Peroxynitrite, a reactive nitrogen species, has been implicated in the development of ischemia–reperfusion injury. The present study investigated the effects of the potent peroxynitrite decomposition catalyst FP15 on myocardial and endothelial function after hypothermic ischemia–reperfusion in a heterotopic rat heart transplantation model.
After a 1-hour ischemic preservation and implantation of donor hearts, reperfusion was started after application of vehicle (5% glucose solution) or FP15 (0.3 mg/kg). The assessment of left ventricular pressure–volume relations, total coronary blood flow, endothelial function, immunohistochemical markers of nitro-oxidative stress, and myocardial high-energy phosphates was performed at 1 and 24 hours of reperfusion.
After 1 hour of reperfusion, myocardial contractility (maximal slope of systolic pressure increment at 140 μL left ventricular volume: 5435 ± 508 mm Hg/s vs 2346 ± 263 mm Hg/s), coronary blood flow (3.98 ± 0.33 mL/min/g vs 2.74 ± 0.29 mL/min/g), and endothelial function were significantly improved, nitro-oxidative stress was reduced, and myocardial high-energy phosphate content was preserved in the FP15-treated animals compared with controls.
Pharmacologic peroxynitrite decomposition reduces reperfusion injury after heart transplantation as the result of reduction of nitro-oxidative stress and prevention of energy depletion and exerts a beneficial effect against reperfusion-induced graft cardiac and coronary endothelial dysfunction.
Aortic valve stenosis is a common cause of left ventricular pressure overload, a pathologic process that elicits myocyte hypertrophy and alterations in extracellular matrix composition, both of which contribute to increases in left ventricular stiffness. However, clinical and animal studies suggest that increased myocardial extracellular matrix fibrillar collagen content occurs later in the time course of left ventricular pressure overload at a time coincident with severe abnormalities in diastolic function followed by the development of symptomatic heart failure. Aortic valve replacement remains the most effective treatment for elimination of chronic pressure overload secondary to aortic stenosis but has traditionally been recommended only after the onset of clinical symptoms. However, long-term follow-up of symptomatic aortic stenosis patients after aortic valve replacement suggests that valve replacement may not result in complete reversal of the maladaptive changes that occur within the myocardial extracellular matrix secondary to the pressure overload state. Quite the contrary, residual left ventricular extracellular matrix abnormalities such as these are likely responsible for persistent abnormalities in diastolic function and increased morbidity and mortality after aortic valve replacement. Thus, defining the mechanisms and pathways responsible for regulating the myocardial extracellular matrix during the natural history of aortic stenosis may provide a means by which to detect crucial structural milestones and thereby permit more precise identification of the development of maladaptive left ventricular remodeling.
Current robotic training approaches lack criteria for automatically assessing and tracking (over time) technical skills separately from clinical proficiency. We describe the development and validation of a novel automated and objective framework for assessment of training.
We are able to record all system variables (stereo instrument video, hand and instrument motion, buttons and pedal events) from the da Vinci surgical systems using a portable archival system integrated with the robotic surgical system. Data can be collected unsupervised, and the archival system does not change system operation in any way. Our open-ended multi-center protocol is collecting surgical skill benchmarking data from 24 trainees to surgical proficiency, subject only to their continued availability. Two independent experts performed structured (OSATS) assessments on longitudinal data from 8 novice and 4 expert surgeons to generate ground truth for training and to validate our computerized statistical analysis methods in identifying ranges of operational and clinical skill measures.
Objective differences in operational and technical skill between known experts and other subjects were quantified. Longitudinal learning curves and statistical analysis for trainee performance measures are reported. Graphical representations of skills developed for feedback to the trainees are also included.
We describe an open-ended longitudinal study and automated motion recognition system capable of objectively differentiating between clinical and technical operational skills in robotic surgery. Our results demonstrate a convergence of trainee skill parameters towards those derived from expert robotic surgeons over the course of our training protocol.
robotic surgery; robotic surgery training; assessment; learning curves
Recent studies suggest adverse events associated with aprotinin in adults may not occur in children, and there is interest in further pediatric study of aprotinin. However, there are limited contemporary data comparing aprotinin to other available antifibrinolytics [aminocaproic acid (ACA) and tranexamic acid (TXA)] to guide current practice and aid in potential trial design. We performed a comparative analysis in a large multicenter cohort.
The Society of Thoracic Surgeons Congenital Heart Surgery Database (2004–2008) was linked to medication data from the Pediatric Health Information Systems Database. Efficacy and safety outcomes were evaluated in multivariable analysis adjusting for patient and center factors overall, and in neonates and those undergoing redo sternotomy.
There were 22,258 patients (25 centers) included: median age 7.6m (interquartile range 2.6–43.4). Aprotinin (vs. no drug) was associated with a significant reduction in combined hospital mortality/bleeding requiring surgical intervention overall (OR 0.81 95%CI 0.68–0.91), and in the redo sternotomy subgroup (OR 0.57 95%CI 0.40–0.80). There was no benefit in neonates, and no difference in renal failure requiring dialysis in any group. In comparative analysis, there was no difference in outcome in aprotinin vs. ACA recipients. TXA (vs. aprotinin) was associated with significantly reduced mortality/bleeding requiring surgical intervention overall (OR 0.47 95%CI 0.30–0.74) and in neonates (OR 0.30 95%CI 0.15–0.58).
These observational data suggest aprotinin is associated with reduced bleeding and mortality in children undergoing heart surgery with no increase in dialysis. Comparative analyses suggest similar efficacy of ACA and improved outcomes associated with TXA.
Marfan syndrome patients with aortic root aneurysms undergo elective aortic root replacement to avoid the life-threatening outcomes of aortic dissection and emergency repair. The long-term implications of failed aortic surveillance leading to acute dissection and emergency repair are poorly defined. We compared the long-term clinical courses of Marfan syndrome patients who survive emergency versus elective proximal aortic surgery.
The GenTAC Registry is an NIH-funded, multicenter database and biorepository that enrolls patients with genetically triggered thoracic aortic aneurysms. Of the 635 patients with Marfan syndrome enrolled as of March 2011, 194 had undergone proximal aortic replacement. Patients were grouped according to emergent (n=47) or elective (n=147) status at the time of surgery.
Patients in the emergent group were more likely to have incomplete proximal aortic resection; 83% of emergency procedures included aortic root replacement, compared with 95% of elective procedures. At long-term follow-up (mean, >6 years), emergent patients had a higher incidence of chronic dissection of the distal aorta and had significantly larger diameters in distal aortic segments than elective patients. Additionally, emergent patients had undergone more operations (1.31 vs 1.11 procedures/patient; P=0.01) and had lower activity scores on a health-related quality-of-life survey.
For Marfan syndrome patients, failed aortic surveillance and consequent emergency dissection repair have important long-term implications with regard to status of the distal aorta, the need for multiple procedures, and quality of life. These findings emphasize the importance of aortic surveillance and timely elective aortic root aneurysm repair for Marfan syndrome patients.
The Single Ventricle Reconstruction trial randomized 555 subjects with a single right ventricle undergoing the Norwood procedure at 15 North American centers to receive either a modified Blalock-Taussig shunt or right ventricle-to-pulmonary artery shunt. Results demonstrated a rate of death or cardiac transplantation by 12 months postrandomization of 36% for the modified Blalock-Taussig shunt and 26% for the right ventricle-to-pulmonary artery shunt, consistent with other publications. Despite this high mortality rate, little is known about the circumstances surrounding these deaths.
There were 164 deaths within 12 months postrandomization. A committee adjudicated all deaths for cause and recorded the timing, location, and other factors for each event.
The most common cause of death was cardiovascular (42%), followed by unknown cause (24%) and multisystem organ failure (7%). The median age at death for subjects dying during the 12 months was 1.6 months (interquartile range, 0.6 to 3.7 months), with the highest number of deaths occurring during hospitalization related to the Norwood procedure. The most common location of death was at a Single Ventricle Reconstruction trial hospital (74%), followed by home (13%). There were 29 sudden, unexpected deaths (18%), although in retrospect, 12 were preceded by a prodrome.
In infants with a single right ventricle undergoing staged repair, the majority of deaths within 12 months of the procedure are due to cardiovascular causes, occur in a hospital, and within the first few months of life. Increased understanding of the circumstances surrounding the deaths of these single ventricle patients may reduce the high mortality rate. (J Thorac Cardiovasc Surg 2012;144:907-14)
Patients with severe left ventricular (LV) pressure overload (LVPO) secondary to aortic stenosis can present with signs and symptoms of heart failure despite normal LV ejection fractions (LVEF). This process occurs, at least in part, as a result of LVPO-induced extracellular matrix (ECM) remodeling which promulgates increased LV stiffness and impaired diastolic function. However, the determinants which drive ECM remodeling in this form of LVPO remain to be fully defined.
LVPO was induced in mature pigs (n=15) by progressive ascending aortic cuff inflation (once/week/4 weeks) whereby LV mass, LVEF, and regional myocardial stiffness (rKm) were compared to referent controls (n=12). Determinants of ECM remodeling were assessed by measuring levels of mRNA expression for fibrillar collagens, matrix metalloproteinases (MMPs), and the tissue inhibitors of MMP-1 and -4 (TIMP-1, -4).
With LVPO, LV mass and rKm increased by 2- and 3-fold, respectively, compared to control, with no change in LVEF. LV myocardial collagen increased approximately 2-fold which was accompanied by reduced solubility (i.e. increased cross-linking) with LVPO, but mRNA expression for fibrillar collagen and MMPs remained relatively unchanged. In contrast, a robust increase in mRNA expression for TIMP-1 and -4 occurred with LVPO.
In a progressive model of LVPO, which recapitulates the phenotype of aortic stenosis, increased ECM accumulation and subsequently increased myocardial stiffness was not due to increased fibrillar collagen expression, but rather due to determinants of post-translational control which included increased collagen stability (thereby resistant to MMP degradation) and increased endogenous MMP inhibition. Targeting these ECM post-translational events with LVPO may hold both diagnostic and therapeutic relevance.
A heightened inflammatory response occurs following cardiac surgery. The perioperative use of glucocorticoids has been advocated as a method to improve postoperative outcomes. Randomized prospective studies to quantify the effect of methylprednisolone on perioperative outcomes in neonatal cardiac surgery have not been performed. We sought to determine whether pre-operative methylprednisolone would improve postoperative recovery in neonates requiring cardiac surgery.
Neonates scheduled for cardiac surgery were randomly assigned to receive either Two Dose (8 hours preoperatively and operatively; n=39) or Single Dose (operatively; n=37) methylprednisolone (30 mg/kg/dose) in a double-blind, placebo-controlled trial. The primary outcome was the incidence of low cardiac output syndrome (standardized score) or death 36 hours postoperatively. Secondary outcomes were death at 30 days, interlukin-6 levels, inotropic score, fluid balance, serum creatinine, and ICU and hospital stay.
Preoperative plasma levels of the inflammatory cytokine interlukin-6 were reduced by 2-fold (p<0.001) in the Two Dose methylprednisolone group, consistent with the anti-inflammatory effects of methylprednisolone. However, the incidence of low cardiac output syndrome was 46% (17/37) in the Single Dose and 38% (15/39) in the Two Dose methylprednisolone groups (p=0.51). Two Dose methylprednisolone was associated with a higher serum creatinine (0.61±0.18 vs. 0.53±0.12 mg/dL, p=0.03), and poorer postoperative diuresis (−96±49 mL, p=0.05). Inotropic requirement, duration of mechanical ventilation, ICU, and hospital stay did not differ between the 2 groups.
Combined preoperative and intraoperative use of glucocorticoids in neonatal cardiac surgery does not favorably affect early clinical outcomes, and may exacerbate perioperative renal dysfunction.
The aim of this study was to compare the cost and effectiveness of a minimally invasive (MI) versus traditional sternotomy (ST) approach for mitral valve surgery (MVS).
From 1/1/03–12/31/08, 847 patients underwent isolated MVS at our institution. Propensity matching on 22 clinical variables was carried out to generate a study cohort of 434 patients (217 matched pairs). Direct and indirect costs from the hospital perspective were retrospectively obtained from our finance department. Total hospital costs were further stratified into 13 standardized institutional billing categories. In addition, data on morbidity, mortality, discharge location, hospital readmissions within one year, and freedom from reoperation were obtained.
Compared to ST, MIMVS was associated with a $9,054 ± 3,302 lower mean total hospital cost (p=0.006), driven largely by a reduction in direct (p=0.003) versus indirect costs (p=0.06). Among the 13 billing categories, MIMVS was associated with a significant reduction in costs of: cardiac imaging (p=0.004), laboratory tests (p=0.005), boarding and nursing (p=0.001), and radiology (p=0.002). More patients in the ST group required intubation for > 72 hours (p=0.019); however, there were no differences in morbidity or long-term survival (p=0.334). There were a higher proportion of MI patients discharged home with no nursing services (p=0.018), and a higher proportion of readmissions among ST patients within one year (p=0.023). There were no differences in freedom from reoperation between groups (p=0.574).
With equivalent efficacy across a range of measures and lower costs compared to ST, MIMVS represents a cost-saving strategy for MVS.
Intracardiac beating-heart procedures require the introduction and exchange of complex instruments and devices. In order to prevent potential complications such as air embolism and bleeding, a universal cardioport was designed and tested.
The design consists of port body and a series of interchangeable sleeves. The port uses a fluid purging system to remove air from the instrument prior to insertion into the heart, and a valve system minimizes blood loss during instrument changes.
The cardioport was tested ex vivo and in vivo in pigs (n=5). Beating-heart procedures such as septal defect closure and mitral valve repair were modeled. Ex vivo trials (n=150) were performed, and no air emboli were introduced using the port. In comparison, air emboli were detected in 40–85% of the cases without use of the port based purging system. Port operation revealed excellent ergonomics, and minimal blood loss.
A novel cardioport system designed to prevent air entry and blood loss from transcardiac instrument introduction was shown to be an enabling platform for intracardiac beating-heart surgery. The port system improves safety and facilitates further development of complex instruments and devices for transcardiac beating-heart surgery.
Mitral valve prolapse; animal study; biomechanics; chordal tension
The present study examined a cardiac passive restraint device which applies epicardial pressure (HeartNetTM Implant) in a clinically relevant model of dilated cardiomyopathy (DCM) to determine effects on hemodynamic and myocardial blood flow patterns.
DCM was established in 10 pigs (3 weeks atrial pacing, 240 beats per minute). Hemodynamic parameters and regional left ventricle (LV) blood flow were measured under baseline conditions and following acute HeartNet (Paracor Medical Inc, Sunnyvale, CA) placement. Measurements were repeated following adenosine infusion, allowing maximal coronary vasodilation and coronary flow reserve determination.
LV dilation and systolic dysfunction occurred relative to baseline as measured by echocardiography. LV end diastolic dimension increased and LV fractional shortening decreased (3.8±0.1 vs 6.1±0.2cm and 31.6±0.5 vs 16.2±2.1%, both p<0.05 respectively) consistent with the DCM phenotype. The HeartNet was successfully deployed without arrhythmias and a computed median mid-LV epicardial pressure of 1.4 mmHg was applied by the HeartNet throughout the cardiac cycle. Acute HeartNet placement did not adversely affect steady state hemodynamics. With the HeartNet in place, coronary reserve was significantly blunted.
In a large animal model of DCM, the cardiac passive restraint device did not appear to adversely affect basal resting myocardial blood flow. However, following acute HeartNet placement, LV maximal coronary reserve was blunted. These unique results suggest that cardiac passive restraint devices which apply epicardial transmural pressure can alter myocardial blood flow patterns in a DCM model. Whether this blunting of coronary reserve holds clinical relevance with chronic passive restraint device placement remains unestablished.
Sublobar resection (SR) is commonly used for patients considered high-risk for lobectomy. Non-operative therapies are increasingly being reported for similar risk patients because of perceived lower morbidity. We report 30 and 90 day adverse events (AEs) from ACOSOG Z4032; a multicenter phase III study for high-risk stage I non-small cell lung cancer (NSCLC) patients.
Data from 222 evaluable patients randomized to SR (n=114) or SR with brachytherapy (SRB) (n=108) are reported. AEs were recorded using the Common Terminology Criteria for Adverse Events, Version 3.0 at 30 and 90 days post surgery. Risk factors (age, baseline DLCO%, and FEV1%, upper lobe versus lower lobe resections, performance status, surgery approach; VATS versus open and extent ; wedge versus segmentectomy) were analyzed using a multivariable logistic model for their impact on the incidence of Grade 3 (G3+) and higher AEs. Respiratory AEs were also specifically analyzed
Median age, FEV1% and DLCO% were similar for the two treatment groups. There was no difference in the location of resection (upper versus lower lobe) or in the use of segmental or wedge resections. There were no differences between the groups with respect to “respiratory” G3+ (30 days: 14.9% vs. 19.4%; p=0.35; 0–90 days: 19.3% vs. 25%; p=0.31) and “any” G3+AEs (30 days: 25.4% vs. 30.6%; p=0.37; 0–90 days: 29.8% vs. 37%; p=0.25). Further analysis combined the two groups. Mortality occurred in 3 (1.4%) patients by 30 days and in 6 (2.7%) patients by 90 days. Four of the six deaths were felt to be attributable to surgery. When considered as continuous variables, FEV1% was associated with “any” grade 3 + AE at days 0–30 (p=0.03; OR=0.98), and days 0–90 (p=0.05; OR=0.98) respectively; and DLCO% was associated with “respiratory” grade 3+AE at days 0–30 (p=0.03; OR=0.97), and days 0–90 (p=0.05; OR=0.98) respectively. Segmental resection was associated with a higher incidence of any G3+ AE compared to wedge at days 0–30(40.3% versus 22.7%; OR=2.56; p<0.01) and days 0–90 (41.5% versus 29.7%; OR=1.96; p=0.04). The median FEV1% was 50% and the median DLCO% was 46%. Using these median values as potential cutpoints, only a DLCO% of less than 46% was significantly associated with an increased risk of “respiratory” and “any” grade 3+ AE for days 0–30, and 0–90.
In a multicenter setting, SRB was not associated with increased morbidity compared to SR alone. SR/SRB can be performed safely in high-risk patients with NSCLC with low 30 and 90 day mortality and acceptable morbidity. Segmental resection was associated with increased “any” G3+ AE, and DLCO% less than 46% was associated with “any” G3+AE as well as “respiratory” G3+ AE at both 30 and 90 days.
Outcomes data for adults undergoing congenital heart surgery are limited. Previous analyses utilized administrative data or focused on single-center outcomes. We describe the most common operations, patient characteristics, and post-operative outcomes using a multicenter clinical database.
Adults (≥ 18 years) in the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database ((2000–2009) were included. Patient characteristics and morbidity and mortality were described. We similarly examined congenital procedures in the STS Adult Cardiac Surgery Database to permit consideration of the primary dataset within a broader context.
5265 patients (68 centers) from the STS Congenital Heart Surgery Database were included. Median age was 25 years (IQR 20–35). Common preoperative risk factors included noncardiac abnormalities (17%) and arrhythmia (14%). Overall, in-hospital mortality was 2.1%, 27% had ≥1 complication and median length of stay was 5 days. Common operations included right ventricular outflow tract procedures (21%) and pacemaker/arrhythmia procedures (20%). We further evaluated cardiopulmonary bypass procedures with n >100. Mortality ranged from 0% (atrial septal defect repair) to 11% (Fontan revision/conversion). Separate evaluation of the STS Adult Cardiac Surgery Database revealed 39,872 adults undergoing congenital heart operations.
Most adult congenital heart operations in the STS Congenital Heart Surgery Database are performed in the third-fourth decades of life; nearly half are for right heart pathology or arrhythmia. Many patients have complications but mortality is low with the exception of those undergoing Fontan revision/conversion. Many more adults undergoing congenital heart surgery are entered into the STS Adult Cardiac Surgery Database.
Adenosine A2A receptor (A2AR) activation following lung transplantation attenuates ischemia-reperfusion (IR) injury by reducing inflammation. However, the effect of A2AR activation in donor lungs prior to transplant remains ill-defined. This study compares the efficacy of three different treatment strategies for A2AR agonist in a clinically relevant porcine lung transplantation model.
Mature porcine lungs underwent six hours cold ischemia prior to allotransplantation and four hours reperfusion. Five groups (n=6/group) were evaluated based upon treatment with ATL-1223, a selective A2AR agonist: Sham (thoracotomy alone), IR (transplant alone), ATL-D (donor pretreatment via ATL-1223 bolus), ATL-R (recipient treatment via ATL-1223 infusion), and ATL-D/R (combination of both ATL-1223 treatments). Lung function and injury were compared.
Blood oxygenation was significantly higher among ATL-D, ATL-R, and ATL-D/R groups versus IR (392.0±52.5, 428.9±25.5, 509.4±25.1 vs. 77.2±17.0 mmHg, respectively, p<0.001). ATL-1223-treated groups had lower pulmonary artery pressures (ATL-D=30.5±1.8, ATL-R=30.2±3.3, ATL-D/R=29.3±4.5 vs. IR=45.2±2.1 mmHg, p<0.001) and lower mean airway pressures versus IR (ATL-D=9.1±0.8, ATL-R=9.1±2.6, ATL-D/R=9.6±1.3 vs. IR=21.1 mmHg, p<0.001). Similarly, ATL-1223-treated groups had significantly lower lung wet/dry weight, proinflammatory cytokine expression and lung injury scores by histology compared to IR. Importantly, all parameters of lung function and injury in ATL-1223-treated groups were similar to Sham (all p>0.05).
Pretreatment of donor lungs with ATL-1223 was as efficacious as other treatment strategies in protecting against IR injury. If necessary, supplemental treatment of recipients with ATL-1223 may provide additional protection. These results support the development of pharmacologic A2AR agonists for use in human clinical trials for lung transplantation.
Ischemia-reperfusion injury; Inflammation; Cytokines; Acute graft failure
This study aimed at developing a murine model of surgically induced acute aortic dissection type A (AAD) for investigation of the formation and progression of AAD, and to test whether this system could be used for biomarker discovery.
Adult fibrillin-1 deficient, Fbn1C1039G/+ mice and wild-type mice were anesthetized, ventilated and the ascending aorta exposed via hemisternotomy. We hypothesized that AAD could be induced either by injecting autologous blood into the aortic wall or by injury to the wall with aortic clamping. Echocardiography was done preoperatively, and serum samples collected before and 30 minutes after surgery, and analyzed by ELISA.
Echocardiography revealed larger aortic root diameters in Fbn1C1039G/+ compared with wild-type mice (P=0.001). Histology showed that aortic clamp injury but not injection of blood leads to large intimal tears, disruption of aortic wall structures and localized dissection of the aortic media in Fbn1C1039G/+ mice. AAD developed in 4 out of 5 Fbn1C1039G/+ mice versus 0 out of 5 wild-type mice after aortic clamping (P<0.01). Elastin staining showed higher elastic fiber fragmentation and disarray in Fbn1C1039G/+ compared with wild-type mice. ELISA analysis revealed elevated circulating TGFβ1 concentrations after inducing AAD in Fbn1C1039G/+ mice (P=0.02, 150±61 ng/ml vs. 456±97 ng/ml), but not in wild-type or sham-operated mice.
Aortic clamp injury can induce AAD in Fbn1C1039G/+, but not in wild-type mice. This murine model of surgically induced AAD is highly reproducible and non-lethal in the short-term. Using this system, we revealed that circulating TGFβ1 is a promising biomarker for AAD.
Temporary biventricular pacing to treat low output states after cardiac surgery is an active area of investigation. Reoperative cases are not studied due to adhesions, which preclude left ventricular mobilization to place epicardial pacing wires. In such patients, inserting a temporary left ventricular lead via the coronary sinus cardioplegia cannula may allow for biventricular pacing. We developed a novel technique for intraoperative left ventricular lead placement.
Eight domestic pigs underwent median sternotomy and pericardiotomy. Temporary pacing wires were sewn to the right atrium and right ventricle. Complete heart block was induced by ethanol ablation of the atrioventricular node. A 13 French retrograde cardioplegia catheter was introduced via the right atrial free wall into the coronary sinus. A 6 French left ventricular pacing lead was inserted into the cardioplegia catheter and advanced into the coronary sinus, during biventricular pacing, until left ventricular capture was detected by electrocardiogram and arterial pressure monitoring. Left ventricular capture success rate and electrical performance were recorded during five placement attempts.
Left ventricular capture was achieved on 80% of insertion attempts. Left ventricular capture without diaphragmatic pacing was achieved in seven pigs. Lead tip locations were mostly in lateral and posterior basal coronary vein branches. There were no arrhythmias, bleeding, or perforation associated with lead insertion.
Intraoperative biventricular pacing with a left ventricular pacing lead inserted via the coronary sinus cardioplegia cannula is feasible, using standard instrumentation and without requiring cardiac manipulation. This approach merits further study in patients undergoing reoperative cardiac surgery.
Z4032 is a randomized clinical trial conducted by the American College of Surgeons Oncology Group that compared sublobar resection alone (SR) to sublobar resection with brachytherapy (SRB) for high-risk operable patients with non-small cell lung cancer (NSCLC). This current report evaluate the early impact that adjuvant brachytherapy has on pulmonary function tests (PFT), dyspnea and perioperative (30-day) respiratory complications on this impaired patient population.
Eligible stage I NSCLC patients with tumors 3cm or less were randomized to SR or SRB. The outcomes measured included the % predicted forced expiratory volume (FEV1%), % predicted carbon monoxide diffusion capacity (DLCO%), dyspnea score using the UC San Diego Shortness of Breath Questionnaire. Pulmonary morbidity was assessed using the Common Terminology Criteria for Adverse Events (AE) Version 3.0 (CTCAE). Outcomes were measured at baseline, and at 3-months. A 10% change in PFT or a 10-point change in dyspnea score was deemed clinically meaningful.
Z4032 permanently closed to patient accrual in January 2010 with a total of 224 patients. At 3-month follow-up, PFT data is currently available on 148 (74 SR/74 SRB) patients described in this report. There were no differences in baseline characteristics between the arms. In the SR arm, 9 (12%) patients reported grade-3 respiratory AE compared to 12 (16%) in the SRB arm (p=0.49). There was no significant change in the percent change in DLCO%, or dyspnea score from baseline to 3-month within either arm. In the case of FEV1%, the percent change from baseline to 3-month was significant within SR arm (p=0.03), with patients reporting an improvement in the FEV1% at month 3. Multivariable regression analysis (adjusted for baseline values) showed no significant impact of treatment arm, tumor location (upper versus other lobe), or surgical approach (VATS versus thoracotomy) on the 3-month values for FEV1%, DLCO% and dyspnea scores. There was no significant difference in the incidence of clinically meaningful (10% PFT change, or 10-point dyspnea score) change between the two arms. Twenty-two percent of patients with lower lobe tumors compared to 9% with upper lobe tumors demonstrated a 10% decline in FEV1% (odds ratio 2.79; 95 CI=1.07 – 7.25; p=0.04).
Adjuvant intraoperative brachytherapy performed in conjunction with sublobar resection does not significantly worsen pulmonary function, or dyspnea at 3-months in a high-risk population with NSCLC. SRB was not associated with increased perioperative pulmonary AE. Lower-lobe resection was the only factor that was significantly associated with a clinically meaningful decline in FEV1%.
Cyclooxygenase-2 inhibitors have been implicated in adverse cardiac events. We hypothesize that hypercholesterolemia and ischemia may alter the myocardial response to the cyclooxygenase-2 inhibitor celecoxib.
Yorkshire swine fed normal chow (CX, n=6) or high-cholesterol diet (HCX, n=6) underwent left circumflex artery ameroid placement, and were started on celecoxib (200 mg/day). After 7 weeks, ischemic and non-ischemic myocardium were analyzed for thrombogenic ratio (thromboxane content divided by prostacyclin content), total protein oxidative stress, and expression of prostacyclin synthase, thromboxane synthase, myeloperoxidase, and superoxide dismutase. Cardiac function, tissue perfusion, and vessel density were measured.
HCX animals were significantly hypercholesterolemic compared to CX animals. Thrombogenic ratio was significantly higher in the HCX group compared to the CX group, but prostacyclin and thromboxane synthase expression was similar in all tissues. Myocardial perfusion was decreased in the HCX group compared to the CX group. Total oxidative stress, myeloperoxidase, and superoxide dismutase were increased in ischemic tissue compared to non-ischemic tissues, but there was no diet-induced difference between groups. There was no difference in capillary or arteriolar density between groups. LV contractility was greater in the HCX group compared to the CX group, but there was no significant difference in heart rate, mean arterial pressure, or left ventricular pressure.
Hypercholesterolemic patients using celecoxib may be at higher risk for thrombotic events than those with normal cholesterol, but the relationship between dyslipidemia, ischemia, and cyclooxygenase-2 inhibition is likely much more complicated than originally thought.
The mitral valve annulus naturally conforms to a saddle shape in systole. This configuration is believed to put the leaflets into a lower-energy equilibrium with the annulus and subvalvular apparatus. Conventional flat annuloplasty rings restrict posterior leaflet motion, which may result in a “monocusp” valve, affecting valvular stress distribution. It is hypothesized that saddle-shaped annuloplasty rings cause less distortion of the physiologic leaflet geometry than do flat rings.
Twelve pigs were studied in an acute setting with 3-dimensional echocardiography and sonomicrometry before and after implantation of rigid flat (n = 5) and saddle-shaped (n = 7) annuloplasty rings. The rings were true sized to the annulus with equal anterior–posterior and commissure–commissure circumferential dimensions. The saddle-shaped rings had an annular height to commissural width ratio of 15%.
Saddle-shaped rings maintained both leaflets operational (P <.01). Flat rings made the posterior leaflet immobile and the anterior leaflet aligned flat along the annulus in systole, effectively resulting in monoleaflet function. The average distance from the papillary muscle tips to the posterior annulus decreased by 2.4 ± 0.4 mm after flat ring implantation (P <.01).
Saddle-shaped annuloplasty rings provide better leaflet coaptation geometry than do flat rings by not hoisting the papillary muscles toward the posterior annulus through the commissural chordae, allowing greater leaflet mobility. This entails a potentially beneficial impact on valvular stress distribution that could affect durability of the repaired valve.
Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. Angiotensin-converting enzyme (ACE) inhibitors are commonly used as cardioprotective agents and have recently been shown in clinical studies to be efficacious in the prevention of anthracycline induced heart failure. Here we evaluated a mechanism for these protective effects by testing the ability of the ACE inhibitor enalapril to preserve mitochondrial function in a model of chronic doxorubicin treatment in rats.
Sprague Dawley rats were divided into three groups and followed for a total of 10 weeks: a) control-untreated, b) Doxorubicin treated (Dox), and c) Doxorubicin + Enalapril treated (DE). Doxorubicin was administered via intraperitoneal injection at weekly intervals from week 2 through week 7. Enalapril was administered in the drinking water of the DE group for the study duration.
Doxorubicin treatment produced a significant loss in left ventricular contractility (P< 0.05), decrease in mitochondrial function via impairment of state-3 respiration, decrease in the cytosolic fraction of ATP, and up-regulation of free radical production. Enalapril significantly attenuated the decrease in percent fractional shortening (P< 0.05) and prevented the doxorubicin-associated reduction in respiratory efficiency and cytosolic ATP content (P< 0.05). Importantly, enalapril also abolished the robust doxorubicin-induced increase in free radical formation.
Administration of enalapril attenuates doxorubicin-induced cardiac dysfunction via preservation of mitochondrial respiratory efficiency and reduction in doxorubicin-associated free radical generation.
doxorubicin; mitochondria; cardiotoxicity; ACE inhibitor; free radicals
Chylothorax resulting from damage to the thoracic duct is often difficult to identify and repair. We hypothesized that near-infrared (NIR) fluorescent light could provide sensitive, real-time, high-resolution intraoperative imaging of thoracic duct anatomy and function.
In 16 rats (n=16), four potential NIR fluorescent lymphatic tracers were compared in terms of signal strength and imaging time: indocyanine green (ICG), the carboxylic acid of CW800, ICG adsorbed to human serum albumin (HSA), and CW800 conjugated covalently to HSA (HSA800). The optimal agent was validated in eight pigs approaching the size of humans, n = 6 by open surgery using the Fluorescence-Assisted Resection and Exploration (FLARE) imaging system and n = 2 by video-assisted thoracoscopic surgery (VATS) using the minimally invasive imaging system (m-FLARE). Lymphatic tracer injection site, dose, and timing were optimized.
For signal strength, sustained imaging time, and clinical translatability, the best lymphatic tracer was ICG, which is already FDA-approved for other indications. In pigs, a simple subcutaneous injection of ICG into the lower leg, at a dose ≥36 μg/kg, provided thoracic duct imaging with an onset of 5 min after injection, sustained imaging for at least 60 min after injection, and a signal-to-background ratio ≥2. Using this technology, normal thoracic duct flow, collateral flow, injury models, and repair models could all be observed under direct visualization.
NIR fluorescent light could provide sensitive, sustained, real-time imaging of thoracic duct anatomy and function during both open surgery and VATS in animal models.
Thoracic duct imaging; image-guided surgery; near-infrared fluorescence; indocyanine green
We sought to evaluate contemporary results after repair of a complete atrioventricular septal defect (AVSD) and to determine factors associated with suboptimal outcomes.
Demographic, procedural, and outcome data were obtained within 1 and 6 months after repair of complete AVSD in 120 children in a multicenter observational study from 6/04-2/06.
Median age at surgery was 3.7 months (range, 9 days-1.1 years). Type of surgical repair was single patch (18%), double patch (72%), and single atrial septal defect patch with primary ventricular septal defect closure (10%). Residual septal defects and degree of left atrioventricular valve regurgitation (LAVVR) did not differ by repair type. Median days of intensive care stay were 4, ventilation 2, and total hospitalization 8; all were independent of the presence of Trisomy 21 (80% of cohort). Hospital mortality was 3/120 (2.5%); overall 6 month mortality was 5/120 (4%). The presence of associated anomalies and younger age at surgery were independently associated with longer hospital stay. Age at repair was not associated with residual VSD or ≥moderate LAVVR at 6 months. Moderate or greater LAVVR occurred in 22% at 6 months; the strongest predictor for this was moderate or greater LAVVR at 1 month, (odds ratio 6.9, 95% CI 2.2, 21.7), P<0.001.
Outcomes following repair of complete AVSD did not differ by repair type or presence of Trisomy 21. Earlier age at surgery was associated with increased resource utilization but had no association with incidence of residual VSD or significant LAVVR.