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Competing Interests: The authors report no conflicts of interest.

Purpose: To examine rates of acute infectious endophthalmitis after pars plana vitrectomy (PPV) in eyes that received intraoperative subconjunctival antibiotics versus eyes that did not., Methods: A retrospective, nonrandomized, comparative case series of 18,886 consecutive cases of transconjunctival 23-, 25-, and 27-gauge PPV over a 5-year period was performed. The impact of prophylactic intraoperative subconjunctival antibiotics on the development of acute infectious postoperative endophthalmitis was examined., Results: Of 18,886 cases of PPV, 14,068 (74.5%) received intraoperative subconjunctival antibiotics, whereas 4,818 (25.5%) did not. Sixteen cases (0.085%, 1/1,176) of post-PPV endophthalmitis were identified. The incidence of endophthalmitis in eyes that received subconjunctival antibiotics was 0.078% (11/14,068 cases, 1/1,282), whereas the incidence in those that did not receive subconjunctival antibiotics was 0.10% (5/4,818 cases, 1/1,000). No statistically significant difference was identified in the incidence of endophthalmitis between those that received subconjunctival antibiotics and those that did not (P = 0.598). Microbial culture was performed in 11 cases with 6 culture-positive cases (5/8 cases that received subconjunctival antibiotics and 1/3 cases that did not)., Conclusion: Prophylactic subconjunctival antibiotics were not associated with a significantly reduced rate of post-PPV endophthalmitis. With consideration of emerging multidrug-resistant bacteria, routine prophylactic subconjunctival antibiotics may not be justified.

Background: Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics., Methods: A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death., Results: Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% ( P =0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk., Conclusions: Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264., (© 2017 The Authors.)

Background: Acute aortic dissection (AAD) is a life-threatening vascular disease without effective pharmaceutical therapy. Matrix metalloproteinases (MMPs) are implicated in the development of chronic vascular diseases including aneurysm, but the key effectors and mechanism of action remain unknown. To define further the role of MMPs in AAD, we screened circulating MMPs in AAD patients, and then generated a novel mouse model for AAD to characterize the mechanism of action., Methods and Results: MMP9 and angiotensin II were elevated significantly in blood samples from AAD patients than in those from the patients with nonruptured chronic aortic aneurysm or healthy volunteers. Based on the findings, we established a novel AAD model by infusing angiotensin II to immature mice that had been received a lysyl oxidase inhibitor, β-aminopropionitrile monofumarate. AAD was developed successfully in the thoracic aorta by angiotensin II administration to β-aminopropionitrile monofumarate-treated wild-type mice, with an incidence of 20%, 80%, and 100% after 6, 12, and 24 hours, respectively. Neutrophil infiltrations were observed in the intima of the thoracic aorta, and the overexpression of MMP9 in the aorta was demonstrated by reverse transcription polymerase chain reaction, gelatin zymography, and immunohistochemistry. The incidence of AAD was reduced significantly by 40% following the administration of an MMP inhibitor and was almost blocked completely in MMP(-/-) mice without any influence on neutrophil infiltration. Neutrophil depletion by injection of anti-granulocyte-differentiation antigen-1 (anti-Gr-1) antibody also significantly decreased the incidence of AAD., Conclusions: These data suggest that AAD is initiated by neutrophils that have infiltrated the aortic intima and released MMP9 in response to angiotensin II.

Objective: It is hypothesized that a male predominance, similar to that in humans, persists in a rodent model of experimental abdominal aortic aneurysm (AAA) via alterations in matrix metalloproteinases (MMPs)., Methods and Results: Group I experiments were as follows: elastase perfusion of the infrarenal aorta was performed in male (M) and female (F) rats. At 14 days, aortas were harvested for immunohistochemistry, real-time polymerase chain reaction (PCR), and zymography. Group II experiments were the following: abdominal aorta was transplanted from F or M donors into F or M recipients. At 14 days, rodents that had undergone transplantation underwent elastase perfusion. In group III, male rats were given estradiol or sham 5 days before elastase perfusion. In group I, M rats had larger AAAs with higher frequency than did F rats. M rat aortas had more significant macrophage infiltrates and increased matrix metalloproteinase (MMP)-9 production and activity. In group II, M-to-M aortic transplants uniformly developed aneurysms after elastase perfusion, whereas F-to-F aortic transplants remained resistant to aneurysm formation. F aortas transplanted into M recipients, however, lost aneurysm resistance. In group III, estradiol-treated rats demonstrated smaller aneurysms and less macrophage infiltrate and MMP-9 compared with M controls after elastase., Conclusions: These data provide evidence of gender-related differences in AAA development, which may reflect an estrogen-mediated reduction in macrophage MMP-9 production.

Unlabelled: The objective of this study was to evaluate the efficacy of nicardipine, a dihydropyridine calcium channel antagonist, administered as an IV bolus dose to acutely decrease arterial pressure in anesthetized cardiac surgical patients. We performed a double-blind, randomized, self-controlled, dose-ranging study in 40 adult cardiac surgical patients to determine the pharmacokinetics and pharmacodynamics of nicardipine 0.25 mg, 0.50 mg, 1.00 mg, and 2.00 mg administered as an IV bolus. Transesophageal echocardiography was used to assess left ventricular preload, afterload, and global systolic function. Plasma nicardipine concentration was measured using high-performance liquid chromatography. Nicardipine selectively decreased arterial pressure in a dose-dependent manner with a maximum response within 100 s and recovery to half the maximum response within 3-7 min without associated changes in heart rate. The decreases in arterial pressure were associated with only small decreases in left ventricular end-systolic wall stress and small increases in global left ventricular systolic function without changes in left ventricular end-diastolic cavity area or cardiac output. The time course for nicardipine bolus was consistent with a two-compartment pharmacokinetic model with rapid redistribution from a small central compartment., Implications: Nicardipine was effective for selectively decreasing arterial blood pressure acutely, but had no effects on ventricular preload or cardiac output. The absence of dose-dependent changes in cardiac output, left ventricular systolic performance, and left ventricular afterload despite significant decreases in arterial pressure suggested that nicardipine had a small negative inotropic action.

Unlabelled: Retrograde cerebral perfusion (RCP) potentially delivers metabolic substrate to the brain during surgery using hypothermic circulatory arrest (HCA). Serial measurements of O2 extraction ratio (OER), PCO2, and pH from the RCP inflow and outflow were used to determine the time course for O2 delivery in 28 adults undergoing aortic reconstruction using HCA with RCP. HCA was instituted after systemic cooling on cardiopulmonary bypass for 3 min after the electroencephalogram became isoelectric. RCP with oxygenated blood at 10 degrees C was administered at an internal jugular venous pressure of 20-25 mm Hg. Serial analyses of blood oxygen, carbon dioxide, pH, and hemoglobin concentration were made in samples from the RCP inflow (superior vena cava) and outflow (innominate and left carotid arteries) at different times after institution of RCP. Nineteen patients had no strokes, five patients had preoperative strokes, and four patients had intraoperative strokes. In the group of patients without strokes, HCA with RCP was initiated at a mean nasopharyngeal temperature of 14.3 degrees C with mean RCP flow rate of 220 mL/min, which lasted 19-70 min. OER increased over time to a maximal detected value of 0.66 and increased to 0.5 of its maximal detected value 15 min after initiation of HCA. The RCP inflow-outflow gradient for PCO2 (slope 0.73 mm Hg/min; P < 0.001) and pH (slope 0.007 U/min; P < 0.001) changed linearly over time after initiation of HCA. In the group of patients with preoperative or intraoperative strokes, the OER and the RCP inflow-outflow gradient for PCO2 changed significantly more slowly over time after HCA compared with the group of patients without strokes. During RCP, continued CO2 production and increased O2 extraction over time across the cerebral vascular bed suggest the presence of viable, but possibly ischemic tissue. Reduced cerebral metabolism in infarcted brain regions may explain the decreased rate of O2 extraction during RCP in patients with strokes., Implications: Examining the time course of oxygen extraction, carbon dioxide production, and pH changes from the retrograde cerebral perfusate provided a means to assess metabolic activity during hypothermic circulatory arrest.

Background: Measuring the effects of intraaortic balloon counterpulsation (IABP) in single cardiac beats may permit an improved understanding of the physiologic mechanisms by which IABP improves the circulation. The objective of the study was to use trans- esophageal echocardiography in combination with hemodynamic measurements to test the hypothesis that IABP improves global left ventricular systolic function selectively in the IABP-augmented cardiac beats by acutely decreasing left ventricular afterload., Methods: Twenty-seven studies in which the IABP-to-R wave trigger ratio was serially changed from 1:1, 1:2, 1:4, 0:1 (IABP off) and back to 1:1 were performed in 20 anesthetized cardiac surgical patients during IABP support. Left ventricular short-axis end-diastolic cross-sectional area, end-systolic area, mean end-systolic wall thickness, and ejection time were measured by transesophageal echocardiography at the midpapillary muscle level. Aortic pressure was measured simultaneously from the central lumen of the intraaortic balloon catheter. These measurements were used to calculate the fractional area change, end-systolic meridional wall stress, and heart rate-corrected velocity of circumferential fiber shortening. The echocardiographic and hemodynamic parameters of left ventricular preload, afterload, and systolic function immediately after balloon deflation (IABP-augmented cardiac beats) were compared to the parameters measured during nonaugmented cardiac beats to determine the beat-to-beat effects of IABP on left ventricular function., Results: IABP-augmented cardiac beats had a decreased systolic arterial pressure and end-systolic meridional wall stress and increased diastolic blood pressure, fractional area change, and velocity of circumferential fiber shortening compared to nonaugmented cardiac beats. IABP did not cause significant beat-to-beat changes in heart rate, pulmonary artery diastolic pressure, or central venous pressure. The improvement in left ventricular systolic function associated with IABP-augmented cardiac beats correlated with the decrease in end-systolic meridional wall stress for that cardiac beat., Conclusions: Beat-to-beat echocardiographic and hemodynamic measurements performed in anesthetized cardiac surgical patients during IABP support demonstrated improved left ventricular systolic function and decreased left ventricular systolic wall stress in the cardiac beats immediately after balloon deflation. The relationship between left ventricular systolic function and left ventricular systolic wall stress during IABP support suggests that afterload reduction was an important mechanism by which IABP instantaneously improved circulatory function in anesthetized cardiac surgical patients.

Background: Transesophageal echocardiography (TEE) is used to diagnose hypovolemia despite the lack of validation studies. The objective was to determine the effects of acute graded hypovolemia on TEE and conventional hemodynamic determinants of left ventricular (LV) preload in anesthetized patients with normal and abnormal LV function., Methods: Determinants of LV preload derived from TEE and hemodynamic monitoring were measured serially in 35 anesthetized cardiac surgical patients without valvular heart disease. Patients were stratified into two groups: those with normal LV function (group 1, n = 17) and those with LV wall motion abnormalities (group 2, n = 13). Patients in groups 1 and 2 were subjected to graded hypovolemia produced by collecting 6 aliquots of blood, each equal to 2.5% of their estimated blood volume (EBV). A third group of patients (group 3, n = 5), not subjected to graded hypovolemia, were studied to test for time-dependent changes., Results: Group 2 had a significantly greater baseline (mean +/- SD) pulmonary artery occlusion pressure (17 +/- 6 vs. 11 +/- 6 mmHg), LV end-diastolic area (23 +/- 5 vs. 18 +/- 4 cm2), LV end-diastolic wall stress (23 +/- 10 vs. 14 +/- 6 x 10(3) dyne.cm-2), and smaller fractional area change (35 +/- 13 vs. 59 +/- 7%). In groups 1 and 2, the LV end-diastolic area, pulmonary artery occlusion pressure, and LV end-diastolic wall stress decreased linearly in response to blood loss in the range of 0-15% of the EBV. No significant changes in the measured parameters occurred in group 3. A significant decrease in the central venous pressure, pulmonary artery occlusion pressure, and LV end-diastolic area was detected in response to a 2.5% EBV deficit (approximately 1.75 ml.kg-1) in groups 1 and 2. The mean change in LV end-diastolic area (0.3 cm2/1.0% EBV deficit) in response to equivalent EBV deficits was the same in groups 1 and 2. In contrast, the mean change in cardiac output and LV end-diastolic wall stress was less in group 2 despite a greater decrease in pulmonary artery occlusion pressure. Compared to group 1, a greater EBV deficit (7.5% to 12.5% vs. 2.5% to 5%) was required in group 2 to cause a significant decrease in the cardiac output, stroke volume, mixed venous oxygen saturation, and LV end-diastolic wall stress., Conclusions: TEE and hemodynamic determinants of LV preload detected changes in LV function caused by acute blood loss. Acute blood loss caused directional changes in LV end-diastolic area, pulmonary artery occlusion pressure, and LV end-diastolic wall stress even in patients with LV wall motion abnormalities. Changes in LV end-diastolic wall stress, derived from both TEE and hemodynamic measurements corresponded to changes in cardiac output, stroke volume, and mixed venous oxygen saturation that occurred during acute blood loss.