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Patterns of Inflammation in Patients with Hyperglycemia after Vascular Surgery
VASCULAR SURGERY
have several comorbidities. With advancements in endovascular technology, more and more patients with peripheral arterial disease are being offered endovascular therapy, which are generally same day operations. The purpose of this study is to review the factors associated with readmission after lower extremity endovascular interventions.
Deletion of Myeloid Receptor for Advanced Glycation End Products (RAGE) Prevents Formation of Abdominal Aortic Aneurysm (AAA) in a Murine Model Kathleen G Raman, MD, FACS, Terri L Ennis, Ann Marie Schmidt, MD, Robert W Thompson, MD, FACS Washington University School of Medicine, Saint Louis, MO, New York University Langone School of Medicine, New York, NY
METHODS: The 2013 American College of Surgeons-NSQIP database was used for this study. Preoperative and intraoperative characteristics of patients undergoing lower extremity endovascular surgery were assessed. Multivariate logistic regression analysis was used to determine risk factors for hospital readmission within 30 days after surgery.
INTRODUCTION: AAA pathophysiology involves chronic inflammation and medial elastic fiber destruction. RAGE upregulates inflammatory and tissue injury-provoking genes. We previously identified increased RAGE expression in human AAAs and showed that absence of RAGE by genetic deletion/pharmacologic blockade prevented AAA. To evaluate if this effect was due to myeloid RAGE expression, we performed bone marrow (BM) transplantation in an experimental mouse model of AAA.
RESULTS: A total of 1,096 patients (males 61%, females 39%) underwent lower extremity endovascular interventions during year 2013. Indications for operations included: asymptomatic (5%), claudication (40%), rest pain (19%) and tissue loss (36%). A total of 145 patients (13.23%) were readmitted within 30 days of index operation. Risk factors, associated with readmission included: septic shock (OR¼ 6.3), return to operation room (OR¼4.87), presence of open wounds in leg (OR ¼ 3.5), need for major intervention on the treated arterial segment (OR¼ 3.4), renal insufficiency (OR¼ 2.8), COPD (OR ¼ 2.7) and hypertension (OR ¼ 2.4) (p <0.05).
METHODS: C57BL/6 (WT) and RAGE null (RKO) mice were lethally irradiated (950 cGy) and rescued 6 hours later with either WT or RKO donor BM. Mice recovered for 8 weeks post-transplantation and then underwent transient elastase perfusion to induce AAAs. Aortic diameter (AD) was measured at perfusion and sacrifice, with AAAs defined as>100% increase from pre-perfusion AD. Histological analysis of day 14 tissues assessed extent of aortic wall inflammation (H&E) and elastin degradation (VVG). Blinded observers graded inflammation and elastin degradation using a scale of 1-4 (1¼25% and 4¼>75% inflammation/degradation).
CONCLUSIONS: Readmission after lower extremity endovascular intervention is a serious complication. Septic shock, return to operating room, presence of open wounds, need for re-intervention, renal insufficiency, and hypertension are independent risk factors for hospital readmission. Return to operating room is associated with a 4.87 fold increase in hospital readmission.
RESULTS: After lethal irradiation/rescue, mean AD was significantly lower in WT rescued with RKO BM (n¼22) vs RKO mice rescued with WT BM (n¼19) 0.830.01 vs 0.940.02 cm, p<0.001. BM transplantation from WT-WT (n¼11) yielded significantly larger AD vs RKO-RKO (n¼10) 1.150.03 vs 0.840.01 cm, p<0.001. WT-WT transplantation revealed significantly larger AD vs RKO-WT, p<0.001. Histological analysis revealed significantly less inflammation and elastin degradation in WT mice reconstituted with RKO BM, p<0.001.
Patterns of Inflammation in Patients with Hyperglycemia after Vascular Surgery Rachel Thompson, Lucas W Thornblade, MD, Sara Khor, David R Flum, MD, FACS, Michael Sobel, MD VA Puget Sound Health Care System, Seattle, WA, University of Nebraska Medical Center, Omaha, NE, University of Washington Medical Center, Seattle, WA
CONCLUSIONS: Myeloid RAGE is functionally important in aneurysmal degeneration in a mouse model of AAAs. The absence of RAGE suppresses AAA formation by reducing aortic wall inflammation and proteolytic activity, which promotes medial elastin preservation. Further studies will identify at which stage in AAA formation RAGE activation becomes functionally important.
INTRODUCTION: Perioperative hyperglycemia is associated with poor outcomes. Compared to patients with diabetes, patients without diabetes have worse surgical outcomes in the setting of hyperglycemia. One possible explanation could be that hyperglycemia is associated with greater inflammation among patients without diabetes. This study evaluated the relationship of inflammatory markers and hyperglycemia.
Factors Predicting Hospital Readmission after Lower Extremity Endovascular Interventions Faisal Aziz, MBBS, FACS, Amy B Reed, MD, FACS Penn State University, Hershey, PA
METHODS: Vascular surgery patients undergoing lower extremity bypass were prospectively enrolled at the VA Puget Sound Health Care System between 2007 and 2015. Inflammatory markers including IL-6 and CRP were measured for change from before to after surgery. Blood glucose levels were gathered retrospectively.
INTRODUCTION: Hospital readmissions after surgical operations are preventable events. Patients with peripheral arterial disease
e61
http://dx.doi.org/10.1016/j.jamcollsurg.2016.08.161 ISSN 1072-7515/16
e62
J Am Coll Surg
Scientific Forum: 2016 Clinical Congress
RESULTS: Among 91 patients (mean age, 64 years; 45% with diabetes), the mean elevation in glucose from preoperative to POD1 was similar between patients with and without diabetes (16 vs 15 mg/dL). Both groups showed a rise in CRP and IL-6 by POD1; however, this rise was not different between those with and without diabetes. After linear regression, rise in either inflammatory marker by POD1 was not associated with hyperglycemia. CONCLUSIONS: Perioperative hyperglycemia was not associated with the elevations seen in IL-6 and CRP by POD1 in this cohort. The mechanism linking hyperglycemia and poor outcomes remains unclear. These findings weaken the likelihood that inflammation is the unifying factor explaining why patients without diabetes have worse outcomes in the setting of hyperglycemia. Other potential factors to consider include: possible under-diagnosis of diabetes and under-treatment with insulin.
Pulsatility Inhibits Non-Pulsatile Laminar Flow Induced-Degradation of IkBa in Endothelial Cells Jiro Kurita, MD, Erik Benitez, MD, Bauer E Sumpio, MD, FACS Nippon Medical School, Tokyo, Japan INTRODUCTION: Nuclear factor-kB (NFkB), which is crucial in regulating inflammatory pathway of atherosclerosis is inhibited by IkBa protein. Phosphorylation of IkBa causes activation of NFkB by degrading IkBa via ubiquitin proteasome system (UPS). Shear stress is known to effect on activation of NFkB but the impact of the different types of mechanical forces are not well-defined. The aim of this study was to investigate the mechanism of the degradation of IkBa in endothelial cells (ECs) exposed to laminar flow with the presence or absence of pulsatility. METHODS: Confluent, serum starved bovine aortic ECs were subjected to 4h of non-pulsatile laminar flow (LF) or pulsatile forward flow (PF) with or without MG132, an UPS inhibitor. Western blot analysis of total, phospho-IkBa, intra-nuclear, and -cytoplasmic NFkB was performed. IkBa activity was based on the ratio of phosphorylated to total IkBa. Fold change compared to static control at 0 h was calculated. RESULTS: Exposure to LF for 4h significantly decreased the levels of IkBa (52.021.7%; p<0.05) but not to PF (86.28.9%; NS). But addition of MG132 failed to inhibit the LF induced-decrease in the level of IkBa (46.518.2%; p<0.05). LF significantly increased the level of p/t-IkBa (5.03.6; p<0.05) but not PF (2.10.9; NS). However, not only LF but also PF did not cause any change of the level of NFkB in Cytoplasm or Nuclear. CONCLUSIONS: The localization of NFkB was stable in ECs exposed to unidirectional flow in spite of the presence or absence of pulsatility. However, the pulsatility produced different effects on activity of IkBa. The degradation of IkBa under LF occurs via an alternative, UPS-independent pathway.
Regional Variation in the Cost of Infra-Inguinal Lower Extremity Bypass Surgery: National Study Besma Nejim, MBChB, MPH, Tammam Obeid, MD, Isibor J Arhuidese, MD, MPH, Satinderjit S Locham, MD, Oluwadamilola O Onasanya, MBChB, MPH, Joseph K Canner, MHS, Mahmoud Malas, MD, MHS, FACS Johns Hopkins University School of Medicine, Baltimore, MD INTRODUCTION: Infra-inguinal lower extremity bypass (LEB) remains the gold standard revascularization procedure for lower limbs. The cost of LEB substantially varies based on patient characteristics and comorbidities. We sought to assess regional variation in cost using a large national database. METHODS: We analyzed all patients who underwent LEB in the Premier database (2009-2015). Patients with concurrent cardiac surgery were excluded. Multivariable linear regression model was used to examine total in-hospital cost adjusting for patient demographics, clinical characteristics and hospital factors. RESULTS: A total of 32,224 patients were identified. Critical limb ischemia was present in 39.3% of the cohort. Mean age was 66.4 (12.7) years. The average total in-hospital LEB cost was Table. Multivariable Linear Regression Analysis of Total InHospital Cost Adjusted for Inflation
Factors
Age>65 vs age65 years female vs male sex Race White Black Hispanic Other Regions South Midwest Northeast West Teaching vs nonteaching hospital Urban vs rural hospital Critical Limb Ischemia vs claudicants Major amputation History of CHF
Adjusted mean difference, USD
95% Confidence Interval
p Value
713
495 e 930
<0.001
506
285 e 728
<0.001
Ref 2,245 3,958 612
1,935 e 2,552 2,613 e 5,302 296 e 927
<0.001 <0.001 <0.001
Ref 2,183 4,961 5,417 537
1,886 4,646 5,075 294
e e e e
<0.001 <0.001 <0.001 <0.001
-241 2,216
36,257 5,897
2,480 5,276 5,760 780
(-590) e 109 1,996 e 2,435
0.177 <0.001
35,245 e 37,269 <0.001 5,450 e 6,344
<0.001
Total n¼28, 832 after excluding influential points by Tukey Method.
have several comorbidities. With advancements in endovascular technology, more and more patients with peripheral arterial disease are being offered endovascular therapy, which are generally same day operations. The purpose of this study is to review the factors associated with readmission after lower extremity endovascular interventions.
Deletion of Myeloid Receptor for Advanced Glycation End Products (RAGE) Prevents Formation of Abdominal Aortic Aneurysm (AAA) in a Murine Model Kathleen G Raman, MD, FACS, Terri L Ennis, Ann Marie Schmidt, MD, Robert W Thompson, MD, FACS Washington University School of Medicine, Saint Louis, MO, New York University Langone School of Medicine, New York, NY
METHODS: The 2013 American College of Surgeons-NSQIP database was used for this study. Preoperative and intraoperative characteristics of patients undergoing lower extremity endovascular surgery were assessed. Multivariate logistic regression analysis was used to determine risk factors for hospital readmission within 30 days after surgery.
INTRODUCTION: AAA pathophysiology involves chronic inflammation and medial elastic fiber destruction. RAGE upregulates inflammatory and tissue injury-provoking genes. We previously identified increased RAGE expression in human AAAs and showed that absence of RAGE by genetic deletion/pharmacologic blockade prevented AAA. To evaluate if this effect was due to myeloid RAGE expression, we performed bone marrow (BM) transplantation in an experimental mouse model of AAA.
RESULTS: A total of 1,096 patients (males 61%, females 39%) underwent lower extremity endovascular interventions during year 2013. Indications for operations included: asymptomatic (5%), claudication (40%), rest pain (19%) and tissue loss (36%). A total of 145 patients (13.23%) were readmitted within 30 days of index operation. Risk factors, associated with readmission included: septic shock (OR¼ 6.3), return to operation room (OR¼4.87), presence of open wounds in leg (OR ¼ 3.5), need for major intervention on the treated arterial segment (OR¼ 3.4), renal insufficiency (OR¼ 2.8), COPD (OR ¼ 2.7) and hypertension (OR ¼ 2.4) (p <0.05).
METHODS: C57BL/6 (WT) and RAGE null (RKO) mice were lethally irradiated (950 cGy) and rescued 6 hours later with either WT or RKO donor BM. Mice recovered for 8 weeks post-transplantation and then underwent transient elastase perfusion to induce AAAs. Aortic diameter (AD) was measured at perfusion and sacrifice, with AAAs defined as>100% increase from pre-perfusion AD. Histological analysis of day 14 tissues assessed extent of aortic wall inflammation (H&E) and elastin degradation (VVG). Blinded observers graded inflammation and elastin degradation using a scale of 1-4 (1¼25% and 4¼>75% inflammation/degradation).
CONCLUSIONS: Readmission after lower extremity endovascular intervention is a serious complication. Septic shock, return to operating room, presence of open wounds, need for re-intervention, renal insufficiency, and hypertension are independent risk factors for hospital readmission. Return to operating room is associated with a 4.87 fold increase in hospital readmission.
RESULTS: After lethal irradiation/rescue, mean AD was significantly lower in WT rescued with RKO BM (n¼22) vs RKO mice rescued with WT BM (n¼19) 0.830.01 vs 0.940.02 cm, p<0.001. BM transplantation from WT-WT (n¼11) yielded significantly larger AD vs RKO-RKO (n¼10) 1.150.03 vs 0.840.01 cm, p<0.001. WT-WT transplantation revealed significantly larger AD vs RKO-WT, p<0.001. Histological analysis revealed significantly less inflammation and elastin degradation in WT mice reconstituted with RKO BM, p<0.001.
Patterns of Inflammation in Patients with Hyperglycemia after Vascular Surgery Rachel Thompson, Lucas W Thornblade, MD, Sara Khor, David R Flum, MD, FACS, Michael Sobel, MD VA Puget Sound Health Care System, Seattle, WA, University of Nebraska Medical Center, Omaha, NE, University of Washington Medical Center, Seattle, WA
CONCLUSIONS: Myeloid RAGE is functionally important in aneurysmal degeneration in a mouse model of AAAs. The absence of RAGE suppresses AAA formation by reducing aortic wall inflammation and proteolytic activity, which promotes medial elastin preservation. Further studies will identify at which stage in AAA formation RAGE activation becomes functionally important.
INTRODUCTION: Perioperative hyperglycemia is associated with poor outcomes. Compared to patients with diabetes, patients without diabetes have worse surgical outcomes in the setting of hyperglycemia. One possible explanation could be that hyperglycemia is associated with greater inflammation among patients without diabetes. This study evaluated the relationship of inflammatory markers and hyperglycemia.
Factors Predicting Hospital Readmission after Lower Extremity Endovascular Interventions Faisal Aziz, MBBS, FACS, Amy B Reed, MD, FACS Penn State University, Hershey, PA
METHODS: Vascular surgery patients undergoing lower extremity bypass were prospectively enrolled at the VA Puget Sound Health Care System between 2007 and 2015. Inflammatory markers including IL-6 and CRP were measured for change from before to after surgery. Blood glucose levels were gathered retrospectively.
INTRODUCTION: Hospital readmissions after surgical operations are preventable events. Patients with peripheral arterial disease
e61
http://dx.doi.org/10.1016/j.jamcollsurg.2016.08.161 ISSN 1072-7515/16
e62
J Am Coll Surg
Scientific Forum: 2016 Clinical Congress
RESULTS: Among 91 patients (mean age, 64 years; 45% with diabetes), the mean elevation in glucose from preoperative to POD1 was similar between patients with and without diabetes (16 vs 15 mg/dL). Both groups showed a rise in CRP and IL-6 by POD1; however, this rise was not different between those with and without diabetes. After linear regression, rise in either inflammatory marker by POD1 was not associated with hyperglycemia. CONCLUSIONS: Perioperative hyperglycemia was not associated with the elevations seen in IL-6 and CRP by POD1 in this cohort. The mechanism linking hyperglycemia and poor outcomes remains unclear. These findings weaken the likelihood that inflammation is the unifying factor explaining why patients without diabetes have worse outcomes in the setting of hyperglycemia. Other potential factors to consider include: possible under-diagnosis of diabetes and under-treatment with insulin.
Pulsatility Inhibits Non-Pulsatile Laminar Flow Induced-Degradation of IkBa in Endothelial Cells Jiro Kurita, MD, Erik Benitez, MD, Bauer E Sumpio, MD, FACS Nippon Medical School, Tokyo, Japan INTRODUCTION: Nuclear factor-kB (NFkB), which is crucial in regulating inflammatory pathway of atherosclerosis is inhibited by IkBa protein. Phosphorylation of IkBa causes activation of NFkB by degrading IkBa via ubiquitin proteasome system (UPS). Shear stress is known to effect on activation of NFkB but the impact of the different types of mechanical forces are not well-defined. The aim of this study was to investigate the mechanism of the degradation of IkBa in endothelial cells (ECs) exposed to laminar flow with the presence or absence of pulsatility. METHODS: Confluent, serum starved bovine aortic ECs were subjected to 4h of non-pulsatile laminar flow (LF) or pulsatile forward flow (PF) with or without MG132, an UPS inhibitor. Western blot analysis of total, phospho-IkBa, intra-nuclear, and -cytoplasmic NFkB was performed. IkBa activity was based on the ratio of phosphorylated to total IkBa. Fold change compared to static control at 0 h was calculated. RESULTS: Exposure to LF for 4h significantly decreased the levels of IkBa (52.021.7%; p<0.05) but not to PF (86.28.9%; NS). But addition of MG132 failed to inhibit the LF induced-decrease in the level of IkBa (46.518.2%; p<0.05). LF significantly increased the level of p/t-IkBa (5.03.6; p<0.05) but not PF (2.10.9; NS). However, not only LF but also PF did not cause any change of the level of NFkB in Cytoplasm or Nuclear. CONCLUSIONS: The localization of NFkB was stable in ECs exposed to unidirectional flow in spite of the presence or absence of pulsatility. However, the pulsatility produced different effects on activity of IkBa. The degradation of IkBa under LF occurs via an alternative, UPS-independent pathway.
Regional Variation in the Cost of Infra-Inguinal Lower Extremity Bypass Surgery: National Study Besma Nejim, MBChB, MPH, Tammam Obeid, MD, Isibor J Arhuidese, MD, MPH, Satinderjit S Locham, MD, Oluwadamilola O Onasanya, MBChB, MPH, Joseph K Canner, MHS, Mahmoud Malas, MD, MHS, FACS Johns Hopkins University School of Medicine, Baltimore, MD INTRODUCTION: Infra-inguinal lower extremity bypass (LEB) remains the gold standard revascularization procedure for lower limbs. The cost of LEB substantially varies based on patient characteristics and comorbidities. We sought to assess regional variation in cost using a large national database. METHODS: We analyzed all patients who underwent LEB in the Premier database (2009-2015). Patients with concurrent cardiac surgery were excluded. Multivariable linear regression model was used to examine total in-hospital cost adjusting for patient demographics, clinical characteristics and hospital factors. RESULTS: A total of 32,224 patients were identified. Critical limb ischemia was present in 39.3% of the cohort. Mean age was 66.4 (12.7) years. The average total in-hospital LEB cost was Table. Multivariable Linear Regression Analysis of Total InHospital Cost Adjusted for Inflation
Factors
Age>65 vs age65 years female vs male sex Race White Black Hispanic Other Regions South Midwest Northeast West Teaching vs nonteaching hospital Urban vs rural hospital Critical Limb Ischemia vs claudicants Major amputation History of CHF
Adjusted mean difference, USD
95% Confidence Interval
p Value
713
495 e 930
<0.001
506
285 e 728
<0.001
Ref 2,245 3,958 612
1,935 e 2,552 2,613 e 5,302 296 e 927
<0.001 <0.001 <0.001
Ref 2,183 4,961 5,417 537
1,886 4,646 5,075 294
e e e e
<0.001 <0.001 <0.001 <0.001
-241 2,216
36,257 5,897
2,480 5,276 5,760 780
(-590) e 109 1,996 e 2,435
0.177 <0.001
35,245 e 37,269 <0.001 5,450 e 6,344
<0.001
Total n¼28, 832 after excluding influential points by Tukey Method.