Chromosome aberrations as a predictor of clinical outcome for smoking associated lung cancer.

The ability to identify individuals at greatest risk of developing lung cancer can significantly enhance the efficacy of intervention modalities. One strategy for identifying these individuals is through biomarkers that reflect the severity of their cancer. In the present study, we evaluated 22 lung cancer patients and 35 controls to determine whether the frequency of chromosome aberrations was significantly associated with specific clinical variables such as the histological type, grade and stage of the tumors. Chromosome aberrations (expressed as total breaks) were investigated on chromosome 1 in interphase nuclei obtained from blood lymphocytes of the study participants using the fluorescence in situ hybridization (FISH) chromosome aberration assay. Our results indicate a significant linear increase (P=0.01) in the level of breaks with respect to the grade of the carcinoma. The poorly differentiated tumors had a significantly higher level of chromosome breaks mean+/-SD (1.7+/-0.46) as compared to the well differentiated tumors (0.98+/-0.23, P<0.05). These results indicate that chromosome aberrations, as determined by the FISH assay, can be used as a biomarker for identifying individuals with aggressive types of lung cancer and potentially, as a predictor for prognostic outcome of the disease.

Percutaneous extracorporeal arteriovenous carbon dioxide removal improves survival in respiratory distress syndrome: a prospective randomized outcomes study in adult sheep.

OBJECTIVE: Arteriovenous carbon dioxide removal (AVCO(2)R) uses a simple arteriovenous shunt for CO(2) removal to minimize barotrauma/volutrauma from mechanical ventilation. We performed a prospective randomized outcomes study of AVCO(2)R in our new, clinically relevant model of respiratory distress syndrome. METHODS: Adult sheep (n = 18) received an LD(50) severe smoke inhalation and 40% third-degree burn. When respiratory distress syndrome developed (PaO (2)/FIO (2) < 200 at 40 to 48 hours), animals were randomized to the AVCO(2)R (n = 9) or sham group (n = 9) for 7 days. Ventilator management protocols mandated reductions in minute ventilation, first tidal volume to peak inspiratory pressure less than 30 cm H(2)O, then respiratory rate when PaCO (2) was less than 40 mm Hg. PaO (2) was kept above 60 mm Hg by adjusting FIO (2). When FIO (2) was 0.21, animals were weaned. RESULTS: The study required 2946 animal-hours of critical care with 696 AVCO(2)R hours. One died in each group during model development. AVCO(2)R flow from 820 mL/min to 970 mL/min (11% to 14% cardiac output) removed CO(2) at a rate of 92 to 116 mL/min (mean 103 mL/min; 93%-97% of CO(2) production). Heart rate, mean arterial pressure, cardiac output, and pulmonary arterial wedge pressure remained relatively constant. Within 48 hours, AVCO(2)R allowed significant ventilator reductions versus baseline in the following measurements: tidal volume (420 to 270 mL), peak inspiratory pressure (25 to 14 cm H(2)O), minute ventilation (13 to 5 L/min), respiratory rate (26 to 16 breaths/min), and FIO (2) (0.88 to 0.35). Ventilator-free days with AVCO(2)R were 3.9 versus 0.2 (P <.01) for sham animals, and ventilator-dependent days with AVCO(2)R were 2.4 versus 6.2 (P <.01) for the 3 sham survivors. All 8 AVCO(2)R animals and 3 of 8 sham animals survived 7 days after randomization. CONCLUSIONS: Percutaneous AVCO(2)R achieved significant reduction in airway pressures, increased ventilator-free days, decreased ventilator-dependent days, and improved survival in a sheep model of respiratory distress syndrome.

Prolonged hemodynamic stability during arteriovenous carbon dioxide removal for severe respiratory failure.

OBJECTIVE: The effects of prolonged arteriovenous carbon dioxide removal on hemodynamics during severe respiratory failure were evaluated in adult sheep with severe smoke inhalation injury. METHODS: Adult female sheep (n = 6,33.8 +/- 5.2 kg) were subjected to intratracheal cotton severe smoke insufflation to a mean carboxyhemoglobin level of 83% +/- 3%. Twenty-four hours after injury, a low-resistance 2.5 m2 membrane oxygenator was placed in a carotid-to-jugular pumpless arteriovenous shunt at unrestricted flow to allow complete carbon dioxide removal and reductions in ventilator support. Animals remained conscious, and heart rate, cardiac output, mean arterial pressure, and pulmonary arterial pressure were measured at baseline, after injury, and daily during support with the arteriovenous carbon dioxide removal circuit for 7 days. RESULTS: All animals survived the study period. Carbon dioxide removal ranged from 99.7 +/- 13.7 to 152.2 +/- 16.2 ml/min, and five (83%) of the six animals were successfully weaned from the ventilator before day 7. During full support with the arteriovenous carbon dioxide removal circuit, shunt flow ranged from 1.24 +/- 0.06 to 1.43 +/- 0.08 L/min and accounted for 20.1% +/- 1.4% to 25.9% +/- 2.4% of cardiac output. No statistically significant changes in heart rate, cardiac output, mean arterial pressure, or pulmonary artery pressure were demonstrated over the study course despite the extracorporeal shunt flow. CONCLUSIONS: Arteriovenous carbon dioxide removal as a simplified means of extracorporeal gas exchange support is relatively safe without adverse hemodynamic effects or complications.

Total extracorporeal arteriovenous carbon dioxide removal in acute respiratory failure: a phase I clinical study.

OBJECTIVE: To evaluate the safety and efficacy of pumpless extracorporeal arteriovenous carbon dioxide removal (AVCO2R) in subjects with acute respiratory failure and hypercapnia. DESIGN: A phase I within-group time series trial in which subjects underwent up to 72 h of support with AVCO2R in intensive care units of two university hospitals. PATIENTS: Eight patients with acute hypercapnic respiratory failure or hypoxemic respiratory failure managed with permissive hypercapnia. INTERVENTIONS: Extracorporeal CO2 removal was achieved through percutaneous cannulation of the femoral artery and vein, and a simple extracorporeal circuit using a commercially available membrane gas exchange device for carbon dioxide exchange. MEASUREMENTS AND RESULTS: Measurements of hemodynamics, blood gases, ventilatory settings, and laboratory values were made before initiation of AVCO2R, and at subsequent intervals for 72 h. PaCO2 decreased significantly from 90.8+/-7.5 mmHg to 52.3+/-4.3 and 51.8+/-3.1 mmHg at 1 and 2 h, respectively. This decrease occurred despite a decrease in minute ventilation from a baseline of 6.92+/-1.64 l/min to 4.22+/-.46 and 3.00+/-.53 l/min at 1 and 2 h. There was a normalization of pH, with an increase from 7.19+/-.06 to 7.35+/-.07 and 7.37+/-.05 at 1 and 2 h. These improvements persisted during the full period of support with AVCO2R. Four subjects underwent apnea trials in which AVCO2R provided total carbon dioxide removal during apneic oxygenation, resulting in steady-state PaCO2 values from 57 to 85 mmHg. Hemodynamics were not significantly altered with the institution of AVCO2R. There were no major complications attributed to the procedure. CONCLUSION: Pumpless extracorporeal AVCO2R is capable of providing complete extracorporeal removal of carbon dioxide during acute respiratory failure, while maintaining mild to moderate hypercapnia. Applied in conjunction with mechanical ventilation and permissive hypercapnia, AVCO2R resulted in normalization of arterial PCO2 and pH and permitted significant reductions in the level of mechanical ventilation.

Safety and efficacy of a heparin removal device: a prospective randomized preclinical outcomes study.

BACKGROUND: Systemic protamine sulfate for heparin reversal after cardiopulmonary bypass (CPB) is associated with uncommon, but life-threatening adverse reactions. METHODS: In a prospective randomized 3-day outcomes study, a heparin removal device (HRD) group (n = 12; 60-, 80-, 100-kg subgroups) was compared with a matched systemic Protamine group (Protamine; n = 6) for safety and efficacy using an adult swine model of CPB (60 minutes, 28 degrees C). RESULTS: HRD run time was 25 to 38 minutes depending on weight without complications. After HRD, heparin concentration decreased from 4.77 +/- 0.17 to 0.45 +/- 0.06 U/mL (activated clotting time [ACT] 776 +/- 83 to 180 +/- 12 seconds), and in Protamine, 3.94 +/- 0.63 to 0.13 +/- 0.02 U/mL (ACT 694 +/- 132 to 101 +/- 5 seconds) (p = 0.01 between groups, but no significant differences 60 minutes later). No significant difference between HRD and Protamine to 72 hours was seen in plasma-free hemoglobin C3a, heparin concentration, thromboelastogram index, platelet count, activated partial thromboplastin time, anti-thrombin III, fibrinogen, ACT, and tissue histology. CONCLUSIONS: In a prospective randomized outcomes study, HRD achieved predictable reversal of systemic heparinization after CPB with no difference in safety or outcomes compared with protamine.

Percutaneous extracorporeal arteriovenous CO2 removal for severe respiratory failure.

BACKGROUND: In previous animal studies, arteriovenous CO2 removal (AVCO2R) achieved significant reduction in ventilator pressures and improvement in the Pao2 to fraction of inspired oxygen ratio during severe respiratory failure. For our initial clinical experience, 5 patients were approved for treatment of severe respiratory failure and CO2 retention to evaluate the feasibility and safety of percutaneous AVCO2R. METHODS: Patients were anticoagulated with heparin (activated clotting time, 260 to 300 seconds), underwent percutaneous femoral cannulation (10F to 12F arterial and 12F to 15F venous catheters), and then were connected to a low-resistance, 2.5-m2 hollow-fiber oxygenator for 72 hours. RESULTS: Mean AVCO2R flow at 24, 48, and 72 hours was 837.4+/-73.9, 873+/-83.6, and 750+/-104.5 mL/min, respectively, with no vascular complications and no significant change in heart rate or mean arterial pressure. Removal of CO2 plateaued at an AVCO2R flow of 1086 mL/min with 208 mL/min CO2 removed. Average CO2 transfer at 24 and 48 hours was 142+/-17 and 129+/-16 mL/min. Use of AVCO2R allowed a significant decrease in minute ventilation from 7.2+/-2.3 L/min at baseline to 3.4+/-0.8 L/min at 24 hours. CONCLUSIONS: All patients survived the experimental period without adverse sequelae. Percutaneous AVCO2R can achieve approximately 70% CO2 removal in adults with severe respiratory failure and CO2 retention without hemodynamic compromise or instability.

Percutaneous venovenous perfusion-induced systemic hyperthermia for advanced non-small cell lung cancer: initial clinical experience.

BACKGROUND: Venovenous perfusion-induced systemic hyperthermia raises core body temperature by extracorporeal heating of the blood. Five patients with advanced non-small cell lung carcinoma stage IV (4.4+/-1 months after initial diagnosis) received venovenous perfusion-induced systemic hyperthermia to 42.5 degrees C (core temperature) to assess technical and patient risks. METHODS: After general anesthesia and systemic heparinization (activated clotting time > 300 seconds), percutaneous cannulation of the right internal jugular vein (15F) for drainage and common femoral vein (15F) for reinfusion allowed extracorporeal flow rates up to 1,500 mL/min (20 mL x kg(-1) x min(-1)) with the ThermoChem System. This device uses charcoal-based sorbent for electrolyte homeostasis. Six monitored sites (rectal, bladder, tympanic x2, nasopharyngeal, and esophageal) determined average core temperature. RESULTS: All patients achieved a core target temperature of 42.5 degrees C for 2 hours. Electrolyte balance was maintained throughout hyperthermia (mean) in mmol/L: Na+, 136.2+/-2.2 mmol/L; K+, 4.0+/-0.3 mmol/L; Ca2+, 4.1+/-0.2 mg/dL; Mg2+, 1.9+/-0.1 mg/dL; PO4-, 4.5+/-0.9 mg/dL). Plasma cytokine concentration revealed significant heat-induced activation of proinflammatory and antiinflammatory cascades. All patients exhibited systemic vasodilation requiring norepinephrine infusion, 4 of 5 patients required vigorous diuresis, and 3 of 5 required intubation for 24 to 36 hours because of pulmonary edema or somnolence, with full recovery. Average length of hospital stay was 5.4 days. Serial tumor measurements (1 patient withdrew) revealed a decrease (64.5%+/-18%) in tumor size in 2 patients, no change in 1, and enlargement in 1, with no 30-day mortality. Median survival after hyperthermia treatment was 172 days (range, 40 to 271 days). CONCLUSIONS: Venovenous perfusion-induced systemic hyperthermia is feasible and provides the following potential advantages for better tumoricidal effect: (1) homogeneous heating, and (2) a higher sustained temperature.

Improved right heart function with a compliant inflow artificial lung in series with the pulmonary circulation.

BACKGROUND: We previously reported a 50% incidence of immediate right heart failure using a rigidly housed, noncompliant inflow artificial lung in series with the pulmonary circulation in a healthy ovine survival model. Three device modifications resulted: (1) an inflow cannula compliance chamber, (2) an inlet blood flow separator, and (3) modification of the artificial lung outlet geometry, all to reduce resistance and mimic the compliance of the pulmonary vascular bed. METHODS: In 7 sheep, arterial grafts were anastomosed end-to-side to the proximal and distal main pulmonary artery, with the paracorporeal artificial lung interposed. A pulmonary artery snare between anastomoses diverted full pulmonary blood flow through the artificial lung for up to 72 hours. RESULTS: Six of 7 sheep exhibited good cardiac function throughout the test period: mean central venous pressure was 6.8 mm Hg (range, 4 to 11 mm Hg), mean cardiac output, 4.17 +/- 0.12 L/min (range, 2.4 to 6.3 L/min); before and after device mean pulmonary arterial pressure, 21.8 and 18.5 mm Hg, and left atrial pressure, 10.8 mm Hg. CONCLUSIONS: This modified artificial lung prototype with an inflow compliance chamber, blood flow separator, and modified outlet geometry has greatly improved cardiac function and initial survival in our healthy ovine model.

Airway simulation to guide stent placement for tracheobronchial obstruction in lung cancer.

BACKGROUND: To effectively palliate large airway obstruction in advanced unresectable lung cancer (stage IIIB or IV), we developed an airway imaging technique to guide selective endobronchial metallic stent placement. METHODS: Fourteen consecutive patients with severe dyspnea (American Thoracic Society grade 4) had a combination of fiberoptic bronchoscopy, chest roentgenography, computed tomographic scanning, helical computed tomography with three-dimensional reconstruction, and intraluminal bronchography with selective bronchial guidewire placement under fluoroscopy to visually reconstruct and simulate the abnormal airway before and during stent placement. Wallstent or Gianturco intraluminal stents were used alone or in combination (up to five stents) to establish patency of the distal trachea and the major bronchi. RESULTS: All 14 patients had successful deployment with initial relief of airway stenosis (>75% predicted diameter). No procedural complications were noted. However, technical problems included stent foreshortening and imprecision of placement, misinterpretation of bronchography (mucous versus tumor), and airway maintenance during manipulation. Length of stay attributable to the procedure averaged 4 days. Stent placement initially improved the dyspnea score in 7 of 14 patients. Five of 14 died in less than 1 month, with the remainder alive at up to 8 months' follow-up. Of those surviving more than 1 month, the Karnofsky score improved in 4 and was unchanged in 5, with 2 dependent (Karnofsky score <50), 3 functional (Karnofsky score, 50 to 70), and 4 active (Karnofsky score >70). CONCLUSIONS: A protocol combining helical computed tomography with three-dimensional reconstruction, bronchography, and bronchoscopy allows accurate assessment of malignant airway obstruction to facilitate intralumenal stent placement for relief of stenosis. Patient selection to favor effective palliation and cost effectiveness has yet to be defined.

Staging and surgery for non-small cell lung cancer (NSCLC).

Despite current advances in diagnosis, staging, and treatment, carcinoma of the lung remains the leading cause of death from cancer in both men and women. Non-small cell lung cancer represents approximately 80% of all new lung cancer cases; however, only one-third of these cases will undergo surgical resection for tumor control. This article reviews the evaluation, latest revisions in staging, and surgical management of non-small cell lung cancer.

High flow/low resistance cannulas for percutaneous arteriovenous carbon dioxide removal.

Percutaneous cannulas with low resistance are necessary for arteriovenous carbon dioxide removal (AVCO2R) to allow highest flow at lowest pressure to maximize CO2 removal. Commercially available arterial (A) and venous (V) percutaneous cannulas (8-18 Fr) were tested for pressure/flow characteristics under conditions that simulated percutaneous AVCO2R at clinically pertinent flow rates between 200-1000 ml/min to obtain the M number previously described by Delius, et al. The Bio-Medicus (Bio-Medicus, Grand Rapids, MI) 17F A, Research Medical, Inc (RMI) (Model FEM II, Research Medical, Inc., Midvale, UT) 16F A, and RMI 18F V cannulas exhibited the lowest M numbers that correlated with low resistance to flow. The four most clinically favorable arterial cannulas (8, 10, 12, and 14 Fr), coupled with a venous cannula four French sizes larger, were used in an AVCO2R circuit in adult sheep (n = 3) at varying mean arterial pressures (MAP) between 65-105 mmHg. The 8, 10, 12, and 14 Fr arterial cannulas allowed an arteriovenous flow of 208 +/- 72, 530 +/- 37, 848 +/- 66, and 944 +/- 96 ml/min, respectively, at a MAP of 65 mmHg. An increase in MAP to 105 mmHg was associated with approximately a 41, 30, 32, and 27% increment in blood flow, respectively. In summary, an arterial percutaneous cannula of 10 Fr or larger will allow AVCO2R blood flow greater than 500 ml/min, as previously shown by Brunston et al. to achieve total CO2 removal without incurring hypercapnia.

Significant reduction in circuit pressure with modified plasma separation chamber for a heparin removal device.

The heparin removal device (HRD), using plasma separation and poly-L-lysine (PLL) affinity adsorption, has been shown to be an effective alternative to protamine after cardiopulmonary bypass (CPB). Previous designs of the HRD used standard Luer-Lok ((phi = 2.3 mm) port connections between the extracorporeal tubing and the plasma separation chambers, which resulted in excessively high circuit pressures (> 750 mm Hg) at an HRD flow of 1,400 ml/min. To reduce circuit pressures, we enlarged the connection ports to phi = 4.2 mm, keeping other circuit components and sorbent amounts unchanged. The modified circuit HRD was divided into the SMALL PORT group (phi = 2.3 mm, A = 4.15 mm2) and the LARGE PORT group (phi = 4.2 mm, A = 13.85 mm2) in adult swine (70+/-5 kg) given 300 U/kg heparin. A dual lumen cannula was inserted into the right atrium and connected to the HRD. Inlet pressure ranged from 749+/-42 to 795+/-57 mm Hg in the SMALL PORT group during the HRD run at 1,400 ml/min, whereas it ranged from 345+/-5 to 372+/-34 mm Hg in the LARGE PORT group (p < 0.01 between groups). Likewise, the chamber pressure ranged from 447+/-21 to 452+/-27 mm Hg in the SMALL PORT group and from 190+/-14 to 204+/-19 mm Hg in the LARGE PORT group (p < 0.01 between groups). There were no significant differences in ACT between groups. We conclude that enlarged chamber ports significantly lower circuit pressures for the HRD without changing heparin removal capability.

Anatomic study of the pulmonary artery as a conduit for an artificial lung.

Our group is developing an artificial lung as a bridge to transplant. We evaluated the sheep pulmonary artery (PA) for the presence or absence of a septum, which may increase PA resistance and affect artificial lung flow. We also measured the PA size to determine whether it is a suitable conduit for artificial lung implantation using a PA-PA shunt. Adult Suffolk ewes in two groups were studied. Group 1 consisted of animals (n = 12, 30-43 kg) prepared for thoracotomy. Group 2 (n = 21, 30-43 kg) consisted of postmortem dissections. In both groups, the length and girth of the PA was measured. The heart and lungs were removed on all postmortem animals (group 2), the ductus arteriosum was crosscut, and the common PA was incised. The average length of the PA in live animals was 5.5 cm and the average diameter was 2.2 cm. The average length of the PA in postmortem animals was 4.8 cm and the average diameter was 2.0 cm. All pulmonary arteries were aseptate, and the ligamentum arteriosum in each PA was not patent. We conclude that the PA is not a source of increased resistance and is a suitable conduit for artificial lung implantation in the PA-PA configuration.

Hemodynamic stability during arteriovenous carbon dioxide removal for adult respiratory distress syndrome: a prospective randomized outcomes study in adult sheep.

To evaluate the ability of arteriovenous carbon dioxide removal (AVCO2R) to maintain hemodynamic stability during treatment of adult respiratory distress syndrome (ARDS), we used our smoke/burn, LD40 sheep model of ARDS. With onset of ARDS (PaO2/FiO2 < 200) animals were randomized to AVCO2R (n = 20) or SHAM (n = 8). With AVCO2R, the carotid artery (10-14 F) and jugular vein (14-16 F) were cannulated; SHAM received identical management, sparing the vessels. AVCO2R maintained stable hemodynamics compared to SHAM at 48 hours; heart rate (114.8+/-6.1 vs. 110.1+/-11.0 beats/min.), mean arterial pressure (112+/-5.1 vs. 107.0+/-8.5 mm Hg), cardiac output (7.4+/-0.5 vs. 7.5+/-0.9 L/min.), pulmonary arterial pressure (26+/-2.4 vs. 21+/-1.3 mm Hg), pulmonary arterial wedge pressure (14.1+/-1.8 vs. 14.0+/-1.2 mm Hg), and central venous pressure (7+/-1.6 vs. 8+/-0.9 mm Hg). At 48 hours, AVCO2R allowed significant reductions (p<0.05) in minute ventilation (13.6+/-2.5 to 7.6+/-0.8 L/min); tidal volume (TV) (389.4+/-24.1 to 295.0+/-10.1 ml); peak inspiratory pressure (PIP) (25.4+/-9.2 to 18.8+/-2.5 cm H2O); RR (27.5+/-0.7 to 21.6+/-1.8 breaths/min); and FiO2 (0.96+/-0.00 to 0.48+/-0.2) while normocapnia was maintained. AVCO2R is an effective method of CO2 removal during severe respiratory failure that is hemodynamically well tolerated.

Development of an ambulatory artificial lung in an ovine survival model.

We are developing an artificial lung (AL) as an eventual bridge to lung transplant or recovery. The device is rigidly housed, noncompliant, and has a very low resistance to blood flow. In eight sheep, arterial cannulae were anastomosed end-to-side to the proximal and distal main pulmonary artery, and attached to the AL. A pulmonary artery snare between anastomoses diverted full pulmonary blood flow through the AL. Eight of eight sheep survived the preparation. Mean pressure gradient across the AL was 8 mm Hg (3 Wood units; 8 mm Hg/2.8 L/min). Four of eight sheep tolerated immediate full diversion of blood flow and died at 24 and 40 hours (exsanguination) or 168 and 168 hours (elective sacrifice). Four of eight sheep were intolerant of full flow: two died of right heart failure at <8 hours with full flow through the device (full snare); the other two survived with partial device flow (partial snare), but the device clotted. These two then underwent successful closed-chest cannula thrombectomy and device change-out at 53 and 75 hours, and subsequently tolerated full flow. Long-term (up to 7 day) survival with complete diversion of pulmonary blood flow through a non-compliant, low-resistance AL is possible. Initial right heart failure in this model was 50% (4 of 8).

Extracorporeal gas exchange.

The high mortality associated with acute respiratory failure and further exacerbation of the lung injury by mechanical ventilation continues to pose a challenge in the management of critically ill patients. By providing total gas exchange and complete lung rest, extracorporeal membrane oxygenation (ECMO) has improved the survival rate of selected neonatal, pediatric, and adult patients. Arteriovenous carbon dioxide removal (AVCO2R) was developed as a less labor intensive, less costly, and less complex technique of extracorporeal gas exchange, allowing near total CO2 removal.