Long-term patient-reported outcomes among patients undergoing revascularization vs medical therapy for intermittent claudication.

OBJECTIVE: Society for Vascular Surgery guidelines recommend revascularization for patients with intermittent claudication (IC) if it can improve patient function and quality of life. However, it is still unclear if patients with IC achieve a significant functional benefit from surgery compared with medical management alone. This study examines the relationship between IC treatment modality (operative vs nonoperative optimal medical management) and patient-reported outcomes for physical function (PROMIS-PF) and satisfaction in social roles and activities (PROMIS-SA). METHODS: We identified patients with IC who presented for index evaluation in a vascular surgery clinic at an academic medical center between 2016 and 2021. Patients were stratified based on whether they underwent a revascularization procedure during follow-up vs continued nonoperative management with medication and recommended exercise therapy. We used linear mixed-effect models to assess the relationship between treatment modality and PROMIS-PF, PROMIS-SA, and ankle-brachial index (ABI) over time, clustering among repeat patient observations. Models were adjusted for age, sex, diabetes, Charlson Comorbidity Index, Clinical Frailty Score, tobacco use, and index ABI. RESULTS: A total of 225 patients with IC were identified, of which 40% (n = 89) underwent revascularization procedures (42% bypass; 58% peripheral vascular intervention) and 60% (n = 136) continued nonoperative management. Patients were followed up to 6.9 years, with an average follow-up of 5.2 ± 1.6 years. Patients who underwent revascularization were more likely to be clinically frail (P = .03), have a lower index ABI (0.55 ± 0.24 vs 0.72 ± 0.28; P < .001), and lower baseline PROMIS-PF score (36.72 ± 8.2 vs 40.40 ± 6.73; P = .01). There were no differences in patient demographics or medications between treatment groups. Examining patient-reported outcome trends over time; there were no significant differences in PROMIS-PF between groups, trends over time, or group differences over time after adjusting for covariates (P = .07, P = .13, and P =.08, respectively). However, all patients with IC significantly increased their PROMIS-SA over time (adjusted P = .019), with patients managed nonoperatively more likely to have an improvement in PROMIS-SA over time than those who underwent revascularization (adjusted P = .045). CONCLUSIONS: Patient-reported outcomes associated with functional status and satisfaction in activities are similar for patients with IC for up to 7 years, irrespective of whether they undergo treatment with revascularization or continue nonoperative management. These findings support conservative long-term management for patients with IC.

Gender differences in autonomy and performance assessments in a national cohort of vascular surgery trainees.

OBJECTIVE: Gender disparities in surgical training and assessment are described in the general surgery literature. Assessment disparities have not been explored in vascular surgery. We sought to investigate gender disparities in operative assessment in a national cohort of vascular surgery integrated residents (VIRs) and fellows (VSFs). METHODS: Operative performance and autonomy ratings from the Society for Improving Medical Professional Learning (SIMPL) application database were collected for all vascular surgery participating institutions from 2018 to 2023. Logistic generalized linear mixed models were conducted to examine the association of faculty and trainee gender on faculty and self-assessment of autonomy and performance. Data were adjusted for post-graduate year and case complexity. Random effects were included to account for clustering effects due to participant, program, and procedure. RESULTS: One hundred three trainees (n = 63 VIRs; n = 40 VSFs; 63.1% men) and 99 faculty (73.7% men) from 17 institutions (n = 12 VIR and n = 13 VSF programs) contributed 4951 total assessments (44.4% by faculty, 55.6% by trainees) across 235 unique procedures. Faculty and trainee gender were not associated with faculty ratings of performance (faculty gender: odds ratio [OR], 0.78; 95% confidence interval [CI], 0.27-2.29; trainee gender: OR, 1.80; 95% CI, 0.76-0.43) or autonomy (faculty gender: OR, 0.99; 95% CI, 0.41-2.39; trainee gender: OR, 1.23; 95% CI, 0.62-2.45) of trainees. All trainees self-assessed at lower performance and autonomy ratings as compared with faculty assessments. However, women trainees rated themselves significantly lower than men for both autonomy (OR, 0.57; 95% CI, 0.43-0.74) and performance (OR, 0.40; 95% CI, 0.30-0.54). CONCLUSIONS: Although gender was not associated with differences in faculty assessment of performance or autonomy among vascular surgery trainees, women trainees perceive themselves as performing with lower competency and less autonomy than their male colleagues. These findings suggest utility for exploring gender differences in real-time feedback delivered to and received by trainees and targeted interventions to align trainee self-perception with actual operative performance and autonomy to optimize surgical skill acquisition.

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men.

BACKGROUND: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. METHODS: We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180 days before surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. RESULTS: We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P < 0.001) that was in the lower extremity. At 5 years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P < 0.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (hazard ratio (HR):1.94, 95% confidence interval (CI):1.4-2.7; P < 0.001) compared to controls. CONCLUSIONS: This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

Impact of Perioperative Blood Transfusion in Anemic Patients Undergoing Infra Inguinal Bypass.

OBJECTIVE: Patients who present with lower extremity ischemia are frequently anemic and the optimal transfusion threshold for this cohort remains controversial. We sought to evaluate the impact of blood transfusion on postoperative major adverse cardiac events (MACE), including myocardial infarction, dysrhythmia, stroke, congestive heart failure, and 30-day mortality for these patients. METHODS: All consecutive patients who underwent infra-inguinal bypass at our institution from 2011 to 2020 were included. Perioperative red blood cell transfusion was the primary exposure, and the primary outcome was MACE. Univariate and multivariable analyses were performed to assess the impact of patient and procedural variables, including red blood cell transfusion, stratified by hemoglobin (Hgb) nadir: <7, 7-8, and >8 g/dL. RESULTS: Of the 287 patients reviewed for analysis, 146 (50.9%) had a perioperative transfusion (mean: 1.6 ± 3 units). Patients who received a transfusion had a mean nadir Hgb of 8.3 ± 1.0 g/dL, compared to 10.1 ± 1.7 g/dL without a transfusion. The overall incidence of MACE was 15.7% (45 of 287 patients). Univariate analysis demonstrated that MACE was associated with blood transfusion (P = 0.009), lower Hgb nadir (P = 0.02), and higher blood loss (P = 0.003). On multivariate analysis, transfusion was independently associated with MACE for patients with a Hgb nadir >8 g/dL (OR: 3.09; P = 0.006), but not for patients with Hgb nadir 7-8 g/dL (OR: 0.818; P = 0.77). Additionally, patients with MACE had significantly longer length of hospital stay than for patients without (13 vs. 7.7 days, P = 0.001). CONCLUSIONS: For patients undergoing infra-inguinal bypass, receiving a red blood cell transfusion with a Hgb nadir >8 g/dL was associated with a 3-fold increase in MACE, with nearly twice the length of stay. For patients with a Hgb 7-8 g/dL, transfusion did not increase or reduce the incidence of MACE. These findings suggest no benefit of blood transfusion for patients with Hgb nadir >7 g/dL and harm for Hgb >8 g/dL, however causation cannot be proven due to the retrospective nature of the study and randomized studies are needed to confirm or refute these findings.

High value care education in general surgery residency programs: A multi-institutional needs assessment.

BACKGROUND: The ACGME mandates that residency programs provide training related to high value care (HVC). The purpose of this study was to explore HVC education in general surgery residency programs. METHODS: An electronic survey was distributed to general surgery residents in geographically diverse programs. RESULTS: The response rate was 29% (181/619). Residents reported various HVC components in their curricula. Less than half felt HVC is very important for their future practice (44%) and only 15% felt confident they could lead a QI initiative in practice. Only 20% of residents reported participating in a root cause analysis and less than one-third of residents (30%) were frequently exposed to cost considerations. CONCLUSION: Few residents feel prepared to lead quality improvement initiatives, have participated in patient safety processes, or are aware of patients' costs of care. This underscores the need for improved scope and quality of HVC education and establishment of formal curricula.

Periscope sandwich stenting as an alternative to open cervical revascularization of left subclavian artery during zone 2 thoracic endovascular aortic repair.

OBJECTIVE: Revascularization of the left subclavian artery (LSA) during zone 2 thoracic endovascular aortic repair (TEVAR) maintains collateral circulation to decrease ischemic complications, including stroke, spinal cord ischemia, and upper extremity ischemia. Both open surgical and endovascular LSA revascularization techniques have been described, each with unique risks and benefits. We describe our "periscope sandwich" technique for the LSA during zone 2 TEVAR, which maintains antegrade access to the distal abdominal aorta if subsequent interventions are necessary. Technical results and short-term outcomes are compared with LSA open surgical debranching. METHODS: A single-institution retrospective review was performed for patients requiring zone 2 TEVAR with LSA revascularization by periscope sandwich technique or open surgical debranching with subclavian to carotid transposition (SCT) or carotid-subclavian bypass (CSB). The presenting aortic disease and perioperative details were recorded. Intraoperative angiography and postoperative computed tomography images were reviewed for occurrence of endoleak and branch patency. RESULTS: Between January 2013 and December 2018, the LSA was revascularized by periscope sandwich in 18 patients, SCT in 22 patients, and CSB in 13 patients. Compared with open surgical debranching, periscope sandwich had a lower median estimated blood loss (100 mL vs 200 mL for pooled SCT and CSB; P = .03) and lower median case duration (133.5 minutes vs 226 minutes; P < .001). Contrast material volume (120 mL vs 120 mL; P = .98) and fluoroscopy time (13.1 minutes vs 13.3 minutes; P = .92) did not differ significantly between the groups. There was no difference in aorta-related mortality (P = .14), and LSA patency was 100%. Median follow-up for the periscope sandwich group was 11 months, with an overall estimated 91% freedom from gutter leak at 6 months. CONCLUSIONS: LSA periscope sandwich technique provides safe and effective LSA revascularization during zone 2 TEVAR. LSA periscope sandwich can be used emergently with off-the-shelf endovascular components and facilitates future branched-fenestrated endovascular repair of thoracoabdominal aortic diseases.

Building a Framework for Self-Regulated Learning in Surgical Education: A Delphi Consensus Among Experts in Surgical Education.

OBJECTIVE: Practice-Based Learning and Improvement is a Core Competency for surgical residents. Self-regulated learning (SRL) skills are an important component of this competency, yet are rarely taught in surgical training. Before we can teach SRL skills to residents we must understand the attributes that are essential. The purpose of this study was to develop a framework for SRL for surgical trainees. DESIGN: This mixed-methods study design utilized a two-round modified-Delphi approach to develop consensus among experts in surgical education regarding SRL in surgical training. Round One included SRL constructs derived from educational, professional, and medical literature. Based upon quantitative data and thematic coding of comments, these constructs were adapted for applicability in the context of surgical residency and reorganized using a constant comparative approach. Revised constructs and groupings were presented to the expert panel in Round Two. Further survey rounds were not needed as all items in Round Two reached the predetermined consensus level of 70%. SETTING: The Delphi panel was a purposeful sample of nationally recognized experts in surgical education, including members of the Association for Surgical Education and the Association for Program Directors in Surgery. PARTICIPANTS: Thirty-eight of 42 experts (90.5%) responded to Round One, representing 29 academic and community medical systems nationally. The response rate for Round Two was 92%, 35 of the 38 Round One participants. RESULTS: In Round One, the SRL constructs were all viewed as important with median scores ranging from 50 to 99.5, on a 100-point scale. Two hundred and ninety-one comments were coded and used to refine SRL definitions into 7 domains for Round Two, which included self-awareness, task analysis, situation awareness, strategic planning, progress evaluation, learning and performance management, and goal attainment and refinement. All Round Two items reached greater than 70% agreement, and received 51 free response comments. Several key themes emerged: clinical prioritization over learning, learner's limited control, value and reliance on external resources, low use of metacognition, and complex goal orientation. Incorporation of common themes generated a novel multi-stage framework of SRL in surgical education. CONCLUSIONS: Surgical residency represents a unique learning context, in which the ideal learner is one who understands their learning environment and utilizes available resources to optimize their own learning. Experts in surgical education believe SRL skills are important in training, and a novel framework of SRL is necessary to support a learner-centered model within the demanding environment of surgical training.

Costs and training results of an objectively validated cadaveric perfusion-based internal carotid artery injury simulation during endoscopic skull base surgery.

BACKGROUND: Internal carotid artery injury (ICAI) is a rare, life-threatening complication of endoscopic endonasal approaches (EEAs). High-fidelity simulation methods exist, but optimization of the training cohort, training paradigm, and costs of simulation training remain unknown. METHODS: Using our previously validated, high-fidelity, perfused-cadaver model, participants attempted to manage a simulated ICAI. After a brief instructional video and coaching, the simulation was repeated. Training success was defined as successful ICAI control on the second attempt after failure on the initial attempt. Marginal costs were measured. RESULTS: Seventy-two surgeons participated in the standardized simulation, which lasted ≤15 minutes. The marginal cost of simulation was $275.00 per surgeon. A total of 44.4% (n = 32) succeeded on the first attempt before training (previously proficient); 44.4% (n = 32) failed the first attempt, but succeeded after training (training successes); and 11.1% (n = 8) failed both attempts. The cost per training success was $618.75. Forty-two surgeons had never treated an ICAI, with 24 becoming training successes (57.1% overall, 82.8% when excluding previously proficient surgeons). Twenty-nine had experienced a real or simulated ICAI, with 8 (27.6% overall, 72.7% excluding previously proficient surgeons) becoming training successes. The cost per training success was lowest in the ICAI-naive group ($481.25) and highest among surgeons with simulated and real ICAI experience ($1650). CONCLUSIONS: Surgeons can be trained to manage ICAI in a single, brief, low-cost session. Although all groups improved, training an ICAI-naive or resident cohort may maximize training results. A perfused-cadaver model is a reproducible, realistic, and low-cost method for training surgeons to manage life-threatening ICAI during an EEA.

Lift Sandwich Grafting Enables Transfemoral Abdominal Aortic Branch Incorporation during Endovascular Aortic Repair for Chronic Type B Aortic Dissection.

Chronic type B aortic dissections with continued aneurysmal expansion of the thoracoabdominal aorta after the initial thoracic endovascular aortic repair represent a subset of aortic pathology in which staged distal extension to seal additional septal tears can be advantageous. This approach may require incorporation of visceral or renal branches into the distal seal zone, while maintaining the possibility of further distal extension in the future. We describe a novel technique for incorporation of the celiac axis, with a branch stent graft delivered from a transfemoral approach, then lifted cranially to create an antegrade sandwich graft configuration in a 59-year-old male who presented with a complicated type B aortic dissection requiring coverage of the celiac artery. Utilizing the previous thoracic endograft as a platform for sandwich grafting, a self-expanding stent graft was deployed into the celiac artery from a femoral approach. A steerable sheath with an anchoring balloon was used to lift the stent into an up-facing snorkel position, which was subsequently sandwiched with another thoracic stent graft terminating proximal to the superior mesenteric artery. When single visceral or renal branch incorporation is desired, sandwich grafting via a "lift" technique limits the extent of aortic coverage and reduces the number of branch components, without increasing the complexity of additional visceral and renal branch incorporation during future endovascular aortic repair.

The financial value of vascular surgeons as operative consultants to other surgical specialties.

OBJECTIVE: Vascular surgeons provide assistance to other surgical specialties through planned and unplanned joint operative cases. The financial impact to the hospital of vascular surgeons as consultants in this context has yet to be quantified. We sought to quantify the financial value of services provided by consulting vascular surgeons in the performance of joint operative procedures, both planned and unplanned. METHODS: Hospital financial data were reviewed for all inpatient operative cases during a 3-year period (2013-2015). Cases in which a vascular surgeon provided operative assistance as a consultant to a nonvascular surgeon were identified and designated planned or unplanned. Contribution margin, defined as hospital revenue minus variable cost, was determined for each case. In addition, the contribution margin ratio (contribution margin divided by revenue) was determined for each cohort. Financial data for consulting cases was compared with all nonconsult cases. Data analysis was performed with nonparametric statistics. RESULTS: There were 208 cases with a primary nonvascular surgeon that required a vascular co-surgeon during the study period, 169 planned and 39 unplanned. For comparison, 19,594 nonconsult cases of other surgical specialties were identified. The median contribution margin was higher for vascular surgery consult cases compared with nonconsult cases ($14,406 [interquartile range, $63,192] vs $5491 [interquartile range $28,590]; P = .002). The overall contribution margin ratio was higher for vascular surgery consult cases (0.41) compared with control nonconsult cases (0.35). There was no difference in contribution margin and contribution margin ratio between planned and unplanned vascular surgery consult cases. CONCLUSIONS: Vascular surgeons provide essential operative assistance to other surgical specialties. This operative assistance is frequent and provides significant financial value, with high contribution margin and contribution margin ratio. Vascular surgeons, as consulting surgeons, enable the completion of highly complex cases and in this capacity provide significant financial value to the hospital.

Impact of proximal seal zone length and intramural hematoma on clinical outcomes and aortic remodeling after thoracic endovascular aortic repair for aortic dissections.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) has become standard treatment of complicated type B aortic dissections (TBADs). Whereas adequate proximal seal is a fundamental requisite for TEVAR, what constitutes "adequate" in dissections and its impact on outcomes remain unclear. The goal of this study was to describe the proximal seal zone achieved with associated clinical outcomes and aortic remodeling. METHODS: A retrospective review was performed of TEVARs for TBAD at a single institution from 2006 to 2016. Three-dimensional centerline analysis of preoperative computed tomography was used to identify the primary entry tear, dissection extent, distances between arch branches, and intramural hematoma (IMH) involvement of the proximal seal zone. Patients were categorized into group A, those with proximal extent of seal zone in IMH/dissection-free aorta, and group B, those with landing zone entirely within IMH. Clinical outcomes including retrograde type A dissection (RTAD), death, and aortic reinterventions were recorded. Postoperative computed tomography scans were analyzed for remodeling of the true and false lumen volumes of the thoracic aorta. RESULTS: Seventy-one patients who underwent TEVAR for TBAD were reviewed. Indications for TEVAR included malperfusion, aneurysm, persistent pain, rupture, uncontrolled hypertension, and other. Mean follow-up was 14 months. In 26 (37%) patients, the proximal extent of the seal zone was without IMH, whereas 45 (63%) patients had proximal seal zone entirely in IMH. Proximal seal zone of 2-cm IMH-free aorta was achieved in only six (8.5%) patients. Review of arch anatomy revealed that to create a 2-cm landing zone of IMH-free aorta, 31 (43.7%) patients would have required coverage of all three arch branch vessels. Postoperatively, two patients developed image-proven RTADs requiring open repair, and one patient had sudden death. All three of these patients had TEVAR with the proximal seal zone entirely in IMH. No RTADs occurred in patients whose proximal seal zone involved healthy aortic segment. At 24 months, overall survival was 93% and freedom from aorta-related mortality was 97.4%. Complete thoracic false lumen thrombosis was seen in 46% of patients. Aortic remodeling, such as true lumen expansion, false lumen regression, and false lumen thrombosis, was similar in both groups of patients. CONCLUSIONS: Whereas achieving 2 cm of IMH-free proximal seal zone during TEVAR for TBAD would often require extensive arch branch coverage, failure to achieve any IMH-free proximal seal zone may be associated with higher incidence of RTAD. The length and quality of the proximal seal zone did not affect the subsequent aortic remodeling after TEVAR.

Focused Resident Education and Engagement in Quality Improvement Enhances Documentation, Shortens Hospital Length of Stay, and Creates a Culture of Continuous Improvement.

PURPOSE: System-based practice with an emphasis on quality improvement (QI) is a recent initiative for the American College of Surgeons and a core-competency for surgical trainees. Few surgical training programs have a curriculum for hospital-based QI. METHODS: Our vascular surgery service implemented several QI initiatives focused on decreasing length of stay (LOS) by targeting resident education and engagement. Residents were educated on terminology and processes impacting hospital and CMS QI metrics such as Medicare geometric mean LOS (CMS GMLOS) and diagnostic-related groups (DRG) with complication or comorbidity (CC/MCC) coding. LOS initiatives focused on identifying, tracking and removing avoidable perioperative delays, and improving accuracy of clinical documentation. Residents were given specific roles in QI initiatives and the impact on LOS was quantified. Patients' CMS GMLOS were compared to actual LOS during daily rounds, with confirmation that resident progress notes contained thorough and accurate documentation of diagnoses, comorbidities, and complications. Ten minutes during weekly preoperative conferences were dedicated to ongoing QI, with LOS metrics for the inpatient census presented by trainees and reviewed by attendings. Feedback was given addressing barriers to avoidable delays and impact on LOS. Data for July 2016-June 2017 (FY17) was compared to preimplementation baseline data (FY16) for vascular discharges overall. Accurate documentation of acuity was evaluated with in-depth review of notes and overall case mix index. RESULTS: Within the first year of implementation, overall vascular admissions demonstrated a 21% reduction in LOS, closing the gap between observed LOS and expected CMS GMLOS, from 2.1days to 0.5days on average. Documentation improved, with a shift in 24% of DRGs to accurately reflect CC/MCC. Overall case mix index increased by 10%, from 3.07 to 3.37. CONCLUSIONS: A culture of continuous quality improvement can be created with the establishment of a QI infrastructure that educates and involves trainees as stakeholders. Assigning discrete roles to increase resident accountability supports both formal and informal resident education that can substantially impact hospital benchmarking metrics.

Use of Double-Barrel Gore Excluder Bifurcated Endografts for Renal Artery Incorporation in an Urgent Endovascular Repair of a Thoracoabdominal Aortic Aneurysm.

Total endovascular repair of a thoracoabdominal aortic aneurysm (TAAA) in an urgent setting requires an advanced endovascular skill set and an innovative approach. We describe a novel technique of treating a symptomatic Crawford extent 4 TAAA with a combination of multilayered parallel endografting and double-barrel Gore Excluder bifurcated endografts to achieve complete aneurysm exclusion with visceral and bilateral renal artery incorporation. A 75-year-old male presented with a symptomatic 10 cm Crawford extent 4 TAAA. Severe medical comorbidities, including chronic obstructive lung disease and cardiac arrhythmia, as well as prior open infrarenal aortic aneurysm repair made him high risk for an urgent re-do open repair. His previous open infrarenal aortic replacement created a short distance between the lowest renal artery and the flow divider of the aortic graft, which posed a challenge in using a bifurcated aortic endograft as a distal component of the previously described multilayered parallel endografting. Therefore, celiac and superior mesenteric arteries were treated with a multilayered parallel grafting configuration, whereas bilateral renal arteries were incorporated using side-by-side bifurcated modular stent grafts in double-barrel fashion. Contralateral gates served as cuffs for renal artery branch stent grafts, and ipsilateral limbs were deployed within the common iliac arteries. The patient recovered well and was discharged 3 days after repair. Follow-up imaging at 1 month demonstrated patent celiac, superior mesenteric, and bilateral renal artery flow, with no endoleak and stable aneurysm sac. The patient is doing well clinically 1 year after the operation.

Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke.

Macrophages are viewed as amplifiers of ischemic brain injury, but the origin of injury-producing macrophages is poorly defined. The role of resident brain macrophages-microglial cells-in stroke remains controversial. To determine whether microglial cells exert injurious effects after neonatal focal stroke, we selectively depleted these cells with intracerebral injection of liposome-encapsulated clodronate before transient middle cerebral artery occlusion in postnatal day 7 rats. Phagocytosis of apoptotic neurons by activated microglia was poor in animals with unmanipulated microglia, and depletion of these cells did not increase the number of apoptotic neurons. Lack of microglia increased the brain levels of several cytokines and chemokines already elevated by ischemia-reperfusion, and also increased the severity and volume of injury, suggesting that microglial cells contribute to endogenous protection during the subacute injury phase. Then, to determine whether accumulation of reactive oxygen species in microglia adversely affects phagocytosis of dying neurons and contributes to injury, we delivered reduced glutathione (GSH) into microglia, again using liposomes. Remarkably, pharmacologically increased intracellular GSH concentrations in microglia induced superoxide accumulation in lipid rafts in these cells, further increased the brain levels of macrophage chemoattractants, and exacerbated injury. Together, these data show that microglia are part of the endogenous defense mechanisms and that, while antioxidants can protect the injured neonatal brain, high levels of reducing equivalents in activated microglia, GSH, trigger superoxide production, favor the reorganization of lipids, amplify local inflammation and exacerbate injury.