Optional active compliance chamber performance in a pulmonary artery-pulmonary artery configured paracorporeal artificial lung.

INTRODUCTION: Our group has developed a paracorporeal artificial lung (PAL) attached in a pulmonary artery (PA) to PA in series configuration to address profound respiratory failure and serve as a bridge to transplant and/or recovery. We recently designed, developed and converted our passive pre-PAL compliance chamber to an active, synchronized, counterpulsating assist device to relieve right heart strain and offset increased work placed on the right ventricle when the PAL is attached. In this study, we evaluated the safety and performance of both a valved and non-valved optional active compliance chamber (OACC) in a PA-PA PAL for right heart assistance in normal adult sheep. METHODS: Eleven sheep (30-50 kg) were divided into non-valved OACC (n = 6) and valved (n = 5) OACC groups. To mimic pulmonary hypertension, a C-clamp was placed distal to the OACC-PAL and occluded until a 20% decrease in cardiac output (CO) was achieved. The OACC was activated, and right ventricular pressure (RVP), pulmonary artery pressure (PAP), mean arterial pressure (MAP) and CO were recorded. RESULTS: All eleven animals tolerated the implantation of the OACC PAL. Activation of the OACC resulted in a significant increase in CO. Systolic and diastolic right ventricular pressure decreased in both groups. Lastly, counterpulsation increased the mean PAP in all animals and peak PAP reached 89 mmHg. Despite providing right heart assistance, synchronizing the counterpulsation was technically difficult, and the high peak PA pressures resulted in anastomotic bleeding in all animals and anastomotic breakdown in 4/11 animals. CONCLUSIONS: An OACC PAL perfused by the right ventricle applied in series with the pulmonary circulation reduces ventricular load and improves cardiac efficiency. These preliminary data suggest the potential of an artificial lung in unloading the strained right ventricle and acting as a bridge to transplantation. The augmented peak PA pressures, resulting in bleeding and anastomotic breakdown, and complexity in synchronizing the cardiac cycle with the pulsations of the augmented OACC, compromise this configuration.

Development of ambulatory arterio-venous carbon dioxide removal (AVCO2R): the downsized gas exchanger prototype for ambulation removes enough CO2 with low blood resistance.

We are developing an ultra compact gas exchanger to allow ambulation during arterial-venous CO2 removal (AVCO2R). The ambulatory AVCO2R gas exchanger (135 ml prime volume and 1.3 M2 gas exchange surface area) is made of polymethylpentene hollow fibers. The gas exchanger was attached to sheep carotid artery (12F) and jugular vein (14F) by percutaneous cannulae for 6 hours (n = 5). Device CO2 removal was measured and calculated at a constant blood flow rate of 1 L/min coupled with varying sweep gas from 1 to 15 L/min, and at constant sweep gas flow of 2 L/min coupled with varying blood flow from 0.5 to 1.25 L/min to determine capacity of CO2 removal at Pa CO2 = 40-50 mm Hg. Blood gases, CO2 removal and hemodynamics were recorded at 0, 3, and 6 hours. CO2 removal increased with sweep gas flow rate and with increase of device blood flow. Hemodynamics remained unchanged throughout study. Gas exchanger resistance remained stable at 2.3 +/- 0.53 mm Hg/L/min. CO2 removal with 1 L/min blood flow and 2 L/min sweep gas was 110 +/- 12 then stabilized at 85 +/- 14 mL/min to 6 hours. The compact ambulatory AVCO2R gas exchanger achieves stable, near total CO2 removal for at least 6 hours with a simple arteriovenous shunt.

Short term performance evaluation of a perfluorocopolymer coated gas exchanger for arteriovenous CO2 removal.

A new perfluorocopolymer coating for micropore hollow fiber gas exchangers was developed to improve gas exchange, reduce plasma leakage, and reduce blood-surface interactions. The present authors evaluated gas exchanger performance using this new coating in a prospective, randomized, controlled, unblinded, large animal model of CO2 retention. Adult sheep (30-40 kg), under general anesthesia, underwent cannulation of the carotid artery (12 F) and jugular vein (14 F). The perfluorocopolymer coated (n = 5) and uncoated (n = 5) gas exchangers were attached to an arteriovenous CO2 removal (AVCO2R) circuit. Blood gases, CO2 removal, and hemodynamics were monitored throughout the 6 hour study. Average CO2 removal was 107.6 +/- 15.6 ml/min (coated) vs. 93.0 +/- 13.9 ml/min (uncoated; p < 0.01). PaCO2 and CO2 removal for both coated and uncoated did not deteriorate significantly over the study. Average AVCO2R blood flow was 1,130 +/- 25 ml/min (coated) versus 1,101 +/- 79 ml/min (uncoated; p = not significant). Likewise, cardiac output and AVCO2R blood flow did not change over the duration of the study. No significant differences in the pressure gradient or resistance between devices (coated, 6.89 +/- 1.14 mm Hg/L/min; uncoated, 6.42 +/- 0.23 mm Hg/L/min) was noted. The authors concluded that the new perfluorocopolymer coated gas exchanger improved CO2 removal without compromising hemodynamics in an acute performance evaluation.

Toward ambulatory arteriovenous CO2 removal: initial studies and prototype development.

Extracorporeal arteriovenous carbon dioxide removal (AVCO2R) using percutaneous cannulae and a low resistance gas exchanger achieves near total CO2 removal, allowing lung rest and potentially improving survival. AVCO2R, redesigned to allow ambulation, has potential as treatment for severe chronic obstructive pulmonary disease or rehabilitation before lung transplant. The purposes of this study were to 1) determine the optimal ambulatory access for AVCO2 removal and 2) develop a prototype Ambulatory-AVCO2R gas exchanger. Initially, reinforced Gore-Tex 6 mm (two) and 8 mm (four) grafts were anastomosed to sheep carotid arteries and jugular veins as a loop in parallel to the cranial circulation to determine blood flow capabilities. Blood flow was 100-150 ml/min with a 14 gauge dialysis needle, and transected 6 mm Gore-Tex grafts achieved 500-900 ml blood flow, whereas transected 8 mm grafts achieved up to 2000 ml/min flow. The polytetrafluoroethylene (PTFE) loops were then connected to our newly developed ultra low resistance pumpless gas exchanger for ambulatory AVCO2R. The average pressure gradient across the prototype Ambulatory-AVCO2R gas exchangers (n = 5) was 2.8 +/- 0.8 mm Hg, and mean CO2 removal was 104.8 +/- 14.0 ml/min, with an average blood flow of 900 ml/min. We conclude that an 8 mm Gore-Tex reinforced graft arteriovenous loop supplies ample blood flow for our new ultra low resistance Ambulatory-AVCO2R to achieve near total CO2 removal.

Effect of epoxide hydrolase polymorphisms on chromosome aberrations and risk for lung cancer.

Microsomal epoxide hydrolase (mEH) gene is polymorphic and its enzyme is involved in the activation and subsequent detoxification of several tobacco carcinogens, for example polycyclic aromatic hydrocarbons. Therefore, we have investigated the association of two polymorphisms at exons 3 and 4 of the mEH gene with the development of lung cancer in 110 patients and 119 matched controls. In addition, we have investigated the relationship between the different mEH alleles and the frequency of chromosome aberrations (CA), as an approach to understand the role of genetic susceptibility on cancer risk. Our results show that only the homozygous exon 4 fast genotype is significantly associated with increased risk for lung cancer (odds ratio [OR]=6.26; 95% confidence interval [CI]=1.02-38.3). When the exons 3 and 4 polymorphisms are considered together, patients carrying the high enzyme activity genotype have a significantly increased risk for lung cancer (OR=2.46; 95% CI=1.06-5.68). More importantly, the increased risk for this group is confirmed by their having the highest frequency of CA compared to any other genotype groups. In addition, genotypes with higher risk had consistently more CA than those with lower risk. Our CA data also indicates that the low activity genotype may exert a protective role in cigarette smokers, as it was associated with a significant decrease in CA compared to the high and intermediate activity genotypes. In conclusion, the CA data provides evidence to support that susceptibility mEH alleles are significantly involved with the development of lung cancer from cigarette smoking.

Paracorporeal artificial lung: perioperative management for survival study in sheep.

An artificial lung may offer a bridge to recovery or transplant. Utilizing our recently developed paracorporeal artificial lung (PAL) in survival studies in sheep, we critically review our perioperative/anesthetic protocol. Adult Suffolk ewes (n = 15) underwent general anesthesia induced by ketamine (7-15 mg/kg, im) and isoflurane by mask, then intubated and maintained by 4.0-5.0% isoflurane titrated to mean arterial pressure (MAP) 70-110 mm Hg. After a latissimus-sparing thoracotomy and systemic heparinization (200 IU/kg), arterial grafts were anastomosed to the proximal and distal main pulmonary artery in an end-of-graft to side-of-artery fashion. A snare was passed around the pulmonary artery between anastomoses. When the snare was tightened, full pulmonary blood flow was diverted through the cannulae and immediately through the PAL. Perioperative crystalloids included a 500-mL prime, lactated Ringer's (LR) titrated to CVP 5-7 mm Hg, and a heparin infusion (activated clotting time [ACT] 250-300 s). Buprenorphine (0.3 mg im tid) controlled postoperative pain. Hemodynamic parameters, arterial blood gases (ABGs), and ACTs were measured every 6 h. Thirteen of 15 sheep survived the operation and were extubated in less than 20 min. Two groups were studied for up to 7-day survival. Both groups underwent immediate connection to the PAL diverting full pulmonary blood flow. Group 1 (n = 8) underwent immediate connection to a rigidly housed PAL, and 4 of 8 demonstrated immediate right heart failure. In Group 2 a compliance chamber was added to the PAL inflow, and 6 of 7 had stable hemodynamic function for the duration of the study. Incremental improvements in the PAL and our anesthetic and perioperative care have resulted in reliable survival in adult sheep allowing for artificial lung development.

The effect of augmented hemodynamics on blood flow during arteriovenous carbon dioxide removal.

Arteriovenous carbon dioxide removal (AVCO2R) as an alternative treatment for acute respiratory distress syndrome uses a low resistance gas exchanger in a simple arteriovenous shunt to achieve total CO2 removal and allow lung rest. We have previously shown in our clinically relevant LD40 ovine model of smoke/burn induced acute respiratory distress syndrome that AVCO2R allows significant decreases in respiratory rate, tidal volume, peak airway pressure, and FiO2, as compared with standard mechanical ventilation. In addition, we have shown in a prospective randomized outcomes study that AVCO2R increases ventilator free days, decreases ventilator dependent days, and significantly improves survival. The purpose of this study is to further define the limits of AVCO2R through hemodynamic augmentation and evaluation of peak end expiratory pressure (PEEP). Administration of an alpha agonist (phenylephrine) and a beta agonist (isoproterenol) increased mean arterial pressure (MAP) and cardiac output (CO), respectively. MAP increases ranged from 2.4% to 94.4% and CO increases ranged from 33% to 146%. Phenylephrine caused elevations in MAP (2.4-94.4%) and AVCO2R flow (9-67%), and CO never decreased more than 10%. Isoproterenol administration increased CO (33-146%), decreased MAP (9-54%), and decreased AVCO2R flow (11-42%). In a second group, PEEP was increased stepwise from 0 (baseline) to 20 cm H2O. Increasing PEEP did not result in significant hemodynamic changes (< 10% change from baseline PEEP) for MAP, CO, or AVCO2R flow. In conclusion, alpha agonist administration increased AVCO2R blood flow, whereas beta agonist administration decreased MAP and AVCO2R blood flow, despite CO elevation. Various levels of PEEP are well tolerated and thus allow a range of options during AVCO2R.

Comparison of L-selectin and CD11b on neutrophils of adults and neonates during the first month of life.

The newborn infant is particularly susceptible to infection in the first weeks of life and this may be, in part, related to functional impairment of neonatal neutrophils in regard to adherence, chemotaxis, and migration. Differences in expression of the neutrophil adherence molecules, L-selectin and CD11b/CD18 (Mac-1), have been previously demonstrated in cord blood and in very young infants (

The paracorporeal artificial lung improves 5-day outcomes from lethal smoke/burn-induced acute respiratory distress syndrome in sheep.

BACKGROUND: Our low-impedence, paracorporeal artificial lung (PAL) prototype is well-tolerated in-series with the normal sheep pulmonary circulation. Using our lethal dose 80% to 100% smoke/burn acute respiratory distress syndrome (ARDS) sheep model, we compared PAL to volume-controlled mechanical ventilation (VCMV) in a prospective, randomized, controlled, unblinded, 5-day outcome study. METHODS: Fourteen sheep were randomized to PAL (n = 8) versus VCMV (n = 6) to assess outcome. For PAL, arterial cannulas were anastomosed to the proximal and distal main pulmonary artery with an interposing snare diverting full flow through a paracorporeal loop. Acute respiratory distress syndrome was induced in both groups (48 breaths smoke insufflation, third degree burn on 40% of total body surface area). When acute respiratory distress syndrome criteria were met (24 to 30 hours after injury), the PAL was interposed in the paracorporeal loop. Both groups were managed with a VCMV algorithm minimizing tidal volume, ventilator rate, and fractional inspired concentration of oxygen (FiO2). RESULTS: Six of eight PAL versus 1 of 6 VCMV sheep survived the 5-day study. In PAL, cardiac output, mean arterial pressure, pulmonary artery pressure, left atrial pressure, and central venous pressure remained stable. Average PAL gas transfer was 218.6 +/- 17.7 mL/min O2 and 183.0 +/- 27.8 mL/min CO2. Ventilator settings 48 hours after lung injury in PAL were significantly lower (p < 0.05) than VCMV (TV 210 versus 425 mL; respiratory rate 6 versus 29 breaths/min; minute ventilation 1.2 versus 10.8 L/min; FiO2 21 versus 100%). Likewise, PaO2/FiO2 ratio was normalized in PAL and still met acute respiratory distress syndrome criteria in VCMV. The PAL wet/dry ratio was significantly lower than VCMV (6.36 +/- 0.63 versus 11.85 +/- 1.54; p = 0.008). CONCLUSIONS: In a prospective, randomized, controlled, unblinded, outcomes study, PAL decreased ventilator-induced lung injury in a lethal dose 80% to 100% ARDS model to improve 5-day survival.

Lobe-sparing resection of multiple pulmonary metastases with a new 1318-nm Nd:YAG laser--first 100 patients.

BACKGROUND: A new 1318-nm Nd:YAG laser has been developed to utilize the second wavelength (1318 nm; 40 watt) to more precisely cut, coagulate, and seal lung tissue adjacent to pulmonary nodules. This laser allows a precise intraparenchymal nodulectomy with a 5-mm rim of tissue destruction and subsequent lung parenchymal reapproximation to avoid lobar distortion. Resection of multiple, bilateral, and recurrent tumors in the lung is facilitated by this laser technique. METHODS: In 100 consecutive patients (53 men, mean age 60 years; 47 women, mean age 61 years) with various primaries (most commonly renal and colorectal), 155 laser resections were performed via anterolateral thoracotomy (staged 3 to 4 weeks, if bilateral) using a new 1318-nm Nd:YAG laser. All palpable and visible masses were removed with 2 to 3-mm visible tumor margins (plus a 5-mm rim of residual lung necrosis secondary to laser energy dispersal) if the tumor or residual lung ratio was judged favorable. No stapling devices or bioadhesives were used. RESULTS: Six hundred thirty-two metastases (6.3 per patient, range 1 to 124) were resected. Despite 41% centrally located metastases, tumor resections were possible in 95% of patients with only a 5% lobectomy rate. Of the 100 patients, 67 were considered "curative" with complete metastasectomy by inspection and palpation, and 23 were judged incomplete from too extensive tumor or residual lung, miliary lung spread, or pleural studding. There were no associated mortalities and two complications, including bleeding (1) and a prolonged airleak (1), both treated conservatively. Follow-up was complete in all patients for a median of 26.5 months with clinic visits and chest computed tomographic scan every 3 to 6 months. Nine recurrences were detected and underwent reoperation. Overall survival in the completely resected "curative" group was 85% at 1 year, 71% at 2 years, 69% at 3 years, 57% at 4 years, and 32% at 5 years; in the completely resected "palliative" group, they were 70% at 1 year, 36% at 2 years, 12% at 3 years, and 0 at 4 years; in the incomplete group, they were 56% at 1 year, 30% at 2 years, and 0 at 3 years. CONCLUSIONS: The new 1318-nm Nd:YAG laser is parenchyma-sparing, improves complete resection rates, and potentially improves survival with fewer required lobectomies.

Artificial lungs: a new inspiration.

An estimated 16 million Americans are afflicted with some degree of chronic obstructive pulmonary disease (COPD), accounting for 100,000 deaths per year. The only current treatment for chronic irreversible pulmonary failure is lung transplantation. Since the widespread success of single and double lung transplantation in the early 1990s, demand for donor lungs has steadily outgrown the supply. Unlike dialysis, which functions as a bridge to renal transplantation, or a ventricular assist device (VAD), which serves as a bridge to cardiac transplantation, no suitable bridge to lung transplantation exists. The current methods for supporting patients with lung disease, however, are not adequate or efficient enough to act as a bridge to transplantation. Although occasionally successful as a bridge to transplant, ECMO requires multiple transfusions and is complex, labor-intensive, time-limited, costly, non-ambulatory and prone to infection. Intravenacaval devices, such as the intravascular oxygenator (IVOX) and the intravenous membrane oxygenator (IMO), are surface area limited and currently provide inadequate gas exchange to function as a bridge-to-recovery or transplant. A successful artificial lung could realize a substantial clinical impact as a bridge to lung transplantation, a support device immediately post-lung transplant, and as rescue and/or supplement to mechanical ventilation during the treatment of severe respiratory failure.

Extracorporeal membrane oxygenation for severe respiratory failure.

The use of extracorporeal technology to accomplish gas exchange with or without cardiac support is based on the premise that "lung rest" facilitates repair and avoids the baso- or volutrauma of mechanical ventilator management. Extracorporeal membrane oxygenation (ECMO), a modified form of cardiopulmonary bypass, has been shown to decrease mortality of neonatal, pediatric and adult respiratory failure and is capable of total gas exchange. In neonates, over 20,638 patients have been treated with an overall survival of 77% in a population thought to have 78% mortality.

Arterio-venous CO2 removal (AVCO2R) perioperative management: rapid recovery and enhanced survival.

Percutaneous arteriovenous CO2 removal (AVCO2R) uses a simple arteriovenous (A-V) shunt for near-total CO2 removal that allows significant reductions in minute ventilation. We critically reviewed our algorithm-directed perioperative anesthesia management in our LD40 ovine smoke-burn injury model of acute respiratory distress syndrome (ARDS) treated with AVCO2R. General anesthesia is required for: (1) Vascular access followed by ARDS model development by smoke insufflation (36 breaths) plus 40% TBSA III degrees burn with mechanical ventilation. Induction: 12.5 mg/kg im ketamine and 4% halothane by mask, then intubation. Maintenance: 1.0-2.5% halothane in 100% O2; (2) When PaO2/FiO2 < 200 (48-52 h), sheep randomized to the AVCO2R (n = 8) or SHAM (n = 8) procedure. Induction: 66% N2O and 5% isoflurane in balance O2. Maintenance: 1.5-2.5% isoflurane in 100% O2 for AVCO2R, cannulation (10F carotid artery, 14F jugular vein); (3) Postop, both groups had algorithm-directed ventilator management, identical heparin (ACT > 300 s), fluid, and analgesia management. All sheep met criteria for ARDS, survived anesthesia, and were standing by 0.5-5 h. There were no complications attributable to anesthesia. The absence of anesthesia-related complications allows model development for outcomes studies for ARDS in general and AVCO2R specifically.

Mediastinal transthoracic needle and core lymph node biopsy: should it replace mediastinoscopy?

STUDY OBJECTIVES: Primary assessment of mediastinal lymph nodes (N2 or N3) for staging lung cancer by transthoracic needle with or without core biopsy. Mediastinoscopy only performed after FNA failed to yield a diagnosis. DESIGN AND SETTINGS: A retrospective study in a university setting. PATIENTS: Eighty-nine patients with mediastinal lymphadenopathy (> 1.5 cm in short-axis diameter) by CT. METHODS: Mediastinal transthoracic fine-needle aspiration (FNA) with or without core biopsy was performed prior to mediastinoscopy in 89 patients with mediastinal lymphadenopathy (lymph node > 1.5 cm in short-axis diameter) or masses by CT. RESULTS: Mediastinal transthoracic FNA was used alone in 39 of 89 patients, or with core biopsy in 50 of 89 patients. Mediastinal transthoracic FNA with or without core biopsy was diagnostic in 69 of 89 patients (77.5%) for cancer cell type, sarcoidosis, or caseating granulomas with or without tuberculosis. Transthoracic FNA with or without core biopsy of nodal stations (total, 94 biopsies) judged readily accessible by mediastinoscopy (n = 59) included paratracheal (n = 56) and highest mediastinal (n = 3); those more difficult (n = 26) included subcarinal (n = 20) and aorticopulmonary window (n = 6); and those impossible (n = 9) included paraesophageal and pulmonary ligament (n = 6), parasternal (n = 2), and para-aortic (n = 1). Innovative lung protective techniques for CT-guided biopsy access windows included "iatrogenic-controlled pneumothorax" (n = 10) or saline solution injection creating a "salinoma" (n = 11). Pneumothorax was detected in only 10% with a "protective" technique but 60% when traversing lung parenchyma. Transthoracic FNA with or without core biopsy failed to yield a diagnosis in 20 of 89 patients (22.5%); all then underwent mediastinoscopy, with 11 of 20 procedures (55%) diagnostic for cancer, and 9 of 20 procedures diagnostic of benign diagnosis or no cancer. CONCLUSION: Transthoracic FNA with or without core biopsy accesses virtually all mediastinal nodal stations is diagnostic in 78% of cases with mediastinal adenopathy or masses, and should precede mediastinoscopy in the staging of lung cancer or workup of mediastinal masses.