Robotics in the diagnosis and staging of lung cancer.

The diagnosis of peripheral small lung lesions by electromagnetic navigational bronchoscopy is still inferior to computed tomography (CT) guided percutaneous transthoracic needle lung biopsy. Robotic bronchoscopy is a new technology that may be a potential breakthrough in the diagnosis of small lung lesions. Real-time tools such as electromagnetic navigation, radial-endobronchial ultrasound, and cone beam CT may further improve the diagnostic yield rate may further improve the diagnostic yield rate. In this article, we reviewed early experience of robotic bronchoscopy for diagnosis and staging of lung cancer.

Mediastinal Masses, Anesthetic Interventions, and Airway Compression in Adults: A Prospective Observational Study.

BACKGROUND: Central airway occlusion is a feared complication of general anesthesia in patients with mediastinal masses. Maintenance of spontaneous ventilation and avoiding neuromuscular blockade are recommended to reduce this risk. Physiologic arguments supporting these recommendations are controversial and direct evidence is lacking. The authors hypothesized that, in adult patients with moderate to severe mediastinal mass-mediated tracheobronchial compression, anesthetic interventions including positive pressure ventilation and neuromuscular blockade could be instituted without compromising central airway patency. METHODS: Seventeen adult patients with large mediastinal masses requiring general anesthesia underwent awake intubation followed by continuous video bronchoscopy recordings of the compromised portion of the airway during staged induction. Assessments of changes in anterior-posterior airway diameter relative to baseline (awake, spontaneous ventilation) were performed using the following patency scores: unchanged = 0; 25 to 50% larger = +1; more than 50% larger = +2; 25 to 50% smaller = -1; more than 50% smaller = -2. Assessments were made by seven experienced bronchoscopists in side-by-side blinded and scrambled comparisons between (1) baseline awake, spontaneous breathing; (2) anesthetized with spontaneous ventilation; (3) anesthetized with positive pressure ventilation; and (4) anesthetized with positive pressure ventilation and neuromuscular blockade. Tidal volumes, respiratory rate, and inspiratory/expiratory ratio were similar between phases. RESULTS: No significant change from baseline was observed in the mean airway patency scores after the induction of general anesthesia (0 [95% CI, 0 to 0]; P = 0.953). The mean airway patency score increased with the addition of positive pressure ventilation (0 [95% CI, 0 to 1]; P = 0.024) and neuromuscular blockade (1 [95% CI, 0 to 1]; P < 0.001). No patient suffered airway collapse or difficult ventilation during any anesthetic phase. CONCLUSIONS: These observations suggest a need to reassess prevailing assumptions regarding positive pressure ventilation and/or paralysis and mediastinal mass-mediated airway collapse, but do not prove that conventional (nonstaged) inductions are safe for such patients.

Finding the "True" N0 Cohort: Technical Aspects of Near-infrared Sentinel Lymph Node Mapping in Non-small Cell Lung Cancer.

OBJECTIVE: To examine technical-, patient-, tumor-, and treatment-related factors associated with NIR guided SLN identification. BACKGROUND: Missed nodal disease correlates with recurrence in early stage NSCLC. NIR-guided SLN mapping may improve staging and outcomes through identification of occult nodal disease. METHODS: Retrospective analysis of 2 phase I clinical trials investigating NIR-guided SLN mapping utilizing ICG in patients with surgically resectable NSCLC. RESULTS: In total, 66 patients underwent NIR-guided SLN mapping and lymphadenectomy after peritumoral ICG injection. There was significantly increased likelihood of SLN identification with injection dose ≥1 mg compared to <1 mg (65.2% vs 35.0%, P = 0.05), lung ventilation after injection (65.2% vs 35.0%, P = 0.05), and albumin dissolvent (68.1%) compared to fresh frozen plasma (28.6%) and sterile water (20.0%) (P = 0.01). In patients receiving the optimized ICG injection, there was significantly increased likelihood of SLN identification with radiologically solid nodules compared to sub-solid nodules (77.4% vs 33.3%, P = 0.04) and anatomic resection compared to wedge resection (88.2% vs 52.2%, P = 0.04). Disease-free and overall survival are 100% in those with a histologically negative SLN identified (n = 25) compared to 73.6% (P = 0.02) and 63.6% (P = 0.01) in patients with node negative NSCLC established via routine lymphadenectomy alone (n = 22). CONCLUSIONS: SLN(s) are more reliably identified with ICG dose ≥1 mg, albumin dissolvent, post-injection lung ventilation, radiologically solid nodules, and anatomic resections. To date, N0 status when established via NIR SLN mapping seems to be associated with decreased recurrence and improved survival after surgery for NSCLC.

Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter.

BACKGROUND AND OBJECTIVE: Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side-effect profiles are poorly understood. METHODS: Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post-injection. RESULTS: Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose-limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)(0-5d) 20- to 50-fold lower than the AUC(0-∞) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post-injection, bronchial PTX tissue concentrations were above a 10-nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX. CONCLUSION: Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow-up period.

Computer control of drug delivery by continuous intravenous infusion: bridging the gap between intended and actual drug delivery.

BACKGROUND: Intravenous drug infusion driven by syringe pumps may lead to substantial temporal lags in achieving steady-state delivery at target levels when using very low flow rates ("microinfusion"). This study evaluated computer algorithms for reducing temporal lags via coordinated control of drug and carrier flows. METHODS: Novel computer control algorithms were developed based on mathematical models of fluid flow. Algorithm 1 controlled initiation of drug infusion and algorithm 2 controlled changes to ongoing steady-state infusions. These algorithms were tested in vitro and in vivo using typical high and low dead volume infusion system architectures. One syringe pump infused a carrier fluid and a second infused drug. Drug and carrier flowed together via a manifold through standard central venous catheters. Samples were collected in vitro for quantitative delivery analysis. Parameters including left ventricular max dP/dt were recorded in vivo. RESULTS: Regulation by algorithm 1 reduced delivery delay in vitro during infusion initiation by 69% (low dead volume) and 78% (high dead volume). Algorithmic control in vivo measuring % change in max dP/dt showed similar results (55% for low dead volume and 64% for high dead volume). Algorithm 2 yielded greater precision in matching the magnitude and timing of intended changes in vivo and in vitro. CONCLUSIONS: Compared with conventional methods, algorithm-based computer control of carrier and drug flows can improve drug delivery by pump-driven intravenous infusion to better match intent. For norepinephrine infusions, the amount of drug reaching the bloodstream per time appears to be a dominant factor in the hemodynamic response to infusion.

Drug infusion system manifold dead-volume impacts the delivery response time to changes in infused medication doses in vitro and also in vivo in anesthetized swine.

BACKGROUND: IV infusion systems can be configured with manifolds connecting multiple drug infusion lines to transcutaneous catheters. Prior in vitro studies suggest that there may be significant lag times for drug delivery to reflect changes in infusion rates set at the pump, especially with low drug and carrier flows and larger infusion system dead-volumes. Drug manifolds allow multiple infusions to connect to a single catheter port but add dead-volume. We hypothesized that the time course of physiological responses to drug infusion in vivo reflects the impact of dead-volume on drug delivery. METHODS: The kinetic response to starting and stopping epinephrine infusion ([3 mL/h] with constant carrier flow [10 mL/h]) was compared for high- and low-dead-volume manifolds in vitro and in vivo. A manifold consisting of 4 sequential stopcocks with drug entering at the most upstream port was contrasted with a novel design comprising a tube with separate coaxial channels meeting at the downstream connector to the catheter, which virtually eliminates the manifold contribution to the dead-volume. The time to 50% (T50) and 90% (T90) increase or decrease in drug delivery in vitro or contractile response in a swine model in vivo were calculated for initiation and cessation of drug infusion. RESULTS: The time to steady state after initiation and cessation of drug infusion both in vitro and in vivo was much less with the coaxial low-dead-volume manifold than with the high-volume design. Drug delivery after initiation in vitro reached 50% and 90% of steady state in 1.4 ± 0.12 and 2.2 ± 0.42 minutes with the low-dead-volume manifold and in 7.1 ± 0.58 and 9.8 ± 1.6 minutes with the high-dead-volume manifold, respectively. The contractility in vivo reached 50% and 90% of the full response after drug initiation in 4.3 ± 1.3 and 9.9 ± 3.9 minutes with the low-dead-volume manifold and 11 ± 1.2 and 17 ± 2.6 minutes with the high-dead-volume manifold, respectively. Drug delivery in vitro decreased by 50% and 90% after drug cessation in 1.9 ± 0.17 and 3.5 ± 0.61 minutes with the low-dead-volume manifold and 10.0 ± 1.0 and 17.0 ± 2.8 minutes with the high-dead-volume manifold, respectively. The contractility in vivo decreased by 50% and 90% with drug cessation in 4.1 ± 1.1 and 14 ± 5.2 with the low-dead-volume manifold and 12 ± 2.7 and 23 ± 5.6 minutes with the high-dead-volume manifold, respectively. CONCLUSIONS: The architecture of the manifold impacts the in vivo biologic response, and the drug delivery rate, to changes in drug infusion rate set at the pump.

Risk prediction of chronic diseases with a two-stage semi-supervised clustering method.

Early detection of chronic diseases such as cardiovascular disease (CVD) and diabetes can make the difference between life and death. Previous studies have demonstrated the feasibility of disease diagnosis and prediction using machine learning and disease-indicating biomarkers. The aim of this study is to develop a method to detect the risk of future disease even when disease-indicating biomarker readings are in the normal range. Data from the US Centers for Disease Control and Prevention (CDC) National Health and Nutrition Examination Surveys (NHANES) are used for this study. A two-stage semi-supervised K-Means (SSK-Means) clustering approach was developed to identify the underlying risk of each individual and categorize them into high or low-risk groups for CVD and diabetes. Our developed method of classification can identify groups as high risk or low risk, even if they would have been considered normal using traditional biomarker threshold criteria. For CVD, the SSK-Means clustering results showed that individuals over 30 years of age in the high-risk group were almost twice as likely to develop CVD as individuals in the low-risk group. For diabetes, the SSK-Means clustering results showed that individuals over 50 years in the high-risk group have at least two times the risk of developing diabetes compared with individuals in the low-risk group.

Computer-based airway stenosis quantification from bronchoscopic images: preliminary results from a feasibility trial.

PURPOSE: Airway Stenosis (AS) is a condition of airway narrowing in the expiration phase. Bronchoscopy is a minimally invasive pulmonary procedure used to diagnose and/or treat AS. The AS quantification in a form of the Stenosis Index (SI), whether subjective or digital, is necessary for the physician to decide on the most appropriate form of treatment. The literature reports that the subjective SI estimation is inaccurate. In this paper, we propose an approach to quantify the SI defining the level of airway narrowing, using depth estimation from a bronchoscopic image. METHODS: In this approach we combined a generative depth estimation technique combined with depth thresholding to provide Computer-based AS quantification. We performed an interim clinical analysis by comparing AS quantification performance of three expert bronchoscopists against the proposed Computer-based method on seven patient datasets. RESULTS: The Mean Absolute Error of the subjective Human-based and the proposed Computer-based SI estimation was [Formula: see text] [%] and [Formula: see text] [%], respectively. The correlation coefficients between the CT measurements were used as the gold standard, and the Human-based and Computer-based SI estimation were [Formula: see text] and 0.46, respectively. CONCLUSIONS: We presented a new computer method to quantify the severity of AS in bronchoscopy using depth estimation and compared the performance of the method against a human-based approach. The obtained results suggest that the proposed Computer-based AS quantification is a feasible tool that has the potential to provide significant assistance to physicians in bronchoscopy.

Predicting reachability to peripheral lesions in transbronchial biopsies using CT-derived geometrical attributes of the bronchial route.

PURPOSE: The bronchoscopist's ability to locate the lesion with the bronchoscope is critical for a transbronchial biopsy. However, much less study has been done on the transbronchial biopsy route. This study aims to determine whether the geometrical attributes of the bronchial route can predict the difficulty of reaching tumors in bronchoscopic intervention. METHODS: This study included patients who underwent bronchoscopic diagnosis of lung tumors using electromagnetic navigation. The biopsy instrument was considered "reached" and recorded as such if the tip of the tracked bronchoscope or extended working channel was in the tumors. Four geometrical indices were defined: Local curvature (LC), plane rotation (PR), radius, and global relative angle. A Mann-Whitney U test and logistic regression analysis were performed to analyze the difference in geometrical indices between the reachable and unreachable groups. Receiver operating characteristic analysis (ROC) was performed to evaluate the geometrical indices to predict reachability. RESULTS: Of the 41 patients enrolled in the study, 16 patients were assigned to the unreachable group and 25 patients to the reachable group. LC, PR, and radius have significantly higher values in unreachable cases than in reachable cases ([Formula: see text], [Formula: see text], [Formula: see text]). The logistic regression analysis showed that LC and PR were significantly associated with reachability ([Formula: see text], [Formula: see text]). The areas under the curve with ROC analysis of the LC and PR index were 0.903 and 0.618. The LC's cut-off value was 578.25. CONCLUSION: We investigated whether the geometrical attributes of the bronchial route to the lesion can predict the difficulty of reaching the lesions in the bronchoscopic biopsy. LC, PR, and radius have significantly higher values in unreachable cases than in reachable cases. LC and PR index can be potentially used to predict the navigational success of the bronchoscope.

Visually Navigated Bronchoscopy using three cycle-Consistent generative adversarial network for depth estimation.

[Background] Electromagnetically Navigated Bronchoscopy (ENB) is currently the state-of-the art diagnostic and interventional bronchoscopy. CT-to-body divergence is a critical hurdle in ENB, causing navigation error and ultimately limiting the clinical efficacy of diagnosis and treatment. In this study, Visually Navigated Bronchoscopy (VNB) is proposed to address the aforementioned issue of CT-to-body divergence. [Materials and Methods] We extended and validated an unsupervised learning method to generate a depth map directly from bronchoscopic images using a Three Cycle-Consistent Generative Adversarial Network (3cGAN) and registering the depth map to preprocedural CTs. We tested the working hypothesis that the proposed VNB can be integrated to the navigated bronchoscopic system based on 3D Slicer, and accurately register bronchoscopic images to pre-procedural CTs to navigate transbronchial biopsies. The quantitative metrics to asses the hypothesis we set was Absolute Tracking Error (ATE) of the tracking and the Target Registration Error (TRE) of the total navigation system. We validated our method on phantoms produced from the pre-procedural CTs of five patients who underwent ENB and on two ex-vivo pig lung specimens. [Results] The ATE using 3cGAN was 6.2 +/- 2.9 [mm]. The ATE of 3cGAN was statistically significantly lower than that of cGAN, particularly in the trachea and lobar bronchus (p < 0.001). The TRE of the proposed method had a range of 11.7 to 40.5 [mm]. The TRE computed by 3cGAN was statistically significantly smaller than those computed by cGAN in two of the five cases enrolled (p < 0.05). [Conclusion] VNB, using 3cGAN to generate the depth maps was technically and clinically feasible. While the accuracy of tracking by cGAN was acceptable, the TRE warrants further investigation and improvement.

Technical Validation of Multi-Section Robotic Bronchoscope With First Person View Control for Transbronchial Biopsies of Peripheral Lung.

This study aims to validate the advantage of new engineering method to maneuver multi-section robotic bronchoscope with first person view control in transbronchial biopsy. Six physician operators were recruited and tasked to operate a manual and a robotic bronchoscope to the peripheral area placed in patient-derived lung phantoms. The metrics collected were the furthest generation count of the airway the bronchoscope reached, force incurred to the phantoms, and NASA-Task Load Index. The furthest generation count of the airway the physicians reached using the manual and the robotic bronchoscopes were 6.6 ±1.2th and 6.7 ±0.8th. Robotic bronchoscopes successfully reached the 5th generation count into the peripheral area of the airway, while the manual bronchoscope typically failed earlier in the 3 rd generation. More force was incurred to the airway when the manual bronchoscope was used ( 0.24 ±0.20 [N]) than the robotic bronchoscope was applied ( 0.18 ±0.22 [N], ). The manual bronchoscope imposed more physical demand than the robotic bronchoscope by NASA-TLX score ( 55 ±24 vs 19 ±16, ). These results indicate that a robotic bronchoscope facilitates the advancement of the bronchoscope to the peripheral area with less physical demand to physician operators. The metrics collected in this study would expect to be used as a benchmark for the future development of robotic bronchoscopes.

Liquid biopsy of fine-needle aspiration supernatant for lung cancer genotyping.

BACKGROUND: Tumor genotyping is transforming lung cancer care but requires adequate tumor tissue. Advances in minimally invasive biopsy techniques have increased access to difficult-to-access lesions, but often result in smaller samples. With the advent of highly sensitive DNA genotyping methods used for plasma analysis, we hypothesized that these same methods might allow genotyping of free DNA derived from fine needle aspiration supernatant (FNA-S). METHODS: We studied patients with known or suspected lung cancer undergoing fine needle aspirate (FNA). After spinning the sample for cellblock, the FNA-S (usually discarded) was saved for genotyping. Supernatant cell-free DNA (SN-cfDNA) was extracted and tested by both droplet digital PCR (EGFR, BRAF, KRAS mutations) and highly sensitive amplicon-based next-generation sequencing (NGS). RESULTS: 17 samples were studied, including 11 FNAs from patients with suspected lung cancer and 6 FNAs from patients with lung cancer and acquired drug resistance. Of 6 newly diagnosed adenocarcinomas, 4 had a driver mutations (1 EGFR, 2 KRAS, 1 HER2) found on tissue; all of these could be detected in SN-cfDNA. The EGFR driver mutation was detected in all 5 adenocarcinomas with acquired EGFR resistance and the EGFR T790 M in three cases, in agreement with cellblock. CONCLUSIONS: FNA-S is a rich source of fresh tumor DNA, potentially increasing the diagnostic yield from small FNAs. Through use of emerging techniques for highly sensitive genotyping, this widely available biospecimen has potential for facilitating rapid cancer genotyping at diagnosis and after drug resistance.

Long-term outcomes after near-infrared sentinel lymph node mapping in non-small cell lung cancer.

OBJECTIVE: To report the first analysis of long-term outcomes using near-infrared (NIR) image-guided sentinel lymph node (SLN) mapping in non-small cell lung cancer (NSCLC). METHODS: Retrospective analysis of patients with NSCLC enrolled in 2 prospective phase 1 NIR-guided SLN mapping trials, including an indocyanine green (ICG) dose-escalation trial, was performed. All patients underwent NIR imaging for SLN identification followed by multistation mediastinal lymph node sampling (MLNS) and pathologic assessment. Disease-free (DFS) and overall survival (OS) were compared between patients with NIR+ SLN (SLN group) and those without (non-SLN group). RESULTS: SLN detection, recurrence, DFS, and OS were assessed in 42 patients with NSCLC who underwent intraoperative peritumoral ICG injection, NIR imaging, and MLNS. NIR+ SLNs were identified in 23 patients (SLN group), whereas SLNs were not identified in 19 patients enrolled before ICG dose and camera optimization (non-SLN group). Median follow-up was 44.5 months. Pathology from NIR+ SLNs was concordant with overall nodal status in all 23 patients. Sixteen patients with SLN were deemed pN0 and no recurrences were, whereas 4 of 15 pN0 non-SLN patients developed nodal or distant recurrent disease. Comparing SLN versus non-SLN pN0 patients, the probability of 5-year OS is 100% versus 70.0% (P = .062) and 5-year DFS is statistically significantly improved at 100% versus 66.1% (P = .036), respectively. Among the 11 pN+ patients, 7 were in the SLN group, with >40% showing metastases in the SLN alone. CONCLUSIONS: Patients with pN0 SLNs showed favorable disease-free and overall survival. This preliminary review of NIR SLN mapping in NSCLC suggests that pN0 SLNs may better represent true N0 status. A larger clinical trial is planned to validate these findings.

A novel technique for tumor localization and targeted lymphatic mapping in early-stage lung cancer.

OBJECTIVE: To investigate safety and feasibility of navigational bronchoscopy (NB)-guided near-infrared (NIR) localization of small, ill-defined lung lesions and sentinel lymph nodes (SLN) for accurate staging in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with known or suspected stage I NSCLC were enrolled in a prospective pilot trial for lesion localization and SLN mapping via NB-guided NIR marking. Successful localization, SLN detection rates, histopathologic status of SLN versus overall nodes, and concordance to initial clinical stage were measured. Ex vivo confirmation of NIR+ SLNs and adverse events were recorded. RESULTS: Twelve patients underwent NB-guided marking with indocyanine green of lung lesions ranging in size from 0.4 to 2.2 cm and located 0.1 to 3 cm from the pleural surface. An NIR+ "tattoo" was identified in all cases. Ten patients were diagnosed with NSCLC and 9 SLNs were identified in 8 of the 10 patients, resulting in an 80% SLN detection rate. SLN pathologic status was 100% sensitive and specific for overall nodal status with no false-negative results. Despite previous nodal sampling, one patient was found to have metastatic disease in the SLN alone, a 12.5% rate of disease upstaging with NIR SLN mapping. SLN were detectable for up to 3 hours, allowing time for obtaining a tissue diagnosis and surgical resection. There were no adverse events associated with NB-labeling or indocyanine green dye itself. CONCLUSIONS: NB-guided NIR lesion localization and SLN identification was safe and feasible. This minimally invasive image-guided technique may permit the accurate localization and nodal staging of early stage lung cancers.

[Video-assisted thoracic surgery (VATS) for lung cancer].

Video-assisted thoracic surgery (VATS) is gaining popularity as a technique for performing lobectomy in lung cancer. However its advantages over a limited or muscle-spearing thoracotomy for lung cancer surgery are still a matter of controversy. There is no obvious advantage in cancer prognosis, invasiveness and postoperative quality of life of VATS comparing with minimal thoracotomy. Recent data illustrate the need for critical evaluation of VATS before the procedure is accepted as a superior approach for thoracotomy, based on unproved advantages. With the wide use of lung cancer CT screening systems, it can be anticipated that early lung cancer cases will increase in the near future. Consequently, the establishment of a surgical procedure with radicality and less invasiveness will be strongly demanded for lung cancer.

Experimental Pilot Study of a Novel Endobronchial Drug Delivery Catheter.

BACKGROUND: An endobronchial infusion catheter introduced through a flexible bronchoscope channel has not been previously described. The aim of this study was to evaluate the technical feasibility of a new device. METHODS: Four porcine models underwent bronchoscopy with the infusion catheter. In the first experiment, methylene blue was injected into airway in volumes of 0.1, 0.3, or 1.0 mL into 2 animals. One animal was killed at 1 hour and the other at 24 hours after the procedure and gross dye diffusion was visually assessed. In the second experiment, a mixture of 80% sterile normal saline and 20% contrast media was injected into the airway in volumes of 0.3, 1.0, and 3.0 mL into 2 animals. One animal was killed at 7 days and the other at 20 days. Histologic evaluations were performed according to a bronchial damage scoring system. RESULTS: There was no perioperative morbidity. In the first experiment, infusion volumes of 0.1, 0.3, and 1.0 mL resulted in dye surrounding 67%±29%, 55%±17%, and 80%±20% of the infusion-site circumference, and longitudinal distribution of 4.0±1.7, 8.1±4.1, and 18.0±3.0 mm each, respectively. In the second experiment, infusion of 0.3 to 3.0 mL resulted in mild injury, inflammation, and hemorrhage/fibrin/thrombus at 7 and 20 days after surgery. CONCLUSIONS: Endobronchial infusion of dye and contrast media by the endobronchial drug delivery catheter showed that the media spread in a dose-dependent manner macroscopically and histologically. Further investigation will be required to assess the catheter as a new tool for localized drug delivery into the airway.

Inhaled Nitric Oxide Augments Left Ventricular Assist Device Capacity by Ameliorating Secondary Right Ventricular Failure.

Clinical right ventricular (RV) impairment can occur with left ventricular assist device (LVAD) use, thereby compromising the therapeutic effectiveness. The underlying mechanism of this RV failure may be related to induced abnormalities of septal wall motion, RV distension and ischemia, decreased LV filling, and aberrations of LVAD flow. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, may reduce RV afterload, and thereby increase LV filling, LVAD flow, and cardiac output (CO). To investigate the mechanisms associated with LVAD-induced RV dysfunction and its treatment, we created a swine model of hypoxia-induced pulmonary hypertension and acute LVAD-induced RV failure and assessed the physiological effects of NO. Increased LVAD speed resulted in linear increases in LVAD flow until pulse pressure narrowed. Higher speeds induced flow instability, LV collapse, a precipitous fall of both LVAD flow and CO. Nitric oxide (20 ppm) treatment significantly increased the maximal achievable LVAD speed, LVAD flow, CO, and LV diameter. Nitric oxide resulted in decreased pulmonary vascular resistance and RV distension, increased RV ejection, promoted LV filling and improved LVAD performance. Inhaled NO may thus have broad utility for the management of biventricular disease managed by LVAD implantation through the effects of NO on LV and RV wall dynamics.

Experimental study of a new tracheal prosthesis: pored Dacron tube.

OBJECTIVE: This study was designed to evaluate how various sizes and densities of pores in Dacron tubing might enhance its utility as a tracheal prosthesis. METHODS: A vascular prosthesis made of knitted external velour polyester was prepared for pore formation with a laser. The first set compared different pore sizes (300, 500, and 700 microm) and pore densities (25/cm(2) or 100/cm(2)). Grafts were reinforced with an externally heat-sealed silicone ring. The second set tested grafts with a pore density of 64/cm(2) and a pore size of 500 microm internally reinforced with a stainless-steel spiral stent. In all experiments, a canine mediastinal trachea 10 cartilage rings in length was resected, and the prosthesis was then implanted with an omental flap. RESULTS: Lower pore size and density (300 microm, 25 pores/cm(2)) led to essentially no tissue ingrowth. Larger pore size (700 microm) and low density (25 pores/cm(2)) led to rapid and excessive ingrowth of granulation. Midrange pore size (500 microm) and high density (100 pores/cm(2)) invited steady tissue ingrowth, but marked luminal stenosis eventually developed. Stent-reinforced prostheses with 500-microm pores at 64 pores/cm(2), as used in the second set, maintained an average patency rate of 60% or more (range, 20%-100%) at least 12 months after implantation. CONCLUSION: Our data show that porosity is a key factor for tissue growth through our Dacron tracheal prostheses. This artificial trachea model has led to long-term survivors up to 27 months after the operation and seems promising as a basic model for clinical tracheal repair.

Intravenous immunoglobulin-induced hemolytic anemia after thoracoscopic thymectomy for myasthenia gravis.

A 24-year-old woman underwent video-assisted thoracoscopic thymectomy for Osserman IIB myasthenia gravis (MG). In preparation for thymectomy, high-dose intravenous immunoglobulin (IVIG) was administered 1 week before the surgical procedure. After uneventful thoracoscopic thymectomy, the postoperative hemoglobin value decreased from 12.1 mg/dL to 8.2 mg/dL. A diagnosis of IVIG-associated hemolytic anemia was made based on a peripheral smear with numerous spherocytes, a positive direct antiglobulin test result, and increased reticulocyte count. Hemoglobin levels after IVIG administration should be monitored closely before and after elective surgical procedures to identify severe anemia. Transfusion of type-matched blood should be avoided and risk factors understood.

Myocardial drug distribution generated from local epicardial application: potential impact of cardiac capillary perfusion in a swine model using epinephrine.

Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart not only enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively toward the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue.