The vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2S) is a highly toxic gas for which no effective antidotes exist. It acts, at least in part, by binding to cytochrome c oxidase, causing cellular asphyxiation and anoxia. We investigated the effects of three different ligand forms of cobinamide, a vitamin B12 analog, to reverse sulfide (NaHS) toxicity. METHODS: New Zealand white rabbits received a continuous intravenous (IV) infusion of NaHS (3 mg/min) until expiration or a maximum 270 mg dose. Animals received six different treatments, administered at the time when they developed signs of severe toxicity: Group 1-saline (placebo group, N = 9); Group 2--IV hydroxocobalamin (N = 7); Group 3--IV aquohydroxocobinamide (N = 6); Group 4--IV sulfitocobinamide (N = 6); Group 5--intramuscular (IM) sulfitocobinamide (N = 6); and Group 6-IM dinitrocobinamide (N = 8). Blood was sampled intermittently, and systemic blood pressure and deoxygenated and oxygenated hemoglobin were measured continuously in peripheral muscle and over the brain region; the latter were measured by diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS). RESULTS: Compared with the saline controls, all cobinamide derivatives significantly increased survival time and the amount of NaHS that was tolerated. Aquohydroxocobinamide was most effective (261.5 ± 2.4 mg NaHS tolerated vs. 93.8 ± 6.2 mg in controls, p < 0.0001). Dinitrocobinamide was more effective than sulfitocobinamide. Hydroxocobalamin was not significantly more effective than the saline control. CONCLUSIONS: Cobinamide is an effective agent for inhibiting lethal sulfide exposure in this rabbit model. Further studies are needed to determine the optimal dose and form of cobinamide and route of administration.

Two-dimensional and 3-dimensional optical coherence tomographic imaging of the airway, lung, and pleura.

BACKGROUND: Methods for obtaining real-time in vivo histologic resolution by means of noninvasive endoscopic optical imaging would be a major advance for thoracic surgical diagnostics and treatment. Optical coherence tomography is a rapidly evolving technology based on near-infrared interferometry that might provide these capabilities. The purpose of this study is to investigate the feasibility of real-time 2- and 3-dimensional optical coherence tomographic imaging of airway, pleural, and subpleural lung tissues in normal, inflammatory, and malignant animal models and patients with known or suspected airway malignancy. METHODS: Freshly excised lungs and pleural tissue obtained from rabbits with inhalation lung injury and induced empyema, metastatic sarcomas, and pleural sarcomas and from patients with airway disease were imaged by using 2- and 3-dimensional optical coherence tomography with a prototype superluminescent diode optical coherence tomographic system constructed in our laboratory. Lungs and pleural tissue were subsequently processed for standard hematoxylin and eosin histology for comparison with optical coherence tomography. RESULTS: Optical coherence tomographic imaging achieved an ex vivo resolution of 10 microm and an in vivo resolution of about 30 microm with a depth penetration of 1 to 2 mm with 2- and 3- dimensional reconstruction capabilities. Tumors as small as 500 microm were detectable with optical coherence tomography. The acquired images closely matched histologic images, demonstrating details at the level of mucosal layers, glands, alveoli, and respiratory bronchioles. CONCLUSIONS: Optical coherence tomography with near-infrared interferometric methods enables near real-time in vivo near-histologic resolution optical imaging. With further advances, optical coherence tomography has the potential for real-time accurate and early pleural and subpleural diagnostics by using small-diameter flexible fiberoptic endoscopic probes for a wide range of thoracic surgical applications.

Effect of lung volume reduction surgery in a rabbit model of bullous lung disease.

Clinical use of staple lung volume reduction surgery (LVRS) has proliferated for treatment of emphysema despite limited data regarding efficacy or optimal techniques. Recent studies in animal models of obstructive lung disease describe the decrease in lung compliance and increase in airway support as mechanisms of an improvement in pulmonary functions analogous to human data. We describe contrasting results in an animal model of bullous lung disease with a mixed but predominantly restrictive pattern of lung disease. Mixed restrictive and bullous lung disease was induced in 17 New Zealand white rabbits with i.v. Sephadex beads and endotracheally instilled carrageenan. Unilateral stapled lung volume reduction surgery was performed at 5 weeks postinduction of emphysema on the right lower lobe by lateral thoracotomy using a pediatric stapler. Static trans-pleural pressures were measured at 60, 40, and 20 cm3 inflation at preinduction (baseline), pre- and postoperatively, and 1 week postoperatively in anesthetized animals. Lungs were then harvested en bloc and examined histopathologically. The effects of volume reduction surgery on static lung compliance, lung conductance, and forced expiratory flows (FEF) were assessed. Five weeks after induction of lung disease, the animals had no significant change in static compliance and forced expiratory volume in 0.5 s (FEV0.5) or lung conductance compared to baseline. Immediately following LVRS, the animals showed a significant decrease in static compliance, FEV0.5, and conductance. One week postoperatively, compliance increased to approximately baseline levels along with a slight increase in FEFs and conductance toward preoperative levels. Histology examination revealed restrictive and bullous lung disease. Thus, we have demonstrated the feasibility of using an animal model for evaluation of volume reduction therapy for restrictive-obstructive lung disease. Physiologically, this model showed decrease conductance and decreased forced expiratory flows following lung volume reduction despite increased recoil. This is in contrast to increased conductance and flows seen in humans with severe emphysema following surgery and suggests that current criteria excluding patients with a significant restrictive component to their lung disease from LVRS surgery may be justified.

Maternal proximity and infant CO2 environment during bedsharing and possible implications for SIDS research.

Sudden infant death syndrome (SIDS) is the leading cause of human infant mortality after the neonatal period in Western countries. Recently, child care practices have been shown to be important in determining infant vulnerability to SIDS. However, very little is known about the impact of parent-infant cosleeping on infant sleep physiology and behavior and SIDS risk. This reflects the failure of Western societal research paradigms to appreciate the human infant's evolutionary history of cosleeping, the recency of the emergence of solitary infant sleeping as a practice and the fact that parent-infant cosleeping is still the preferred sleeping arrangement for the majority of contemporary societies. Incorporating current hypotheses on the mechanisms of SIDS, we have hypothesized that the comparatively sensory-rich cosleeping environment might be protective against SIDS in some contexts. As a first step to characterize cosleeping environments, this investigation is aimed at assessing, in routinely bedsharing mothers and infants, their relative sleeping positions and the potential for sleeping in close face-to face proximity and for infant exposure to increased environmental CO2 produced by maternal respiration. The latter is important in that breathing elevated levels of CO2 can have diverse effects, ranging from respiratory stimulation at low levels to suffocation at very high levels. Two related laboratory studies were performed. In the first, all-night videotapes of 12 healthy, routinely bedsharing mother-infant pairs were analyzed for sleeping positions and time spent in face-to-face orientation and distances separating their faces. Infants were 11-15 wk old. Mothers predominantly positioned themselves on their sides facing their infants, with the infants placed either supine or on their sides. Mothers and infants slept oriented face-to-face for 64 +/- 27% (S.D.) of non-movement time, with distance less than 20 cm commonly separating their faces. In the second study, concentrations of CO2 in air were measured in six young women at distances of up to 21 cm from their nares. Peak expiratory CO2 concentrations remained above 1.0% at distances up to 9 cm and above 0.5% at 18 cm. Both baseline and peak CO2 levels were further increased at all distances when measured within a partial air pocket created to simulate a bedding environment sometimes seen during bedsharing. We conclude that during bedsharing there is potential for 1) a high degree of face-to-face orientation and close proximity and consequently 2) increased environmental CO2, as a result of maternal respiration, to non-lethal levels that might stimulate infant respiration. The close proximity would also maximize the sensory impact of the mother on the infant through other modalities. We also suggest that bedsharing may minimize prone infant positioning, a known risk factor for SIDS.

Almost simultaneous measurement of cardiovascular and gas exchange variables during maximal exercise.

We measured gas exchange variables such as oxygen uptake, carbon dioxide output, and lung diffusing capacity using noninvasive techniques almost simultaneous with assessment of cardiovascular variables such as pulmonary blood flow at several levels of treadmill exercise up to and including maximal capacity. We utilized a single breath exhalation technique for measurement of diffusing capacity and cardiac output and breath by breath methodology for evaluating oxygen uptake. The equipment required for these measurements--rapid gas analyzers, oximeters, on-line computation, and pneumatic valves--are well within the capabilities of many exercise laboratories and are not difficult to use with subjects even at the heaviest levels of exercise. The results agreed well with values reported in the literature. From these entirely noninvasive measures, we calculated mixed venous oxygen saturation and maximal tissue oxygen diffusing capacity.

Determination of DLCO and cardiac output from expired gas slopes with cardiogenic oscillations.

Effects of 'cardiogenic oscillations' on alveolar plateau gas concentration slope measurements, constant expiratory pulmonary capillary blood flow, and DLCO determination have not been previously described. We examined cardiogenic oscillations during constant expiratory maneuvers to assess factors influencing magnitude of oscillations as well as effect of oscillatory phase at the start and end of exhalation measurement period on alveolar gas slope. Five normal volunteers performed repeated single breath constant exhalation vital capacity maneuvers using test gas containing 2 physiologically 'inert' gases: Helium (He Mw 4) and argon (Ar Mw 40). The mixture contained 3 absorbable gases, acetylene (C2H2 Mw 26), carbon monoxide (C18O Mw 30), and oxygen. Alveolar plateau slope, magnitude of cardiogenic oscillations, relative signal to noise ratios, and effect of cardiogenic oscillation phase on measured slope were determined for each gas. Cardiogenic oscillations were present for all inert gases. Oscillations were less evident for CO. However, the effects on calculated Qc and DLCO were negligible. Cardiac oscillations of considerable magnitude are seen during single breath constant exhalation maneuvers and affect constant expiratory gas slope calculations. Cardiogenic oscillation phase does not have a significant effect on measured Qc and DLCO using constant expiratory techniques.

A device for overcoming discoordination with metered-dose inhalers.

BACKGROUND: Despite widespread acceptance of metered-dose inhalers (MDIs) in the treatment of asthma, many patients fail to operate these devices correctly. Inability to properly coordinate activation with onset of inhalation is regarded as the major factor in suboptimal MDI therapy. METHODS: We evaluated Autohaler Inhalation Device (3M Pharmaceuticals, St. Paul, Minn.), a breath-activated MDI that is typically activated at a triggering flow rate of approximately 0.5 L/sec. We compared bronchodilator effect of pirbuterol acetate (Maxair), inhaled from Autohaler and a standard MDI, under conditions that ensured optimal technique in 20 patients with asthma. Spirometric variables (forced expiratory volume in 1 second [FEV1], forced expiratory flow between 25% and 75% of vital capacity [FEF25-75], forced vital capacity [FVC]) were measured before and at 15, 30, 60, and 90 minutes after two inhalations of full inspiratory reserve volume for each device. RESULTS: Both devices produced significant and similar bronchodilation. Mean FEV1 increased 32% above baseline 60 minutes after use of Autohaler and 31% after use of a standard MDI. Similar changes were noted in FEF25-75 and FVC for the two devices. Differences between devices for all spirometric variables were not statistically significant. CONCLUSION: Autohaler provides a promising alternative to the standard MDI by overcoming breath-hand discoordination.

Effect of canister temperature on performance of metered-dose inhalers.

We studied the effects of ambient temperatures between 0 degrees C and 42 degrees C in an anatomically realistic model of the upper airway ventilated with warm, moist air. Metered-dose inhalers of metaproterenol maintained at the experimental temperatures were activated in the mouth of the model at the onset of inspiration. We measured the amount of drug released and that which was able to penetrate the model at each temperature. At low canister temperatures considerably more drug was released than at higher temperatures. However, at higher temperatures much more drug was able to traverse the upper airway, raising lower airway deposition from 17.7% at 4 degrees C to 32.2% at 37 degrees C. Aerosol size became progressively smaller as temperature was raised: mass median diameter (MMD) was 3.65 microns at 0 degrees C and 2.50 microns at 37 degrees C. These findings are most likely due to greater canister vapor pressures at higher temperatures. We conclude that patients should probably be instructed to prewarm metered-dose inhaler canisters prior to use when canister temperatures are low.

A new method for measurement of airway occlusion pressure.

Airway occlusion pressure correlates with central respiratory drive. The airway occlusion pressure (P0.1) may be an excellent predictor of the ability of patients with obstructive lung disease to wean from mechanical ventilation. We describe a new method for measuring P0.1 using digitized signals generated from standard respiratory equipment and a computer program to automatically determine P0.1 values. The accuracy of this new method was tested by comparison with standard analog recorder methods using a mechanical lung model, in ventilated patients in an intensive care unit, and in normal volunteers. In all settings, excellent correlation was obtained between P0.1 measurements by the digital Servo and standard analog methods (r = 0.99). This new method permits accurate and automatic determination of P0.1 in ventilated patients using standard respiratory equipment. The rapid response and ease of use of this method should enable evaluation of a number of physiologic variables involved in respiratory control in ventilated and nonventilated patients.

Dose-response effects of two sizes of monodisperse isoproterenol in mild asthma.

The dose-response effect of monodispersed isoproterenol of two different sizes (diameters 2.5 and 5 microns) was examined in eight mild asthmatic subjects (baseline FEV, 81.5% of predicted). Pulmonary and cardiovascular variables were measured before and following 1, 2, 4, 8, and 16 cumulative min of aerosol inhalation. Subjects inhaled 1 to 30 micrograms (2.5-microns particles) or 2 to 50 micrograms (5-microns particles) of isoproterenol. Pulmonary but not cardiac responses were significantly greater for the 2.5-microns particles as compared to equivalent doses of 5-microns particles. Pulmonary dose-related response differences were particularly marked for variables associated with small airway function (FEF25-75 and FEF75-85). These findings suggest that small particles penetrate more deeply into the lung and thereby more effectively dilate small airways and that small amounts of appropriately sized inhaled bronchodilator may produce considerable therapeutic effects.

Effects of thoracic gas compression on maximal and partial flow-volume maneuvers.

Airway hysteresis can be evaluated by comparing maximal (MEFV) and partial (PEFV) expiratory flow-volume curves. The maneuvers are often obtained from pulmonary function systems that are subject to gas-compression artifacts. Because gas-compression artifacts might differentially affect PEFV vs. MEFV curves, we simultaneously obtained MEFV and PEFV curves by use of a spirometer and a volume-displacement plethysmograph (a method not subject to gas-compression artifacts) in normal and asthmatic subjects. Plethysmographic flow rates exceeded spirometric flow rates on all MEFV and PEFV maneuvers. When maximal flow exceeded partial flow (or vice versa) in the plethysmograph, the same result was virtually always observed for spirometric measurements. Alveolar pressure (PA) was higher on MEFV than on PEFV maneuvers in asthmatic subjects; comparisons between PA (on PEFV and MEFV maneuvers) in normal subjects varied at different lung volumes. Ratios of Vmax on PEFV maneuvers to Vmax on MEFV maneuvers (Vmax-p/Vmax-c) obtained from a volume-displacement plethysmograph differ quantitatively from ratios determined in systems subject to gas-compression artifacts; qualitatively, however, failure to account for thoracic gas compression ordinarily will not influence the ability to identify airway hysteresis (or lack thereof) by use of Vmax-p-to-Vmax-c ratios.

Dialysis hypoxemia. Role of dialyzer membrane and dialysate delivery system.

Arterial blood gas values, carbon monoxide diffusion capacity, oxygen consumption, carbon dioxide production, respiratory quotient, minute ventilation, and pulmonary capillary blood flow were determined before and during hemodialysis. In addition, the effect of single passage through the dialyzer on blood carbon dioxide tension, pH, and bicarbonate concentration was evaluated. Acetate-based dialysate was used in all experiments. Cellulosic dialyzer with single-pass dialysate delivery system was used in one group, and polyacrylonitrile dialyzers with recirculating delivery system in another. Although hypoxemia occurred in both groups, it was more severe in the former group. Dialyzer carbon dioxide loss was significantly greater with single-pass dialysate delivery system and cellulosic dialyzers than with recirculating delivery system and polyacrylonitrile dialyzer. To differentiate the role of dialysate delivery system from that of the membrane, the experiments were repeated using recirculating delivery system and cellulosic dialyzer. This resulted in marked attenuation of hypoxemia and dialyzer carbon dioxide tension losses. Since other experimental conditions were the same, the observed differences were thought to be due to the difference in the mode of dialysate delivery. It thus appears that the mode of dialysate delivery per se can modify the changes in arterial oxygen tension during hemodialysis and should be added to the list of factors implicated in the genesis of dialysis hypoxemia.