Aerosolized tacrolimus: a case report in a lung transplant recipient.

Long-term outcomes after lung transplantation remain poor mainly to the development of bronchiolitis obliterans syndrome (BOS). Currently, treatment options for BOS are very limited. Strategies to prevent and treat this complication include the use of aerosolized therapy with only cyclosporine used in patients to date. We describe the use of aerosolized tacrolimus in a lung transplant recipient with BOS. The patient demonstrated clinical improvement in functional capacity and oxygenation while receiving tacrolimus by nebulization. Further research is needed to study whether aerosolized tacrolimus is beneficial in lung transplant recipients with BOS.

A mechanical model of the human heart relating septal function to myocardial work and energy.

A thorough understanding of ventricular interaction and the effects of septal function on right and left ventricular performance in the human heart requires measurement of interventricular pressure gradients using high fidelity pressure transducers. The advent of newer echocardiographic techniques provides an opportunity to combine high resolution images with bi-ventricular catheterization data in the cardiac catheterization laboratory, and obtain the detailed hemodynamic and echocardiographic information necessary to more fully understand the clinical manifestations of normal and abnormal septal and free wall mechanical function. We have anticipated these developments and modified the description of heart mechanics in our integrated multi-scale model of the human cardio-respiratory system (H-CRS) to closely analyze how the mechanical properties of the inter-ventricular septum affect the work, energy utilization, and oxygen consumption of the atria, ventricles, septum, and each ventricular free wall. Combined with the H-CRS model, these modifications allow one to observe how tissue properties of the septum affect the entire heart and circulation. For example, the normal septum transfers energy from the left to the right ventricle, and assists the pre-load of both, acting as a third pump. Diseases that increase septal elastance cause abnormalities resembling left ventricular diastolic dysfunction (LVDD), including a decrease in cardiac output and an increase in pulmonary pressures despite a normal left ventricular ejection fraction. Similar applications of the H-CRS model to other regional disorders such as hypertrophic obstructive cardiomyopathy and myocardial infarction might likewise allow one to study their clinical implications in greater detail.

Using a human cardiopulmonary model to study and predict normal and diseased ventricular mechanics, septal interaction, and atrio-ventricular blood flow patterns.

We upgraded our human cardiopulmonary (CP) model with additional data that enables it to more accurately simulate normal physiology. We then tested its ability to explain human disease by changing two parameter values that decrease ventricular compliance, and found that it could predict many of the hemodynamic, gas exchange, and autonomic abnormalities found in patients with left ventricular diastolic dysfunction (LVDD). The newly incorporated information includes high-fidelity pressure tracings simultaneously recorded from the RV and LV of a normal human in a cardiac catheterization laboratory, Doppler echocardiographic inlet flow velocity patterns, measures of right and left ventricular impedance, and atrial volumes. The revised cardiovascular section details the hemodynamics of a normal subject to the extent that it can now explain the effects of septal compliance on ventricular interaction, the differences in left and right ventricular pressure development, and venous blood gas mixing in the right atrium. The model can isolate the highly interrelated features of normal and abnormal physiology, and simultaneously demonstrate their interaction in a manner that would be very difficult or impossible using an intact organism. It may therefore help physicians and scientists understand, diagnose, and improve their treatment of complicated cardiovascular and pulmonary diseases. It could also simulate the hemodynamic and respiratory effects of ventricular and pulmonary assist devices, and thus help with their development.

The role of the bronchial circulation in the acute lung injury resulting from burn and smoke inhalation.

Smoke inhalation in burn patients is a serious medical problem around the world. Inhalation injury increases mortality in addition to increasing infections, ventilator-days, and hospital stays. There are also large numbers of patients subjected to smoke inhalation without burns from cooking fires, burning crops and forest fires. The injury results in a fall in arterial oxygenation as a result of airway blockade, increased pulmonary transvascular fluid flux and loss of hypoxic pulmonary vasoconstriction. The changes in cardiopulmonary function are mediated at least in part by reactive oxygen and nitrogen species. Nitric oxide (NO) is generated by both inducible and constitutive isoforms of nitric oxide synthase (NOS). NO combines with superoxide to form reactive nitrogen species such as peroxynitrite. These reactive nitrogen species can be detected by measuring their reaction products such as 3-nitrotyrosine. The latter is elevated in the airway following smoke/burn injury. The control of NO formation involves poly (ADP ribose) polymerase (PARP) and its ability to up-regulate the activity of nuclear transcription factors through ribosylation. Present data also support a major role for the bronchial circulation in the injury since blockade of bronchial blood flow will also minimize the pulmonary injury. The data suggest that cytotoxins or activated cells are formed in the airway and carried to the parenchyma. These materials cause the formation of oedema and a reduction of PaO(2).

Tracheoinnominate fistula: surgical management of an iatrogenic disaster.

Tracheoinnominate fistula (TIF) is a rare condition with significant potential for mortality if surgical intervention is not immediate. We present two cases of successfully managed TIF. Both cases involve ligation and resection of the innominate artery at the TIF followed by a pectoralis major muscle flap. In both cases, success was largely due to a high index of suspicion and immediate control of the bleeding with transport to the operating room for surgical repair. The history, aetiology, and pathogenesis of TIF are reviewed, yielding an algorithm for recommended management of TIF.

Cerebral autoregulation and gas exchange studied using a human cardiopulmonary model.

The goal of this work is to study the cerebral autoregulation, brain gas exchange, and their interaction by means of a mathematical model. We have previously developed a model of the human cardiopulmonary (CP) system, which included the whole body circulatory system, lung and peripheral tissue gas exchange, and the central nervous system control of arterial pressure and ventilation. In this study, we added a more detailed description of cerebral circulation, cerebrospinal fluid (CSF) dynamics, brain gas exchange, and cerebral blood flow (CBF) autoregulation. Two CBF regulatory mechanisms are included: autoregulation and CO(2) reactivity. Central chemoreceptor control of ventilation is also included. We first established nominal operating conditions for the cerebral model in an open-loop configuration using data generated by the CP model as inputs. The cerebral model was then integrated into the larger CP model to form a new integrated CP model, which was subsequently used to study cerebral hemodynamic and gas exchange responses to test protocols commonly used in the assessment of CBF autoregulation (e.g., carotid artery compression and the thigh-cuff deflation test). The model can closely mimic the experimental findings and provide biophysically based insights into the dynamics of cerebral autoregulation and brain tissue gas exchange as well as the mechanisms of their interaction during test protocols, which are aimed at assessing the degree of autoregulation. With further refinement, our CP model may be used on measured data associated with the clinical evaluation of the cerebral autoregulation and brain oxygenation in patients.

Computed tomographic-pathologic correlation of gross tumor volume and clinical target volume in non-small cell lung cancer: a pilot experience.

CONTEXT: Computed tomographic (CT) scan data are used regularly in radiation treatment planning for patients with lung cancer. To our knowledge, the relationship of the CT images of tumors and their corresponding microscopic extent has not yet been studied in detail. OBJECTIVE: To correlate tumor sizes on CT with tumor sizes measured microscopically (ie, the gross tumor volume [GTV]-clinical target volume margin) in non-small cell lung cancers. DESIGN: Prospective pilot study. SETTING: Single institution. PATIENTS: Patients with operable non-small cell lung cancer were identified preoperatively. INTERVENTIONS: Once the surgical specimen was available, it was oriented with the surgeon and the pathologist. Seven whole-mount, cross-sectional histologic glass slides were made from 5 tumors using formalin fixation and hematoxylin-eosin staining. The pathologist then outlined the cancer-containing area under the microscope (Micro-GTV) and the area of surrounding inflammatory response (Micro-GTV + inflammation). Preoperative CT scans were used for outlining tumor on the corresponding slice (CT-GTV). MAIN OUTCOME MEASURES: Correlation of the areas of Micro-GTV, Micro-GTV + inflammation, and CT-GTV was performed. RESULTS: There was an obvious trend that the CT-GTV was bigger than the Micro-GTV, except in specimen 1, in which the 2 areas were about equal. However, on comparing the values for the CT-GTV and the Micro-GTV + inflammation, the difference between the 2 areas became smaller. CONCLUSIONS: Modern CT scans might overestimate the GTV in non-small cell lung cancer. The GTV-clinical target volume margin could actually be zero or even a negative value. The findings in this small study are interesting and provoking. Further study with a larger number of patients and more rigid quality control is warranted to confirm our findings.

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).

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.

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.

Development of an implantable artificial lung: challenges and progress.

Unlike dialysis, which functions as a bridge to renal transplantation, or a ventricular assist device, which serves as a bridge to cardiac transplantation, no suitable bridge to lung transplantation exists. Our goal is to design and build an ambulatory artificial lung that can be perfused entirely by the right ventricle and completely support the metabolic O2 and CO2 requirements of an adult. Such a device could realize a substantial clinical impact as a bridge to lung transplantation, as a support device immediately post-lung transplant, and as a rescue and/or supplement to mechanical ventilation during the treatment of severe respiratory failure. Research on the artificial lung has focused on the design, mode of attachment to the pulmonary circulation, and intracorporeal versus paracorporeal placement of the device.

Interleukin-8, aquaporin-1, and inducible nitric oxide synthase in smoke and burn injured sheep treated with percutaneous carbon dioxide removal.

We previously showed that a percutaneous arteriovenous gas exchanger was effective in removing CO2 and reversing respiratory failure in an ovine model of adult respiratory distress syndrome (ARDS) produced by smoke inhalation and burn injury (Alpard et al., Ann Surg 230:215-224, 1999). In this study, we tested the hypothesis that arteriovenous CO2 removal (AVCO2R) lessened endogenous inflammation in the lung. Myeloperoxidase activity, aquaporin-1 (AQP-1), interleukin-8 (IL-8), and inducible nitric oxide synthase mRNAs as well as aquaporin-1, and IL-8 protein were measured in ovine lung tissue. Lung tissue was taken at 96 h (time of sacrifice) from animals with combined smoke inhalation and 40% third degree dermal burn and subsequently treated with AVCO2R or sham (ventilator alone) after onset of ARDS (PaO2:FiO2 ratio of < 200). Myeloperoxidase activity was 1.862 +/- 0.302 U/mg protein in the ventilator group and 0.830 +/- 0.141 in the AVCO2R plus ventilator group. AQP-1 mRNA was 140,482 +/- 31,702 copies/microg total RNA in the ventilator group and 61,854 +/- 22,433 copies/microg total RNA in the AVCO2R plus ventilator group (p = 0.076). mRNA for IL-8 mRNA in the ventilator alone treated animals was 74,000 +/- 3,300 copies/microg total RNA compared to < 1,000 copies/microg total RNA in the ventilator plus AVCO2R group. This result was highly significant (p < 0.001) Inducible nitric oxide synthase mRNA was 7,853 +/- 2,229 copies/microg total RNA for the AVCO2R group and 5,854 +/- 2,070 copies/microg total RNA for the ventilator managed animals. These differences were not statistically significant (p = 0.54). Percutaneous AVCO2R produced a specific decrease in IL-8 in the smoke and burn injured animals. Furthermore, this effect was consistent with cell signaling mechanisms that increase the expression of IL-8 by cyclic stretching and the observed reduction in the number of neutrophils in the lung parenchyma. Therefore, we speculate that the mechanism by which CO2 removal exerts a beneficial effect may be due to both decreases in ventilatory requirements, with an accompanying reduction in alveolar stretching, and reduction of neutrophil numbers in lung tissue.

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.

Veno-venous perfusion-induced systemic hyperthermia: case report with perfusion considerations.

Cancer cells are more susceptible to destruction by heat than are their normal counterparts. However, optimization of this hyperthermic susceptibility for selective cancer cell kill has been difficult to define and technically difficult to achieve. A whole-body hyperthermic technique veno-venous perfusion-induced systemic hyperthermia (VV-PISH) was designed in in vitro and in swine experiments to achieve selective hyperthermic cancer cell destruction. In this case report, VV-PISH is studied for its safety and therapeutic efficiency in a Food and Drug Administration (FDA) approved phase-I study, where hyperthermia is used to treat advanced (Stage III B or IV) lung cancer. VV-PISH, utilizing the ThermoChem HT system in an extracorporeal circuit, was used to induce hyperthermia to 42.5 degrees C sustained for 120 min. Cooling returned the body temperature to 37 degrees C. After completion of the treatment, the patient was transferred to the intensive care unit on a ventilator, norepinephrine and diuretics. The patient remained somnolent for 36 h, developed pulmonary congestion requiring an additional 48 h before extubation, was transferred to the intermediate unit on day 4 and discharged in good condition on day 8. He did experience hyperthermia-related shrinkage of his lung cancer; however, he succumbed 270 days after this treatment from further progression of this disease. Hyperthermia is not a benign therapy; management techniques have been developed that have ameliorated many of the problems associated with extremely high temperatures, but pathophysiology still exists. Using these techniques, VV-PISH can be safety implemented, albeit not without temporary sequelae and further hospitalization.

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.

Usefulness of surveillance cultures in neonatal extracorporeal membrane oxygenation.

Sepsis is difficult to identify in patients treated with extracorporeal membrane oxygenation (ECMO). This study evaluates the usefulness of surveillance cultures obtained during ECMO. We retrospectively reviewed the records of 187 patients from four ECMO centers with birth weights 1,574 to 4,900 gm and gestational ages 33-43 weeks, over a 4 year interval. Most patients had surveillance blood cultures daily, and tracheal aspirates and urine culture every other day. Charts were reviewed for culture results before, during, and for the 7 days after ECMO, and clinical response to the culture results. A total of 2,423 cultures were obtained during 1,487 days of ECMO, of which 155 were positive (6.4%): 13 of 1,370 blood cultures (0.9%), 137 of 850 tracheal aspirate cultures (16%), and 5 of 203 urine cultures (2.3%). After 72 hours, tracheal aspirate cultures became positive with nosocomial organisms in 33 of 131 patients. None of 153 bacterial urine cultures were positive, and only one of 34 viral urine cultures were positive (CMV). We conclude that routine daily blood cultures are not useful in neonatal ECMO. Tracheal aspirate cultures may be helpful in the management of antibiotic therapy in patients on ECMO for more than 5 days. Routine bacterial urine cultures did not provide useful information.

Giant left atrial intrapericardial aneurysm: noninvasive preoperative imaging.

Congenital giant intrapericardial aneurysms of the left atrium are rare. A 17-year-old boy presented with paroxysmal episodes of palpitations, chest pain, and dyspnea. A chest roentgenogram showed an enlarged left cardiac silhouette. Transthoracic echocardiography imaging showed an intrapericardial aneurysm of the left atrium. Cardiac magnetic resonance imaging confirmed the diagnosis and delineated adjacent structures to plan the surgical resection. We have found no previous reports of cases of diagnosis and preoperative assessment based solely on noninvasive imaging.