from 12% to 29%. The National Health and Nutrition Examination Survey (NHANES) estimated that the prevalence of PAD is 14.5% among individuals 70 years of age and over.
Modifiable and non-modifiable risk factors associated with PAD include advanced age, male gender, family history, smoking, diabetes, hypertension and hyperlipidemia. PAD is a strong predictor of myocardial infarction (MI), stroke and cardiovascular death. Annually, approximately 10% of ischemic cardiovascular and cerebrovascular events can be attributed to the progression of PAD. Compared with patients without PAD, the 10-year risk of all-cause mortality is 3-fold higher in patients with PAD with 4-5 times greater risk of dying from cardiovascular event. The risk of coronary heart disease is 6 times greater and increases 15-fold in patients with advanced or severe PAD. Among subjects with diabetes, the risk of PAD is often severe and associated with extensive arterial calcification. In these patients the risk of PAD increases two to four fold. The results of the Canadian public survey of knowledge of PAD demonstrated that Canadians are unaware of the morbidity and mortality associated with PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.
The diagnosis of PAD is difficult as most patients remain asymptomatic for many years. Symptoms do not present until there is at least 50% narrowing of an artery. In the general population, only 10% of persons with PAD have classic symptoms of claudication, 40% do not complain of leg pain, while the remaining 50% have a variety of leg symptoms different from classic claudication. The severity of symptoms depends on the degree of stenosis. The need to intervene is more urgent in patients with limb threatening ischemia as manifested by night pain, rest pain, ischemic ulcers or gangrene. Without successful revascularization those with critical ischemia have a limb loss (amputation) rate of 80-90% in one year.
Diagnosis of PAD is generally non-invasive and can be performed in the physician offices or on an outpatient basis in a hospital. Most common diagnostic procedure include: 1) Ankle Brachial Index (ABI), a ratio of the blood pressure readings between the highest ankle pressure and the highest brachial (arm) pressure; and 2) Doppler ultrasonography, a diagnostic imaging procedure that uses a combination of ultrasound and wave form recordings to evaluate arterial flow in blood vessels. The value of the ABI can provide an assessment of the severity of the disease. Other non invasive imaging techniques include: Computed Tomography (CT) and Magnetic Resonance Angiography (MRA). Definitive diagnosis of PAD can be made by an invasive catheter based angiography procedure which shows the roadmap of the arteries, depicting the exact location and length of the stenosis / occlusion. Angiography is the standard method against which all other imaging procedures are compared for accuracy.
More than 70% of the patients diagnosed with PAD remain stable or improve with conservative management of pharmacologic agents and life style modifications. Significant PAD symptoms are well known to negatively influence an individual quality of life. For those who do not improve, revascularization methods either invasive or non-invasive can be used to restore peripheral circulation.
Technology Under Review
A Stent is a wire mesh “scaffold” that is permanently implanted in the artery to keep the artery open and can be combined with angioplasty to treat PAD. There are two types of stents: i) balloon-expandable and ii) self expandable stents and are available in varying length. The former uses an angioplasty balloon to expand and set the stent within the arterial segment. Recently, drug-eluting stents have been developed and these types of stents release small amounts of medication intended to reduce neointimal hyperplasia, which can cause re-stenosis at the stent site. Endovascular stenting avoids the problem of early elastic recoil, residual stenosis and flow limiting dissection after balloon angioplasty.
Research Questions
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting more effective than percutaneous transluminal angioplasty (PTA) in improving patency?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting provide immediate success compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting associated with less complications compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting compared to PTA reduce the rate of re-intervention?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion) is primary stenting more effective than PTA in improving clinical and hemodynamic success?
Are drug eluting stents more effective than bare stents in improving patency, reducing rates of re-interventions or complications?
Research Methods
Literature Search
A literature search was performed on February 2, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports from 1950 to January Week 3, 2010
Comparative randomized controlled trials (RCTs), systematic reviews and meta-analyses of RCTs
Proven diagnosis of PAD of the lower extremities in all patients.
Adult patients at least 18 years of age.
Stent as at least one treatment arm.
Patency, re-stenosis, re-intervention, technical success, hemodynamic (ABI) and clinical improvement and complications as at least an outcome.
Exclusion Criteria
Non-randomized studies
Observational studies (cohort or retrospective studies) and case report
Feasibility studies
Studies that have evaluated stent but not as a primary intervention
Outcomes of Interest
The primary outcome measure was patency. Secondary measures included technical success, re-intervention, complications, hemodynamic (ankle brachial pressure index, treadmill walking distance) and clinical success or improvement according to Rutherford scale. It was anticipated, a priori, that there would be substantial differences among trials regarding the method of examination and definitions of patency or re-stenosis. Where studies reported only re-stenosis rates, patency rates were calculated as 1 minus re-stenosis rates.
Statistical Analysis
Odds ratios (for binary outcomes) or mean difference (for continuous outcomes) with 95% confidence intervals (CI) were calculated for each endpoint. An intention to treat principle (ITT) was used, with the total number of patients randomized to each study arm as the denominator for each proportion. Sensitivity analysis was performed using per protocol approach. A pooled odds ratio (POR) or mean difference for each endpoint was then calculated for all trials reporting that endpoint using a fixed effects model. PORs were calculated for comparisons of primary stenting versus PTA or other alternative procedures. Level of significance was set at alpha=0.05. Homogeneity was assessed using the chi-square test, I2 and by visual inspection of forest plots. If heterogeneity was encountered within groups (P < 0.10), a random effects model was used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, these analyses were repeated within subgroups of patients defined by time of outcome assessment to evaluate sustainability of treatment benefit. Results were pooled based on the diseased artery and stent type.
Summary of Findings
Balloon-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, there is no significant difference in patency between primary stenting using balloon-expandable bare metal stents and PTA at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 1.26 (0.74, 2.13); 12 months 0.95 (0.66, 1.38); and 24 months 0.72 (0.34. 1.55).
There is no significant difference in clinical improvement, re-interventions, peri and post operative complications, mortality and amputations between primary stenting using balloon-expandable bare stents and PTA in patients with superficial femoral artery. The pooled OR and their corresponding 95% CI are clinical improvement 0.85 (0.50, 1.42); ankle brachial index 0.01 (-0.02, 0.04) re-intervention 0.83 (0.26, 2.65); complications 0.73 (0.43, 1.22); all cause mortality 1.08 (0.59, 1.97) and amputation rates 0.41 (0.14, 1.18).
Self-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, primary stenting using self-expandable bare metal stents is associated with significant improvement in patency at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 2.35 (1.06, 5.23); 12 months 1.54 (1.01, 2.35); and 24 months 2.18 (1.00. 4.78). However, the benefit of primary stenting is not observed for clinical improvement, re-interventions, peri and post operative complications, mortality and amputation in patients with superficial femoral artery disease. The pooled OR and their corresponding 95% CI are clinical improvement 0.61 (0.37, 1.01); ankle brachial index 0.01 (-0.06, 0.08) re-intervention 0.60 (0.36, 1.02); complications 1.60 (0.53, 4.85); all cause mortality 3.84 (0.74, 19.22) and amputation rates 1.96 (0.20, 18.86).
Balloon expandable stents vs PTA in iliac artery occlusive disease
Based on moderate quality of evidence, despite immediate technical success, 12.23 (7.17, 20.88), primary stenting is not associated with significant improvement in patency, clinical status, treadmill walking distance and reduction in re-intervention, complications, cardiovascular events, all cause mortality, QoL and amputation rates in patients with intermittent claudication caused by iliac artery occlusive disease. The pooled OR and their corresponding 95% CI are: patency 1.03 (0.56, 1.87); clinical improvement 1.08 (0.60, 1.94); walking distance 3.00 (12.96, 18.96); re-intervention 1.16 (0.71, 1.90); complications 0.56 (0.20, 1.53); all cause mortality 0.89 (0.47, 1.71); QoL 0.40 (-4.42, 5.52); cardiovascular event 1.16 (0.56, 2.40) and amputation rates 0.37 (0.11, 1.23). To date no RCTs are available evaluating self-expandable stents in the common or external iliac artery stenosis or occlusion.
Drug-eluting stent vs balloon-expandable bare metal stents in crural arteries
Based on a very low quality of evidence, at 6 months of follow-up, sirolimus drug-eluting stents are associated with a reduction in target vessel revascularization and re-stenosis rates in patients with atherosclerotic lesions of crural (tibial) arteries compared with balloon-expandable bare metal stent. The OR and their corresponding 95% CI are: re-stenosis 0.09 (0.03, 0.28) and TVR 0.15 (0.05, 0.47) in patients with atherosclerotic lesions of the crural arteries at 6 months follow-up. Both types of stents offer similar immediate success. Limitations of this study include: short follow-up period, small sample and no assessment of mortality as an outcome. Further research is needed to confirm its effect and safety.
PMCID: PMC3377569  PMID: 23074395
6.  A Team Approach to the Management of Intractable Leg Ulcers 
Annals of Vascular Diseases  2013;6(1):39-45.
Objectives: The management of intractable leg ulcers requires a team approach which includes vascular surgeons and plastic surgeons. We retrospectively reviewed the results of the management of intractable leg ulcers by plastic surgeons.
Patients and Methods: A total of 73 patients with intractable leg ulcers, (79 limbs) were treated at the Department of Plastic Surgery at our institution. Skin perfusion pressure (SPP) around the ulcer on the limb was measured before and after arterial reconstructive procedures. Local ulcer management involved intra-wound continuous negative pressure and irrigation therapy or negative pressure wound therapy. We examined the rates of wound healing and associated prognostic factors.
Results: There were 21 limbs without ischemia (non-peripheral arterial disease [Non-PAD] group) and 58 limbs with ischemia (PAD group). The healing rates were 66% in the PAD group and 81% in the Non-PAD group, but the difference between the groups was not significant. A total of 41 limbs in the PAD group underwent revascularization, which involved bypass surgery in 18 limbs and endovascular therapy in 23 limbs. The salvage rate of the revascularized limbs was 83% at 1 year. The primary patency rates at 1 year were 87% for bypass surgery and 58% for endovascular therapy. The healing rate of the revascularized limbs was 66%, and the presence of concomitant hemodialysis, infected ulcers, and limbs without improved SPP were shown to be poor prognostic factors. Limbs treated with bypass surgery had a better healing rate than limbs treated with endovascular therapy, but the difference was not significant.
Conclusion: Good ulcer-healing rates were achieved by effective revascularization and aggressive local management. These results suggest that a team approach is useful for the management of intractable leg ulcers. (English translation of Jpn J Vasc Surg 2011; 20: 913-920)
PMCID: PMC3634998  PMID: 23641282
peripheral arterial disease (PAD); foot ulcer; skin perfusion pressure (SPP); wound healing
7.  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
8.  Variation in the Use of Lower Extremity Vascular Procedures for Critical Limb Ischemia 
Many believe that variation in vascular practice may affect limb salvage rates in patients with severe PAD. However, the extent of variation in procedural vascular care obtained by patients with critical limb ischemia (CLI) remains unknown.
Methods and Results
Using Medicare 2003–2006, we identified all patients with CLI who underwent major lower extremity amputation in the 306 hospital referral regions (HRRs) described in the Dartmouth Atlas of Healthcare. For each patient, we studied the use of lower extremity vascular procedures (open surgery or endovascular intervention) in the year prior to amputation. Our main outcome measure was the intensity of vascular care, defined as the proportion of patients in the HRR undergoing vascular procedure in the year before amputation. Overall, 20,464 patients with CLI underwent major lower extremity amputations during the study period, and collectively underwent 25,800 vascular procedures in the year prior to undergoing amputation. However, these procedures were not distributed evenly − 54% of patients had no vascular procedures performed in the year prior to amputation, 14% underwent 1 vascular procedure, and 21% underwent more than one vascular procedure. In the regions in the lowest quintile of vascular intensity, vascular procedures were performed in 32% of patients. Conversely, in the regions in the highest quintile of vascular intensity, revascularization was performed in 58% of patients in the year prior to amputation (p<0.0001). In analyses accounting for differences in age, sex, race, and comorbidities, patients in high intensity regions were 2.4 times as likely to undergo revascularization in the year prior to amputation than patients in low intensity regions (adjusted OR=2.4, 95% CI 2.1–2.6, p<0.001).
Significant variation exists in the intensity of vascular care provided to patients in the year prior to major amputation. In some regions, patients receive intensive care, while in other regions, far less vascular care is provided. Future work is needed to determine the association between intensity of vascular care and limb salvage.
PMCID: PMC3281555  PMID: 22147886
epidemiology; outcomes research; peripheral vascular disease; treatment disparities; vascular disease
9.  Electrocautery causes more ischemic peritoneal tissue damage than ultrasonic dissection 
Surgical Endoscopy  2010;25(6):1827-1834.
Minimizing peritoneal tissue injury during abdominal surgery has the benefit of reducing postoperative inflammatory response, pain, and adhesion formation. Ultrasonic dissection seems to reduce tissue damage. This study aimed to compare electrocautery and ultrasonic dissection in terms of peritoneal tissue ischemia measured by microdialysis.
In this study, 18 Wistar rats underwent a median laparotomy and had a peritoneal microdialysis catheter implanted in the left lateral sidewall. The animals were randomly assigned to receive two standard peritoneal incisions parallel to the catheter by either ultrasonic dissection or electrocautery. After the operation, samples of microdialysis dialysate were taken every 2 h until 72 h postoperatively for measurements of pyruvate, lactate, glucose, and glycerol, and ratios were calculated.
The mean lactate–pyruvate ratio (LPR), lactate–glucose ratio (LGR), and glycerol concentration were significantly higher in the electrocautery group than in the ultrasonic dissection group until respectively 34, 48, and 48 h after surgery. The mean areas under the curve (AUC) of LPR, LGR, and glycerol concentration also were higher in the electrocautery group than in the ultrasonic dissection group (4,387 vs. 1,639, P = 0.011; 59 vs. 21, P = 0.008; 7,438 vs. 4,169, P = 0.008, respectively).
Electrosurgery causes more ischemic peritoneal tissue damage than ultrasonic dissection.
PMCID: PMC3109994  PMID: 21140171
Adhesions; Electrocautery; Ischemia; Microdialysis; Ultrasonic dissection
10.  Endovascular management of patients with coronary artery disease and diabetic foot syndrome: A long-term follow-up 
To investigate the long-term results of global coronary and peripheral interventional treatment of diabetic foot patients.
We retrospectively included 220 diabetic patients (78.5 ± 15.8 years, 107 females, all with Fontaine III or IV class) who were referred to our centre for diabetic foot syndrome and severe limb ischemia from January 2006 to December 2010. Patients were evaluated by a team of interventional cardiologists and diabetologists in order to assess presence of concomitant coronary artery disease (CAD) and eventual need for coronary revascularization. Stress-echo was performed in all patients before diagnostic peripheral angiography. Patients with indications for coronary angiography were submitted to combined diagnostic angiography and then to eventual staged peripheral and coronary interventions. Doppler ultrasonography and foot transcutaneous oximetry of transcutaneous oxygen pressure (TcPO2) before and after the procedure were performed as well as stress-echocardiography and combined cardiologic and diabetic examination at 1 and 6 month and yearly.
Stress-echocardiography was performed in 94/220 patients and resulted positive in 56 patients who underwent combined coronary and peripheral angiography. In the rest of 126 patients, combined coronary and peripheral angiography was performed directly for concomitant signs and symptoms of coronary heart disease in 35 patients. Coronary revascularization was judged necessary in 85/129 patients and was performed percutaneously after peripheral interventions in 72 patients and surgically in 13 patients. For Diabetic foot interventions the preferred approach was ipsilateral femoral antegrade in 170/220 patients (77.7%) and contralateral cross-over in 40/220 patients (18.8%) and popliteal retrograde + femoral antegrade in 10/220 patients (4.5%). Balloon angioplasty was performed in 252 legs (32 patients had bilateral disease): the procedure was successful in 239/252 legs with an immediate success rate of 94.8% and a significant improvement in TcPO2 and ABI with ulcer healing in 233/252 legs (92.4%). Freedom from major amputation was 82.8% at a mean follow-up of 3.1 ± 1.8 years (range 1 to 5 years) whereas survival was 88%.
Global coronary and peripheral endovascular management of diabetic foot syndrome patients seems to lead to an high immediate success and limb salvage rates and increasing survival compared to historical series.
PMCID: PMC3390080  PMID: 22783289
intervention; angioplasty; diabetes; complications
11.  Combined Arterial Reconstruction and Free Tissue Transfer for Patients with Critical Limb Ischemia 
Annals of Vascular Diseases  2013;6(4):706-710.
Objective: The purpose of treatment for critical limb ischemia (CLI) is to prevent major amputation. The purpose of this study was to evaluate our experience of treating CLI with free tissue transfer (FTT) and revascularization.
Materials and Methods: From January 2010 to December 2012, seven lower extremities in seven patients were treated with revascularization and free tissue transfer for CLI with tissue loss. All seven patients had tissue loss with a Rutherford category 6 status. Six patients underwent bypass surgery, and one patient underwent percutaneous transluminal angioplasty for revascularization. All patients also underwent free tissue transfer using the latissimus dorsi muscle simultaneously and separately in two and five patients, respectively.
Results: Five of the seven patients exhibited flap patency and survival. One patient obtained flap survival and limb salvage, although the flap graft was occluded after the patient achieved limb salvage. One patient developed partial flap necrosis requiring skin grafting and acquired limb salvage. The flap survival rate was 85%, and the limb salvage rate was 100%.
Conclusion: FTT with arterial reconstruction for CLI achieves successful wound healing and limb salvage. Both bypass surgery and endovascular treatment are useful for maintaining the vascular supply.
PMCID: PMC3866359  PMID: 24386019
free tissue transfer; bypass surgery; endovascular treatment
12.  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
13.  Validation of Intraluminal and Intraperitoneal microdialysis in ischemic small intestine 
BMC Gastroenterology  2013;13:170.
We sought to define the sensitivity and specificity of intraperitoneal (IP) and intraluminal (IL) microdialysate metabolites in depicting ex vivo small intestinal total ischemia during GI-tract surgery. We hypothesized that IL as opposed to IP microdialysis detects small intestinal ischemia with higher sensitivity and specificity.
IL and IP microdialysate lactate, pyruvate, glucose and glycerol were analysed from small intestine of pancreaticoduodenectomy patients before and after occluding the mesenteric vasculature and routine resection of a segment of small intestine. Ex vivo time sequences of microdialysate metabolites were described and ROC analyses after 0–30, 31–60, 61–90 and 91–120 minutes after the onset ischemia were calculated.
IL lactate to pyruvate ratio (L/P ratio) indicated ischemia after 31–60 minutes with 0.954 ROC AUC (threshold: 109) in contrast to IP L/P (ROC AUC of 0.938 after 61–90 minutes, threshold: 18). At 31–60 minutes IL glycerol concentration indicated ischemia with 0.903 ROC AUCs (thresholds: 69 μmol/l). IP glycerol was only moderately indicative for ischemia after 91–120 minutes with 0,791 ROC AUCs (threshold 122 μmol/l). After 31–60 minutes IL and IP lactate to glucose ratios (L/G ratio) indicated ischemia with 0.956 and 0,942 ROC AUCs (thresholds: 48,9 and 0.95), respectively.
The results support the hypothesis that intraluminal application of microdialysis and metabolic parameters from the small intestinal lumen indicate onset of ischemia earlier than intraperioneal microdialysis with higher sensitivity and specificity.
PMCID: PMC3880346  PMID: 24325174
Microdialysis; Ischemia; Lactate to pyruvate ratio; Lactate to glucose ratio; Gut; Human; Glycerol
14.  Lactate Uptake by the Injured Human Brain: Evidence from an Arteriovenous Gradient and Cerebral Microdialysis Study 
Journal of Neurotrauma  2013;30(24):2031-2037.
Lactate has been regarded as a waste product of anaerobic metabolism of glucose. Evidence also suggests, however, that the brain may use lactate as an alternative fuel. Our aim was to determine the extent of lactate uptake from the circulation into the brain after traumatic brain injury (TBI) and to compare it with levels of lactate in the brain extracellular fluid. We recruited 19 patients with diffuse TBI, monitored with cerebral microdialysis and jugular bulb catheters. Serial arteriovenous (AV) concentration differences of glucose and lactate were calculated from arterial and jugular blood samples, providing a measure of net uptake or export by the brain. Microdialysis was used to measure brain extracellular glucose and lactate. In 17/19 patients studied for 5 days post-injury, there were periods of net lactate uptake into the brain, most frequently on day 3 after injury. Brain microdialysate lactate had a median (interquartile range [IQR]) concentration of 2.5 (1.5–3.2) mmol/L during lactate uptake and 2.2 (1.7–3.0) mmol/L during lactate export. Lactate uptake into the brain occurred at a median (IQR) arterial lactate concentration of 1.6 (1.0–2.2) mmol/L. Lactate uptake was associated with significantly higher AV difference in glucose values with a median (IQR) of 0.4 (0.03–0.7) mmol/L during uptake and 0.1 (−0.2–0.3) mmol/L during lactate export (Mann-Whitney U p=0.003). Despite relatively high brain lactate compared with arterial lactate concentrations, the brain appears to up-regulate lactate transport into the brain after TBI. This may serve to satisfy greater demands for energy substrate from the brain after TBI.
PMCID: PMC3868386  PMID: 23968221
metabolism; microdialysis; traumatic brain injury (human)
15.  Patient delay is the main cause of treatment delay in acute limb ischemia: an investigation of pre- and in-hospital time delay 
The prognosis of acute limb ischemia is severe, with amputation rates of up to 25% and in-hospital mortality of 9-15%. Delay in treatment increases the risk of major amputation and may be present at different stages, including patient delay, doctors´ delay and waiting time in the emergency department. It is important to identify existing problems in order to reduce time delay.
The aim of this study was to collect data for patients with acute limb ischemia and to evaluate the time delay between the different events from onset of symptoms to specialist evaluation and further treatment with focus on pre-hospital and in-hospital time delays.
We conducted a prospective cross-sectional cohort study including all patients suspected with acute limb ischemia who were admitted to the emergency department of a community hospital in a six months period. Temporal delay in the different phases between the time of occurrence of symptoms and completion of treatment was recorded prospectively. All patients who underwent intervention had a 30 days follow-up with regard to major amputation of the leg and survival.
A total of 42 patients (21 men and 21 women) age 73 (20–95) years (median (range)) was identified.
From onset of symptoms to first contact with a doctor the time for all patients were 24 (0–1200) hours. Thirty patients needed immediate intervention. In the group of fourteen patients who had immediate operation, the median time from vascular evaluation to revascularization was 324.5 (122–873) minutes and in the group of eight patients that went through an imaging procedure before an operation the median delay was 822 (494–1185) minutes from specialist assessment to revascularization. The median time for revascularization among four patients, who were treated with arterial thrombolysis was 5621 (1686–8376) minutes.
At 30 days follow up, six patients had had the ischemic limb amputated above the ankle and four patients had died.
We found that the largest time delay was between onset of symptoms and first contact to a medical doctor. A greater public awareness is needed, so as to facilitate urgent revascularisation and improve outcomes.
PMCID: PMC4232613  PMID: 25400690
Acute limb ischemia; ALI; Treatment delay; Fast track department; Diagnostic packages; Patient delay
16.  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
17.  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
18.  The Outcomes of Salvage Surgery for Vascular Injury in The Extremities: A Special Consideration For Delayed Revascularization 
Malaysian Orthopaedic Journal  2014;8(1):14-19.
A seven years retrospective study was performed in 45 consecutive vascular injuries in the extremities to investigate the pattern of injuries, managements and outcomes.
Motor-vehicle accidents were the leading cause of injuries (80%), followed by industrial injuries (11.1%) and iatrogenic injuries (4.4%). Popliteal and brachial artery injuries were commonly involved (20%). Fifteen (33.3%) patients had fractures, dislocation or fracture dislocation around the knee joint and 6 (13.3%) patients had soft tissue injuries without fracture. Traumatic arterial transection accounted for 34 (75.6%) cases, followed by laceration in 7 (15.6%) and 9 (6.7%) contusions. Associated nerve injuries were seen in 8 (17.8 %) patients using intra-operative findings as the gold standard, both conventional angiogram (CA) and computerized tomography angiogram (CTA) had 100% specificity and 100% sensitivity in determining the site of arterial injuries.
The mean ischemic time was 25.31 hours (4 - 278 hours). Thirty-three (73.3 %) patients were treated more than 6 hours after injury and 6 patients underwent revascularization after 24 hours; all had good collateral circulation without distal pulses or evidence of ischemic neurological deficit. The mean ischemic time in 39 patients who underwent revascularization within 24 hours was 13.2 hours. Delayed amputation was performed in 5 patients (11.1%). Of the 6 patients who underwent delayed revascularization, one patient had early amputation, one -had delayed amputation following infection and multiple flap procedures while the rest of the patients’ limbs survived. Joint stiffness was noted in 10 patients (22.2%) involving the knee joint, elbow and shoulder in two patients each. Infection was also noted in 5 patients (11.1%) with two of them were due to infected implants. Other complications encountered included nonunion (2 patients, 4.4%), delayed union (1 patient, 2.2%),limb length discrepancy (1 patient, 2.2%), hematoma (1 patient, 2.2%) and leaking anastomosis in one patient (2.2%). Volkmann’s ischemic contracture occurred in 3 (6.7%) patients. There was no complication noted in 8 (17.8%) patients Three patients (6.7%) died of whom two were not due to vascular causes. We conclude that early detection and revascularization of traumatic vascular injuries is important but delayed revascularization also produced acceptable results.
PMCID: PMC4093557  PMID: 25279079
19.  Acute Limb Ischemia: Surgical Thromboembolectomy and the Clinical Course of Arterial Revascularization at Ankle 
Surgical thromboembolectomy for acute limb ischemia using Fogarty catheter is basically a blind procedure. Therefore, the complete removal of thromboemboli in all calf arteries is difficult even if completion angiography or radiological intervention is performed. The purpose of this study is to identify whether limb salvage could be achieved if at least one ankle artery was revascularized by surgical thromboembolectomy. We also observed the effectiveness of below-knee popliteal approach. Over 1 year, surgical thromboembolectomy via below-knee popliteal artery was performed on 18 acutely ischemic limbs in 14 consecutive patients. All patients were diagnosed based on clinical symptoms and computed tomography (CT) angiography. Surgical thromboembolectomy was terminated when a pulse was detected by a handheld vascular Doppler device in at least one ankle artery after closing the arteriotomy. Patients were observed during postoperative anticoagulation therapy. Of the 14 patients, 1 died and 1 underwent amputation due to the already necrotized lesion in the foot. After 1 week of anticoagulation therapy, two or more arterial pulses were detected at the ankles in all 15 limbs from the remaining 12 patients. During the 6 to 18 months of follow-up, all 15 limbs were salvaged successfully. In acute limb ischemia, successful limb salvage could be achieved by the revascularization of at least one ankle artery by surgical thromboembolectomy with concomitant anticoagulation therapy. Below-knee popliteal approach is an effective method and is worth for further study compared with other approaches.
PMCID: PMC3709946  PMID: 24436594
thromboembolectomy; angiography; intervention; anticoagulation; Doppler
20.  Anaerobic metabolism associated with traumatic hemorrhagic shock monitored by microdialysis of muscle tissue is dependent on the levels of hemoglobin and central venous oxygen saturation: a prospective, observational study 
Traumatic hemorrhagic shock resulting in tissue hypoxia is a significant cause of morbidity and mortality in polytraumatized patients. Early identification of tissue hypoxia is possible with microdialysis. The aim of this study was to determine the correlation between a marker of tissue hypoxia (L/P; lactate to pyruvate ratio) and selected parameters of systemic oxygen delivery (Hb; hemoglobin) and oxygen extraction (ScvO2; central venous oxygen saturation). We also investigated the severity of tissue hypoxia over the course of care.
Adult patients with traumatic hemorrhagic shock were enrolled in this prospective, observational study. Microdialysis of the peripheral muscle tissue was performed. Demographic data and timeline of care were collected. Tissue lactate, pyruvate, glycerol, glucose levels, hemoglobin, serum lactate and oxygen saturation of the central venous blood (ScvO2) levels were also measured.
The L/P ratio trend may react to changes in systemic hemoglobin levels with a delay of 7 to 10 hours, particularly when systemic hemoglobin levels are increased by transfusion. Decrease in tissue L/P ratio may react to increase in ScvO2 with a delay of up to 10 hours, and such a decrease may signify elimination of tissue hypoxia after transfusion. We also observed changes in the L/P trend in the 13 hours preceding a change in the hemoglobin level. Fluid administration, which is routinely used as a first-line treatment of hypovolemic shock, can cause hemodilution and decreased hemoglobin. When ScvO2 decreases, increase in L/P ratio may precede the ScvO2 trend by 10 or 11 hours. An increase in the L/P ratio is an early warning sign of insufficient tissue oxygenation and should lead to intensive observation of hemoglobin levels, ScvO2 and other hemodynamic parameters. Patients who were treated more rapidly had lower maximal L/P values and a lower degree of tissue ischemia.
The L/P ratio is useful to identify tissue ischemia and can estimate the effectiveness of fluid resuscitation. An increase in the L/P ratio is an early warning sign of inadequate tissue oxygenation and should lead to more detailed hemodynamic and laboratory monitoring. This information cannot usually be obtained from global markers.
PMCID: PMC3923388  PMID: 24499479
Microdialysis; Shock; Lactate; Hemoglobin
21.  Relationship between regional spending on vascular care and amputation rate 
JAMA surgery  2014;149(1):34-42.
While lower extremity revascularization is effective in preventing amputation, the relationship between spending on vascular care and regional amputation rates remains unclear.
To test the hypothesis that higher regional spending on vascular care is associated with lower amputation rates in patients with severe peripheral arterial disease (PAD).
Retrospective cohort study.
United States Medicare patients, 2003-2010
18,463 patients who underwent major PAD-related amputation.
Price-adjusted Medicare spending on revascularization procedures and related vascular care in the year before lower extremity amputation, across hospital referral regions.
Main Outcome Measure(s)
Correlation coefficient between regional spending on vascular care and regional rates of PAD-related amputation.
Among patients ultimately subject to amputation, 64% were admitted to the hospital in the year prior to amputation for revascularization, wound-related care, or both; 36% were admitted only for their amputation. The mean cost of inpatient care in the year before amputation, including the amputation itself, was $22,405, but varied from $11,077 (Bismarck, North Dakota) to $42,613 (Salinas, California) (p<0.001). Patients in high-spending regions were more likely to undergo vascular procedures in crude analyses (12.0 procedures per 10,000 patients in the lowest quintile of spending, 20.4 procedures per 10,000 patients in the highest quintile of spending, p<0.0001), as well as in risk-adjusted analyses (adjusted OR for receiving a vascular procedure in highest quintile of spending = 3.5, 95 % CI 3.2-3.8, p<0.0001). While revascularization was associated with higher spending (R=0.38, p<0.001), higher spending was not associated with lower regional amputation rates (R=0.10, p=0.06). Regions most aggressive in the use of endovascular interventions which most likely to have high spending (R=0.42, p=0.002) and high amputation rates (R=0.40, p=0.004).
Regions that spend the most on vascular care is highest perform the most procedures, especially endovascular interventions, in the year before amputation. However, there is little evidence that higher regional spending is associated with lower amputation rates. This suggests an opportunity to limit costs in vascular care without compromising quality.
PMCID: PMC4279246  PMID: 24258010
Cardiovascular sugery; endovascular interventions; cost; peripheral vascular disease; health policy and outcomes research
22.  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
23.  Endovascular treatment of lower extremity arteries is associated with an improved outcome in diabetic patients affected by intermittent claudication 
BMC Surgery  2012;12(Suppl 1):S19.
Lower extremity peripheral arterial disease (LE-PAD) is a highly prevalent condition among diabetic patients, associated with reduced walking capacity and a high incidence of cardiovascular events. Endovascular revascularization of lower extremities arteries improves walking performance and quality of life of diabetic patients affected by intermittent claudication, but few studies evaluated the impact of revascularization on cardiovascular outcome in this high-risk population. Accordingly, in the present study we evaluated if leg-ischemia resolution by effective lower limbs percutaneous revascularization can also impact cardiovascular outcome in a homogeneous group of diabetic patients affected by intermittent claudication.
236 diabetic patients affected by LE-PAD at stage II of Fontaine’s classification, with ankle/brachial index ≤0.90 and one or more hemodynamically significant stenosis in at least one artery of the ileo-femoro-popliteal axis were enrolled in the study. According to the Trans-Atlantic Inter Society Consensus II recommendations, 123 (52.1%) underwent percutaneous transluminal angioplasty (PTA group), while 113 (47.9%) underwent conservative medical therapy only (MT group). The incidence of major cardiovascular events (cardiovascular death, myocardial infarction, ischemic stroke, coronary or carotid revascularization) was prospectively analyzed with Kaplan-Meier curves and the risk of developing a cardiovascular event calculated by Cox analyses.
No baseline difference in cardiovascular risk factors were observed between the PTA and MT groups, except for a lower prevalence of males in PTA group (74.8% vs. 85.8%, p=0.034). Furthermore, patients in the PTA group showed a worse walking capacity as expressed by maximum walking distance (108.7 ± 300.9 vs 378.4 ± 552.3 meters, p<0.001). During a median follow-up of 20 months (12.0-29.0), the incidence of cardiovascular events was markedly lower in patients in the PTA group with respect to patients in the MT group (7.3% vs. 22.1%, p=0.001), and patients of the MT group had at Cox analysis a 3.9 increased risk with respect to PTA group, after adjustment for potential confounding factors (95% CI 1.1-15.3, p=0.049).
The present study shows that lower limbs revascularization of diabetic patients affected by intermittent claudication, in addition to improve walking performance, is associated with a reduction in the incidence of future major cardiovascular events.
PMCID: PMC3499211  PMID: 23174008
24.  Lactate and the Lactate-to-Pyruvate Molar Ratio Cannot Be Used as Independent Biomarkers for Monitoring Brain Energetic Metabolism: A Microdialysis Study in Patients with Traumatic Brain Injuries 
PLoS ONE  2014;9(7):e102540.
For decades, lactate has been considered an excellent biomarker for oxygen limitation and therefore of organ ischemia. The aim of the present study was to evaluate the frequency of increased brain lactate levels and the LP ratio (LPR) in a cohort of patients with severe or moderate traumatic brain injury (TBI) subjected to brain microdialysis monitoring to analyze the agreement between these two biomarkers and to indicate brain energy metabolism dysfunction.
Forty-six patients with an admission Glasgow coma scale score of ≤13 after resuscitation admitted to a dedicated 10-bed Neurotraumatology Intensive Care Unit were included, and 5305 verified samples of good microdialysis data were analyzed.
Lactate levels were above 2.5 mmol/L in 56.9% of the samples. The relationships between lactate and the LPR could not be adequately modeled by any linear or non-linear model. Neither Cohen’s kappa nor Gwet’s statistic showed an acceptable agreement between both biomarkers to classify the samples in regard to normal or abnormal metabolism. The dataset was divided into four patterns defined by the lactate concentrations and the LPR. A potential interpretation for these patterns is suggested and discussed. Pattern 4 (low pyruvate levels) was found in 10.7% of the samples and was characterized by a significantly low concentration of brain glucose compared with the other groups.
Our study shows that metabolic abnormalities are frequent in the macroscopically normal brain in patients with traumatic brain injuries and a very poor agreement between lactate and the LPR when classifying metabolism. The concentration of lactate in the dialysates must be interpreted while taking into consideration the LPR to distinguish between anaerobic metabolism and aerobic hyperglycolysis.
PMCID: PMC4099374  PMID: 25025772
25.  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

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