Gap analysis of diabetes-related foot disease management systems in Pacific Islands Countries and Territories.

BACKGROUND: Pacific Island Countries and Territories (PICTs) are known to have high prevalence of Diabetes Mellitus and high incidence of diabetes-related foot disease. Diabetes-related foot disease can lead to lower limb amputation and is associated with poor outcomes, with increased morbidity and mortality. The purpose of this study was to gain a better understanding of diabetes-related foot disease management in selected countries in PICTs and to identify potential barriers in management of diabetes-related foot disease management in the region. METHODS: A cross-sectional survey was sent to eleven hospitals across six selected PICTs. The survey instrument was designed to provide an overview of diabetes-related foot disease (number of admissions, and number of lower limb amputations over 12 months) and to identify clinical services available within each institution. Two open-ended questions (free text responses) were included in the instrument to explore initiatives that have helped to improve management and treatment of diabetes-related foot diseases, as well as obstacles that clinicians have encountered in management of diabetes-related foot disease. The survey was conducted over 6 weeks. RESULTS: Seven hospitals across four countries provided responses. Number of admissions and amputations related to diabetes-related foot disease were only reported as an estimate by clinicians. Diabetes-related foot disease was managed primarily by general medicine physician, general surgeon and/or orthopaedic surgeon in the hospitals surveyed, as there were no subspecialty services in the region. Only one hospital had access to outpatient podiatry. Common themes identified around barriers faced in management of diabetes-related foot disease by clinicians were broadly centred around resource availability, awareness and education, and professional development. CONCLUSION: Despite the high prevalence of diabetes-related foot disease within PICTs, there appears to be a lack of functional multi-disciplinary foot services (MDFs). To improve the outcomes for diabetes-related foot disease patients in the region, there is a need to establish functional MDFs and engage international stakeholders to provide ongoing supports in the form of education, mentoring, as well as physical resources.

Australian evidence-based guidelines for the prevention and management of diabetes-related foot disease: a guideline summary.

INTRODUCTION: Diabetes-related foot disease (DFD) - foot ulcers, infection, ischaemia - is a leading cause of hospitalisation, disability, and health care costs in Australia. The previous 2011 Australian guideline for DFD was outdated. We developed new Australian evidence-based guidelines for DFD by systematically adapting suitable international guidelines to the Australian context using the ADAPTE and GRADE approaches recommended by the NHMRC. MAIN RECOMMENDATIONS: This article summarises the most relevant of the 98 recommendations made across six new guidelines for the general medical audience, including: prevention - screening, education, self-care, footwear, and treatments to prevent DFD; classification - classifications systems for ulcers, infection, ischaemia and auditing; peripheral artery disease (PAD) - examinations and imaging for diagnosis, severity classification, and treatments; infection - examinations, cultures, imaging and inflammatory markers for diagnosis, severity classification, and treatments; offloading - pressure offloading treatments for different ulcer types and locations; and wound healing - debridement, wound dressing selection principles and wound treatments for non-healing ulcers. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: For people without DFD, key changes include using a new risk stratification system for screening, categorising risk and managing people at increased risk of DFD. For those categorised at increased risk of DFD, more specific self-monitoring, footwear prescription, surgical treatments, and activity management practices to prevent DFD have been recommended. For people with DFD, key changes include using new ulcer, infection and PAD classification systems for assessing, documenting and communicating DFD severity. These systems also inform more specific PAD, infection, pressure offloading, and wound healing management recommendations to resolve DFD.

Guidelines development protocol and findings: part of the 2021 Australian evidence-based guidelines for diabetes-related foot disease.

BACKGROUND: Diabetes-related foot disease (DFD) is a leading cause of the Australian disease burden. The 2011 Australian DFD guidelines were outdated. We aimed to develop methodology for systematically adapting suitable international guidelines to the Australian context to become the new Australian evidence-based guidelines for DFD. METHODS: We followed the Australian National Health Medical Research Council (NHMRC) guidelines for adapting guidelines. We systematically searched for all international DFD guideline records. All identified records were independently screened and assessed for eligibility. Those deemed eligible were further assessed and included if scoring at least moderate quality, suitability and currency using AGREE II and NHMRC instruments. The included international guidelines had all recommendations extracted into six sub-fields: prevention, wound classification, peripheral artery disease, infection, offloading and wound healing. Six national panels, each comprising 6-8 multidisciplinary national experts, screened all recommendations within their sub-field for acceptability and applicability in Australia using an ADAPTE form. Where panels were unsure of any acceptability and applicability items, full assessments were undertaken using a GRADE Evidence to Decision tool. Recommendations were adopted, adapted, or excluded, based on the agreement between the panel's and international guideline's judgements. Each panel drafted a guideline that included all their recommendations, rationale, justifications, and implementation considerations. All underwent public consultation, final revision, and approval by national peak bodies. RESULTS: We screened 182 identified records, assessed 24 full text records, and after further quality, suitability, and currency assessment, one record was deemed a suitable international guideline, the International Working Group Diabetic Foot Guidelines (IWGDF guidelines). The six panels collectively assessed 100 IWGDF recommendations, with 71 being adopted, 27 adapted, and two excluded for the Australian context. We received 47 public consultation responses with > 80% (strongly) agreeing that the guidelines should be approved, and ten national peak bodies endorsed the final six guidelines. The six guidelines and this protocol can be found at: https://www.diabetesfeetaustralia.org/new-guidelines/ CONCLUSION: New Australian evidence-based guidelines for DFD have been developed for the first time in a decade by adapting suitable international guidelines. The methodology developed for adaptation may be useful for other foot-related conditions. These new guidelines will now serve as the national multidisciplinary best practice standards of DFD care in Australia.

Incidence and causes of early unplanned readmission after hospitalisation with peripheral arterial disease in Australia and New Zealand.

OBJECTIVE: To evaluate the characteristics and predictors of unplanned readmission within 30 days of hospitalisation for the treatment of peripheral arterial disease (PAD) in Australia and New Zealand. DESIGN: Analysis of hospitalisations data in the Admitted Patient Collection for each Australian state and territory and the New Zealand National Minimum Dataset (Hospital Events). SETTING: All public and 80% of private hospitals in Australia and New Zealand. PARTICIPANTS: Adults (18 years or older) hospitalised with a primary or conditional secondary diagnosis of PAD during 1 January 2010 - 31 December 2015. MAIN OUTCOME MEASURE: Rate of unplanned readmission (any cause) within 30 days of hospitalisation with PAD. RESULTS: Of 104 979 admissions included in our analysis (mean patient age, 73.7 years; SD, 12.4 years), 9765 were followed by at least one unplanned readmission within 30 days of discharge (9.3%): 3395 within one week (34.8%) and 7828 within three weeks (80.2%). The most frequent readmission primary diagnoses were atherosclerosis (1477, 15.3%), type 2 diabetes (1057, 10.8%), and "complications of procedures not elsewhere classified" (963, 9.9%). Readmission was more frequent after acute (4830 of 26 304, 18.4%) than elective PAD hospitalisations (4935 of 78 675, 6.3%), but the readmission characteristics were similar. Factors associated with greater likelihood of readmission included acute PAD hospitalisations (odds ratio [OR], 2.04; 95% CI, 1.96-2.17), surgical intervention during the PAD hospitalisation (OR, 1.74; 95% CI, 1.64-1.84), and chronic limb-threatening ischaemia (OR, 1.55; 95% CI, 1.47-1.63). CONCLUSION: Unplanned readmissions within 30 days of hospitalisation for PAD are often for potentially preventable reasons. Their number should be reduced to improve clinical outcomes for people with PAD.

Update of a Model to Predict Outcomes after Endovascular Aneurysm Repair.

BACKGROUND: Risk assessment models must be continuously validated and updated to ensure that predictions remain valid. Here, the Endovascular Aneurysm Repair Risk Assessment Model, developed in 2008, is updated and improved. METHODS: We used prospectively collected data from Australian patients who underwent elective endovascular aneurysm repair between 2009 and 2013 (n = 695). Data were provided by treating surgeons and the National Death Index. Key outcomes were early and midterm survival, early complications (endoleak, operative, and graft-related) and late complications (endoleak and graft-related). Multinomial logistic regression determined which preoperative variables best predicted each outcome. Area under Receiver Operating Characteristic curve (AUROC), model P-value and internal validation statistics were used to select the best model. RESULTS: Ten preoperative variables were included in the modeling for 10 key outcomes. The most valid outcomes with AUROC>0.7 were 1- and 3-year survival, 30 and 90-day mortality, early and late endoleak (types I, III and IV) and type II endoleak (with an increase in sac size ≥5 mm). The 10 preoperative variables that contributed to outcome models were self-reported fitness, American Society of Anesthesiologists physical status score, history of stroke/transient ischemic attack, age, aneurysm angle, infrarenal neck length, white cell count, respiratory assessment, diabetes and statin therapy. Fitness alone statistically significantly predicted 30 and 90-day deaths better than any other preoperative variable; achieving high AUROCs (0.78 and 0.80), and high odds ratios (12.8 [95% CI: 1.5-110.4] and 18.1 [95% CI: 2.2-149]). CONCLUSIONS: An updated interactive predictive model of outcomes after endovascular aneurysm repair has been created. Many of the variables used in the 2008 model continued to be significant, however, new variables including fitness and respiratory assessment, improved the model. The new model uses variables routinely collected preoperatively, and hence can better support surgeon-patient discussions prior to operation. Informing patients of potential risks or likely outcomes following elective surgery can assist with preoperative shared decision-making.

Supporting surgeons in patient-centred complex decision-making: a qualitative analysis of the impact of a perioperative physician clinic.

OBJECTIVE: Patients with comorbidities can be referred to a physician-led high-risk clinic for medical optimisation prior to elective surgery at the discretion of the surgical consultant, but the factors that influence this referral are not well understood. The aims of this study were to understand the factors that influence a surgeon's decision to refer a patient to the clinic, and how the clinic impacts on the management of complex patients. DESIGN: Qualitative study using theoretical thematic analysis to analyse transcribed semi-structured interviews. SETTING: Interviews were held in either the surgical consultant's private office or a quiet office/room in the hospital ward. PARTICIPANTS: Seven surgical consultants who were eligible to refer patients to the clinic. RESULTS: When discussing the factors that influence a referral to the clinic, all participants initially described the optimisation of comorbidities and would then discuss with examples the challenges with managing complex patients and communicating the risks involved with having surgery. When discussing the role of the clinic, two related subthemes were dominant and focused on the management of risk in complex patients. The participants valued the involvement of the clinic in the decision-making and communication of risks to the patient. CONCLUSIONS: The integration of the high-risk clinic in this study appears to offer additional value in supporting the decision-making process for the surgical team and patient beyond the clinical outcomes. The factors that influence a surgeon's decision to refer a patient to the clinic appear to be driven by the aim to manage the uncertainty and risk to the patient regarding surgery and it was seen as a strategy for managing difficult and complex cases.

Circulating biomarkers are not associated with endoleaks after endovascular repair of abdominal aortic aneurysms.

OBJECTIVE: Endoleak is a common complication of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) but can be detected only through prolonged follow-up with repeated aortic imaging. This study examined the potential for circulating matrix metalloproteinase 9 (MMP9), osteoprotegerin (OPG), D-dimer, homocysteine (HCY), and C-reactive protein (CRP) to act as diagnostic markers for endoleak in AAA patients undergoing elective EVAR. METHODS: Linear mixed-effects models were constructed to assess differences in AAA diameter after EVAR between groups of patients who did and did not develop endoleak during follow-up, adjusting for potential confounders. Circulating MMP9, OPG, D-dimer, HCY, and CRP concentrations were measured in preoperative and postoperative plasma samples. The association of these markers with endoleak diagnosis was assessed using linear mixed effects adjusted as before. The potential for each marker to diagnose endoleak was assessed using receiver operating characteristic curves. RESULTS: Seventy-five patients were included in the study, 24 of whom developed an endoleak during follow-up. Patients with an endoleak had significantly larger AAA sac diameters than those who did not have an endoleak. None of the assessed markers showed a significant association with endoleak. This was confirmed through receiver operating characteristic curve analyses indicating poor diagnostic ability for all markers. CONCLUSIONS: Circulating concentrations of MMP9, OPG, D-dimer, HCY, and CRP were not associated with endoleak in patients undergoing EVAR in this study.

Effectiveness of preoperative medical consultations by internal medicine physicians: a systematic review.

OBJECTIVE: Clinics have been established to provide preoperative medical consultations, and enable the anaesthetist and surgeon to deliver the best surgical outcome for patients. However, there is uncertainty regarding the effect of such clinics on surgical, in-hospital and long-term outcomes. A systematic review of the literature was conducted to determine the effectiveness of preoperative medical consultations by internal medicine physicians for patients listed for elective surgery. DESIGN: Systematic searches of MEDLINE, EMBASE, CINAHL, PubMed, Current Contents and the NHS Centre for Reviews and Dissemination were conducted up to 30 April 2017. SETTING: Elective surgery. STUDY SELECTION: Randomised controlled trials and non-randomised comparative studies conducted in adults. OUTCOME MEASURES: Length of hospital stay, perioperative morbidity and mortality, costs and quality of life. RESULTS: The one randomised trial reported that preadmission preoperative assessment was more effective than the option of an inpatient medical assessment in reducing the frequency of unnecessary admissions with significantly fewer surgical cancellations following admission for surgery. A small reduction in length of stay in patients was also observed. The three non-randomised studies reported increased lengths of stay, costs and postoperative complications in patients who received preoperative assessment. The timing and delivery of the preoperative medical consultation in the intervention group differed across the included studies. CONCLUSION: Further research is required to inform the design and implementation of coordinated involvement of physicians and surgeons in the provision of care for high-risk surgical patients. A standardised approach to perioperative decision-making processes should be developed with a clear protocol or guideline for the assessment and management of surgical patients.

Fitness plus American Society of Anesthesiologists grade improve outcome prediction after endovascular aneurysm repair.

BACKGROUND: Although the American Society of Anesthesiologists (ASA) grade was established for statistical purposes, it is often used prognostically. However, older patients undergoing elective surgery are typically ASA III, which limits patient stratification. We look at the prognostic effect on early complications and survival of using ASA and self-reported physical fitness to stratify patients undergoing endovascular repair of abdominal aortic aneurysms. METHODS: Data were extracted from a trial database. All patients were assigned a fitness level (A (fit) or B (unfit)) based on their self-reported ability to walk briskly for 1 km or climb two flights of stairs. Fitness was used to stratify ASA III patients, with fitter patients assigned ASA IIIA and less fit patients ASA IIIB. Outcomes assessed included survival, reinterventions, endoleak, all early and late complications and early operative complications. RESULTS: A combined ASA/fitness scale (II, IIIA, IIIB and IV) correlated with 1- and 3-year survival (1-year P = 0.001, 3-year P = 0.001) and early and late complications (P = 0.001 and P = 0.05). On its own, ASA predicted early complications (P = 0.0004) and survival (1-year P = 0.01, 3-year P = 0.01). Fitness alone was predictive for survival (1-year P = 0.001, 3-year P = 0.001) and late complications (P = 0.009). CONCLUSION: This study shows that even a superficial assessment of fitness is reflected in surgical outcomes, with fitter ASA III patients showing survival patterns similar to ASA II patients. Physicians should be alert to differences in fitness between patients in the ASA III group, despite similarities based on preexisting severe systemic disease.

A comparison of propensity score-based approaches to health service evaluation: a case study of a preoperative physician-led clinic for high-risk surgical patients.

RATIONALE, AIMS AND OBJECTIVES: A physician-led clinic for the preoperative optimization and management of high-risk surgical patients was implemented in a South Australian public hospital in 2008. This study aimed to estimate the costs and effects of the clinic using a mixed retrospective and prospective observational study design. METHOD: Alternative propensity score estimation methods were applied to retrospective routinely collected administrative and clinical data, using weighted and matched cohorts. Supplementary survey-based prospective data were collected to inform the analysis of the retrospective data and reduce potential unmeasured confounding. RESULTS: Using weighted cohorts, clinic patients had a significantly longer mean length of stay and higher mean cost. With the matched cohorts, reducing the calliper width resulted in a shorter mean length of stay in the clinic group, but the costs remained significantly higher. The prospective data indicated potential unmeasured confounding in all analyses other than in the most tightly matched cohorts. CONCLUSIONS: The application of alternative propensity-based approaches to a large sample of retrospective data, supplemented with a smaller sample of prospective data, informed a pragmatic approach to reducing potential observed and unmeasured confounding in an evaluation of a physician-led preoperative clinic. The need to generate tightly matched cohorts to reduce the potential for unmeasured confounding indicates that significant uncertainty remains around the effects of the clinic. This study illustrates the value of mixed retrospective and prospective observational study designs but also underlines the need to prospectively plan for the evaluation of costs and effects alongside the implementation of significant service innovations.

International trends in patient selection for elective endovascular aneurysm repair: sicker patients with safer anatomy leading to improved 1-year survival.

BACKGROUND: To review the trends in patient selection and early death rate for patients undergoing elective endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) in 3 countries. For this study, audit data from 4,163 patients who had undergone elective infrarenal EVAR were amalgamated. The data originated from Australia, Canada (Ontario), and England (London, Cambridge, and Leicester). METHODS: Statistical analyses were undertaken to determine whether patient characteristics and early death rate varied between and within study groups and over time. The study design was retrospective analysis of data collected prospectively between 1999 and 2012. RESULTS: One-year survival improved over time (P = 0.0013). Canadian patients were sicker than those in Australia or England (P < 0.001). American Society of Anesthesiologists classification (ASA) increased over time across all countries although more significantly in Canada. Age at operation remained constant, although older patients were treated more recently in London (P < 0.001). English centers treated larger aneurysms compared with Australia and Canada (P < 0.001). Australian centers treated a much larger proportion of aneurysms that were <55 mm than other countries. Preoperative creatinine levels decreased over time for all countries and centers (P < 0.001). Infrarenal neck angles have significantly decreased over time (P < 0.001). Recent data from London (UK) showed that operations were performed on longer (P < 0.001) and wider (P < 0.001) infrarenal necks than elsewhere. CONCLUSIONS: In this international comparison, several trends were noted including improved 1-year survival despite declining patient health (as measured by increasing ASA status). This may reflect greater knowledge regarding EVAR that centers from different countries have gained over the last decade and improved medical management of patients with aneurysmal disease.

External validation of the Endovascular aneurysm repair Risk Assessment model in predicting survival, reinterventions, and endoleaks after endovascular aneurysm repair.

OBJECTIVE: The Endovascular aneurysm repair Risk Assessment (ERA) model predicts survival (early death, 3-year survival, and 5-year survival), reinterventions, and endoleaks after elective endovascular aneurysm repair. We externally validated the ERA model in our cohort of patients. METHODS: This was a retrospective validation study of 433 consecutive patients with an asymptomatic abdominal aortic aneurysm treated with endovascular aneurysm repair in three hospitals (Amsterdam, The Netherlands) between 1997 and 2010. The area under the receiver operating characteristic curve was used as measure of accuracy (>0.70 was considered as sufficiently accurate). RESULTS: The early death rate was 1% (3 of 433; 95% confidence interval [CI], 0%-2%), the 5-year survival rate was 65% (95% CI, 61%-70%), the 5-year reintervention rate was 18% (95% CI, 14-78%), and the 5-year rate of type I, II, or III endoleak was 25% (95% CI, 20%-29%). The areas under the curve varied between 0.64 and 0.66 for predictions of survival and between 0.47 and 0.61 for reinterventions and endoleaks. CONCLUSIONS: The predictions of survival, reinterventions, and endoleaks made by the ERA model were not sufficiently accurate to be used in our clinical practice.

Long-term follow-up of last autogenous option arm vein bypass.

BACKGROUND: The superiority of autogenous conduits in infrainguinal bypass surgery is well established. At our institution, arm vein is utilized as the last autogenous option for infrainguinal bypass surgery. The aim of this study was to review the long-term outcomes of last autogenous option arm vein bypass. METHODS: All infrainguinal arm vein bypasses performed between 1997 and 2005 by The Queen Elizabeth Hospital vascular surgeons were identified. Patency, reintervention, limb salvage and survival were calculated using the Kaplan-Meier survival estimate method. RESULTS: Thirty-eight arm vein bypasses were performed in 35 patients. Eighty-nine per cent were performed for critical limb ischaemia. Median follow-up was 58 months (range 2-121). Twelve-month primary, assisted primary and secondary patency rates were 52%, 73% and 76%, respectively. Three-year primary, assisted primary and secondary patency rates were 32%, 61% and 63%, respectively. Five-year primary, assisted primary and secondary patency rates were 21%, 47% and 49%, respectively. Patency was superior in single compared with spliced vein grafts (P < 0.05). Limb salvage rates at 1, 3 and 5 years were 94%, 87% and 76%, respectively. Patient survival at 1, 3 and 5 years was 92%, 68% and 49%, respectively. DISCUSSION: Infrainguinal bypass surgery with arm vein can be performed safely with favourable patency and high rates of limb salvage. Secondary interventions to maintain patency are common and we recommend a vigilant surveillance programme to identify the threatened graft.

Quality of life of patients with peripheral arterial disease and chronic stable angina.

The Coronary Artery Disease in gENeral practiCE (CADENCE) study examined chronic stable angina (CSA). This further analysis examined atherosclerotic risk factors, symptomatic status, clinical management, and quality of life in patients with CSA with and without peripheral arterial disease (PAD). The CADENCE study involved 207 Australian general practitioners (GPs) recruiting 10 to 15 consecutively presenting patients with CSA (n = 2031). General practitioners completed a 2-page case report form, detailing demographic data, cardiovascular status, risk factors, and GP perception of control. Patients completed the Seattle Angina Questionnaire. Patients with coexisting CSA and PAD (17%) were more likely to be older and had more comorbidities than patients with CSA without coexisting PAD. Patients with peripheral arterial disease had a longer history of heart disease and were more likely to experience angina on a weekly basis. Patients with peripheral arterial disease had poorer quality-of-life indices.

Systematic review of treatments for varicose veins.

This systematic review compares the safety and efficacy of varicose vein treatments, including conservative therapy, sclerotherapy, phlebectomy, endovenous laser therapy, radiofrequency ablation, and surgery involving saphenous ligation and stripping. Systematic searches of medical bibliographic databases were conducted in February 2008 to identify suitable studies published from January 1988 onward. Articles were considered eligible for inclusion through the application of a predetermined protocol. Safety and effectiveness data from the comparison of two or more varicose vein procedures were extracted and analyzed. Seventeen studies, published between 2003 and 2007, were included in this review. Serious adverse events were rare. Minor adverse events were more common but generally self-limiting. All treatments displayed levels of effectiveness depending on the extent of the vein in question. Short-term advantages appeared to be associated with sclerotherapy and endovenous treatments, and long-term effectiveness was more apparent following surgical intervention. Evidence suggests conservative therapy is less effective than sclerotherapy and surgery for the treatment of varicose veins. Ligation with stripping plus phlebectomy is generally regarded as the "gold standard" for treating primary long saphenous veins. Sclerotherapy and surgery both appear to have a place in the management of varicose veins. Sclerotherapy and phlebectomy may also be more appropriate in patients with minor superficial varicose veins not related to reflux of the saphenous system or as a post- or adjunctive treatment to other procedures, such as surgery. Current evidence suggests endovenous laser therapy and radiofrequency ablation are as safe and effective as surgery, particularly in the treatment of saphenous veins. Most importantly, the type of varicose vein should govern the intervention of choice, with no single treatment universally employed.

Statins inhibit neutrophil infiltration in skeletal muscle reperfusion injury.

BACKGROUND: Neutrophil infiltration is a major determinant of ischemia-reperfusion injury (IRI). Statins improve endothelial function by elevating nitric oxide synthase activity and inhibiting adhesion molecule expression and may, therefore, inhibit IRI-induced neutrophil extravasation. Although statins are protective against myocardial IRI and stroke, a role for statins in ameliorating skeletal muscle IRI has not yet been confirmed. This study, therefore, addressed the hypothesis that simvastatin would attenuate the severity of tissue damage during skeletal muscle IRI. METHODS: Rats were administered simvastatin for 6 d before 4 h hind limb ischemia and 24 h reperfusion. Neutrophil infiltration was assessed using myeloperoxidase (MPO) assays and tissue damage by quantitative immunohistochemical analysis of collagen IV. The effect of reducing nitric oxide levels on the severity of IRI was assessed by administering the NOS inhibitor, N-Imino-L-ornithine (L-NIO), before ischemia. RESULTS: Simvastatin significantly inhibited IRI-induced MPO activity but not collagen degradation in postischemic skeletal muscle. Inhibition of nitric oxide synthase by L-NIO markedly inhibited neutrophil infiltration and protected against IRI-induced collagen degradation. When both simvastatin and L-NIO were administered before IRI, the IRI-induced elevation in MPO activity was completely inhibited. However, paradoxically, simvastatin counteracted the protective effect of L-NIO against IRI-induced collagen IV degradation. CONCLUSIONS: The inhibition by simvastatin of IRI-induced neutrophil infiltration in skeletal muscle suggests that statins may be a useful therapy to attenuate the severity of IRI but their precise mechanisms of action remains to be determined. Nitric oxide also plays a cytotoxic, rather than protective, role in mediating IRI in this model.