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Objectives Lung cancer is one of the most lethal cancers. Currently, there are no biomarkers for early detection, monitoring treatment response, and detecting recurrent lung cancer. We undertook this study to determine if 1 H magnetic resonance spectroscopy (MRS) of sputum and exhaled breath condensate (EBC), as a noninvasive tool, can identify metabolic biomarkers of lung cancer. Materials and Methods Sputum and EBC samples were collected from 20 patients, comprising patients with pathologically confirmed non-small cell lung cancer ( n = 10) and patients with benign respiratory conditions ( n = 10). Both sputum and EBC samples were collected from 18 patients; 2 patients provided EBC samples only. 1 H MR spectra were obtained on a Bruker Avance 400 MHz nuclear magnetic resonance (NMR) spectrometer. Sputum samples were further confirmed cytologically to distinguish between true sputum and saliva. Results In the EBC samples, median concentrations of propionate, ethanol, acetate, and acetone were higher in lung cancer patients compared to the patients with benign conditions. Median concentration of methanol was lower in lung cancer patients (0.028 mM) than in patients with benign conditions (0.067 mM; P = 0.028). In the combined sputum and saliva and the cytologically confirmed sputum samples, median concentrations of N -acetyl sugars, glycoprotein, propionate, lysine, acetate, and formate were lower in the lung cancer patients than in patients with benign conditions. Glucose was found to be consistently absent in the combined sputum and saliva samples (88%) as well as in the cytologically confirmed sputum samples (86%) of lung cancer patients. Conclusion Absence of glucose in sputum and lower concentrations of methanol in EBC of lung cancer patients discerned by 1 H MRS may serve as metabolic biomarkers of lung cancer for early detection, monitoring treatment response, and detecting recurrence.

Summary Background Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. Methods The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II–IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150–450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. Findings Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70–0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). Interpretation In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. Funding Actelion Pharmaceuticals Ltd.

Introduction: Predictors of lung function decline in systemic sclerosis (SSc) are unknown. Serum pneumoprotein levels, surfactant protein-D (SP-D) and Krebs von den Lungen-6 (KL-6), correlate with pulmonary damage. We aimed to test whether levels can predict rapid lung function decline in SSc. Methods: SSc patients who had serial pulmonary function tests (PFT) were analyzed for SP-D and KL-6 levels by enzyme linked immunosorbent assay. Levels were correlated with an annual rate of decline in % predicted forced vital capacity (FVC) of >﹣2% (out-come); controls did not experience this FVC decline. Uni- and multi-variate analysis, adjusting for age, disease duration, gender, baseline % predicted FVC, SP-D, and KL-6, was performed. Results are reported as mean ± SD. Results: Thirty three cases and 25 controls had a disease duration of 8.8 ± 7.3 and 8.3 ± 6.1 years, respectively. In adjusted analyses, lung function decline correlated with greater baseline FVC OR = 1.03 [95% CI of 1.00-1.07]; a trend towards significance was observed for greater levels of SP-D with FVC decline, OR = 1.37 [95% CI of 0.96-2.12]. Conclusion: Our data provide evidence that SSc patients with long-standing disease are still at risk for lung function decline and SP-D levels may predict lung function decline.

Background Loads on the respiratory muscles, reflected by noninvasive measurement of the real-time power of breathing (POBn), and tolerance of these loads, reflected by spontaneous breathing frequency (f) and tidal volume (Vt), should be considered when evaluating patients with respiratory failure. Pressure support ventilation (PSV) should be applied so that muscle loads are not too high or too low. We propose a computerized, ventilator advisory system employing a load (POBn) and tolerance (f and Vt) strategy in a fuzzy logic algorithm to provide guidance for setting PSV. To validate these recommendations, we performed a multisite study comparing the advisory system recommendations to experienced physician decisions. Methods Data were obtained from adults who were receiving PSV (n = 87) at three university sites via a combined pressure/flow sensor, which was positioned between the endotracheal tube and the Y-piece of the ventilator breathing circuit and was directed to the advisory system. Recommendations from the advisory system for increasing, maintaining, or decreasing PSV were compared at specific time points to decisions made by physician intensivists at the bedside. Results There were no significant differences in the recommendations by the advisory system (n = 210) compared to those of the physician intensivists to increase, maintain, or decrease PSV (p > 0.05). Physician intensivists agreed with 90.5% of all recommendations. The advisory system was very good at predicting intensivist decisions (r2 = 0.90; p Conclusions The novel load-and-tolerance strategy of the advisory system provided automatic and valid recommendations for setting PSV to appropriately unload the respiratory muscles that were as good as the clinical judgment of physician intensivists.

The metabolic demands of the body, including consumption of oxygen and removal of carbon dioxide, vary widely in health and disease. Ventilation must adjust to meet these demands and accommodate volitional and behavioral activities. Control of breathing depends on a complex and intricate feedback control system that integrates these automatic and volitional aspects of ventilation. Sensors, including chemoreceptors and lung volume receptors, relay information to a central controller located primarily in the medulla. The central controller integrates this information and determines the level of activation of the effectors (the respiratory motoneurons and muscles), which affects ventilation and gas exchange. Inputs from suprapontine structures, including the cerebral cortex, are also important in integrating volitional aspects of breathing into the control system.

The respiratory response to CO2 during pressure-support ventilation (PSV) was studied in 16 conscious normal humans. The subjects breathed through a mouthpiece connected to a ventilator in PSV mode, with pressure set to the highest comfortable level for each subject (10.1 +/- 0.6 cm H2O, mean +/- SE). Compared with breathing spontaneously through the ventilator (CPAP mode with zero positive end-expiratory pressure), with PSV, tidal volume (VT) increased significantly (1.16 +/- 0.1 versus 0.85 +/- 0.04 L), whereas breathing frequency (f) remained stable (16.0 +/- 0.9 versus 15.6 +/- 1.1 breaths/min). As a result, the subjects hyperventilated, decreasing significantly end-tidal PCO2 (PETCO2, 23.5 +/- 1.2 versus 35.5 +/- 1.1 mm Hg). Fraction of inspired CO2 (FICO2) was then increased in steps, and changes in respiratory motor output were quantitated from changes in f, VT, ventilation (VI), peak inspiratory flow (Vpeak), and muscle pressure (Pmus). Pmus was calculated by the equation of motion, based on respiratory system mechanics, which were measured previously by airway occlusion at end-inspiration, VT, VI, and Pmus increased significantly with increasing PETCO2, and the response was detectable even below eupneic levels; f remained relatively stable over a wide range of PETCO2 (23 to 45 mm Hg) and increase significantly only when PETCO2 approached 50 mm Hg. These results indicate that in conscious normal humans during PSV, CO2 responsiveness extends well into hypocapnia and is expressed principally as an increase in intensity of respiratory motor output with little change in respiratory rate.

Inspiratory muscle output is downregulated when the mechanical load is reduced in awake humans. It is not known whether this is related to reduction in PCO2 or to removal of load-related neural responses. To address this issue, we did Read CO2 rebreathing tests in 13 normal subjects with and without unloading and compared respiratory output at identical end-tidal PCO2 (PET(CO2)) levels. Unloading was carried out with proportional assist ventilation (flow assist = 2 cm H2O/L/s plus volume assist = 4 cm H2O/L, representing approximately 50% reduction of the normal resistance and elastance). Ventilatory output (n = 13), total pressure of respiratory muscles (Pmus, n = 8), and transdiaphragmatic pressure (Pdi, n = 5) were computed at different PET(CO2) levels. Pmus was computed from esophageal pressure (Pes) using the Campbell diagram, and Pdi was measured from the difference between gastric pressure and Pes. Unloading caused an increase in ventilation (VI) and tidal volume (VT) at all PET(CO2) levels with no significant effect on slope (VI/PET(CO2) or VT/PET(CO2)) or respiratory rate. At low PET(CO2) (50 mm Hg), Pdi and Pmus waveforms did not differ with and without unloading. At high PET(C02) (59 mm Hg), peak Pdi and Pmus decreased by only 18.8 +/- 8.3% and 13.8 +/- 9.5%, respectively (NS, p0.05). Using a model that allows nonlinearity in the pressure-volume relation and for intrinsic muscle properties (force-length and force-velocity relations), we estimated the expected changes in mean VT and VI when the level of assist used in this study was applied in the absence of any change in neural output response to CO2. The predicted and observed changes in VT and VI were similar. We conclude that when chemical stimuli are rigorously controlled, unloading does not result in downregulation of respiratory muscle activation.

BACKGROUND: The most effective approaches to escalating advanced therapies in pulmonary arterial hypertension (PAH) are controversial.OBJECTIVE: To compare outcomes before and after introducing a target 6 min walk distance (6MWD) treatment strategy in PAH using registry data.METHODS: From 2001 to 2005, WHO class II to IV patients were treated with bosentan or prostanoids. In July 2005, a target 6MWD strategy was adopted. Monotherapy continued if 6MWD remained >350 m. For patients in whom 6MWD was ≤350 m, sildenafil was added. If 6MWD remained ud_less_than350 m, prostanoids were considered. Changes in 6MWD, WHO class and survival rate were compared between periods.RESULTS: Before using the 6MWD strategy, there was a statistically significant improvement in mean WHO class at six, nine and 12 months (2.5±0.8 [Pud_less_than0.015]; 2.5±0.8 [Pud_less_than0.005]; and 2.5±0.9 [Pud_less_than0.03], respectively) compared with baseline (2.9±0.9). There was a statistically significant increase in mean 6MWD at three, six, nine and 12 months (383±113 m [Pud_less_than0.005]; 401±102 m [Pud_less_than0.006]; 400±109 m [Pud_less_than0.001]; and 399±110 m [Pud_less_than0.004], respectively) compared with baseline (321±119 m). The survival rate was 95% at one and two years. From 2005 to 2009, there was a statistically significant improvement in mean WHO class at three, six, nine and 12 months (2.6±0.8 [Pud_less_than0.05]; 2.3±0.9 [Pud_less_than0.0001]; 2.3±0.9 [Pud_less_than0.0001]; and 2.3±1.0 [Pud_less_than0.0005], respectively) compared with baseline (2.8±0.7). There was statistically significant improvement in 6MWD at six months (381±126 m [Pud_less_than0.05]), followed by a decline toward baseline (354±117 m). One- and two-year survival rates in the 6MWD target era were 95% and 80%, respectively.CONCLUSION: Based on registry data, adoption of this strategy did not affect survival rates, nor cause a sustained improvement in 6MWD by 12 months. WHO class improved similarly in both treatment groups.

The determinants of the response of the respiratory output to inspiratory flow rates (VI) were examined in awake normal subjects. Subjects were connected to a volume-cycle ventilator in the assist/control mode, and VI was increased in steps from 30 to 90 L/min and then back to 30 L/min. VI pattern was square, and all breaths were subject-triggered. In six subjects the effects of breathing route (nasal or mouth) and temperature and volume of inspired gas (Protocol A) and in 8 subjects the effects of airway anesthesia (upper and lower airways; Protocol B) on the response of respiratory output to varying VI were studied. In Protocol B, in order to calculate muscle pressure during inspiration (Pmus), respiratory system mechanics were measured using the interrupter method at end-inspiration. Independent of conditions studied, breathing frequency increased significantly and end-tidal concentration of CO2 decreased as VI increased. The response was graded and reversible and not affected by breathing route, temperature and volume of inspired gas, and airway anesthesia. With and without airway anesthesia (Protocol B), neural inspiratory and expiratory time and neural duty cycle, estimated from Pmus waveform, decreased significantly as VI increased. At all conditions studied, the rate of change in airway pressure prior to triggering the ventilator tended to increase as VI increased. The changes in timing and drive were nearly complete within the first two breaths after transition, with no evidence of adaptation during a given VI period. We conclude that VI exerts an excitatory effect on respiratory output which is independent of breathing route, temperature and volume of inspirate, and airway anesthesia. The response most likely is neural in origin, mediated through receptors not accessible to anesthesia, such as those located in the chest wall or below the airway mucosa.

ObjectivesLung cancer is one of the most lethal cancers. Currently, there are no biomarkers for early detection, monitoring treatment response, and detecting recurrent lung cancer. We undertook this study to determine if1H magnetic resonance spectroscopy (MRS) of sputum and exhaled breath condensate (EBC), as a noninvasive tool, can identify metabolic biomarkers of lung cancer.Materials and MethodsSputum and EBC samples were collected from 20 patients, comprising patients with pathologically confirmed non-small cell lung cancer ( n = 10) and patients with benign respiratory conditions ( n = 10). Both sputum and EBC samples were collected from 18 patients; 2 patients provided EBC samples only.1H MR spectra were obtained on a Bruker Avance 400 MHz nuclear magnetic resonance (NMR) spectrometer. Sputum samples were further confirmed cytologically to distinguish between true sputum and saliva.ResultsIn the EBC samples, median concentrations of propionate, ethanol, acetate, and acetone were higher in lung cancer patients compared to the patients with benign conditions. Median concentration of methanol was lower in lung cancer patients (0.028 mM) than in patients with benign conditions (0.067 mM; P = 0.028). In the combined sputum and saliva and the cytologically confirmed sputum samples, median concentrations of N-acetyl sugars, glycoprotein, propionate, lysine, acetate, and formate were lower in the lung cancer patients than in patients with benign conditions. Glucose was found to be consistently absent in the combined sputum and saliva samples (88%) as well as in the cytologically confirmed sputum samples (86%) of lung cancer patients.ConclusionAbsence of glucose in sputum and lower concentrations of methanol in EBC of lung cancer patients discerned by1H MRS may serve as metabolic biomarkers of lung cancer for early detection, monitoring treatment response, and detecting recurrence.

Introduction: We set out to determine the frequency of respiratory symptoms, abnormal lung function, and shrinking lung syndrome (SLS) among patients with systemic lupus erythematosus (SLE) and to determine correlates of SLS. Methods: Consecutive adult patients who fulfilled the American College of Rheumatology classification criteria for SLE were enrolled. Demographics, clinical, and serologic characteristics were recorded; all patients underwent pulmonary function tests (PFT) and had either a chest X-ray or computed tomography scan. SLS was defined as dyspnea with restrictive lung physiology (defined as a forced vital capacity (FVC)

Hepatocellular enzyme elevation is a known side effect of both bosentan and atorvastatin. However, a rise in liver enzyme level not characteristic of either agent individually may represent a reaction to their combination or an atypical reaction to bosentan alone.The present case report describes a patient who had been taking atorvastatin for many years and was started on bosentan for chronic thromboembolic pulmonary hypertension. After 19 weeks of therapy, she developed severe liver enzyme elevation that necessitated the discontinuation of both bosentan and atorvastatin. Although the safety of reintroducing bosentan in such a case is unknown, it was reintroduced in this patient because of the severity of her disease, the demonstrated treatment benefit and the lack of alternative treatment options. On reintroduction of bosentan alone, she again demonstrated significant liver enzyme elevation – this time occurring after only two doses. The present case highlights that bosentan can cause more rapid and severe hepatocellular enzyme elevation than previously believed, thus necessitating more frequent monitoring.

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy.OBJECTIVES: To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy.METHODS: Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes.RESULTS: Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (PDISCUSSION: Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with mono-therapy may result in further improvement in exercise tolerance.

Loads on the respiratory muscles, reflected by noninvasive measurement of the real-time power of breathing (POBn), and tolerance of these loads, reflected by spontaneous breathing frequency (f) and tidal volume (Vt), should be considered when evaluating patients with respiratory failure. Pressure support ventilation (PSV) should be applied so that muscle loads are not too high or too low. We propose a computerized, ventilator advisory system employing a load (POBn) and tolerance (f and Vt) strategy in a fuzzy logic algorithm to provide guidance for setting PSV. To validate these recommendations, we performed a multisite study comparing the advisory system recommendations to experienced physician decisions.Data were obtained from adults who were receiving PSV (n = 87) at three university sites via a combined pressure/flow sensor, which was positioned between the endotracheal tube and the Y-piece of the ventilator breathing circuit and was directed to the advisory system. Recommendations from the advisory system for increasing, maintaining, or decreasing PSV were compared at specific time points to decisions made by physician intensivists at the bedside.There were no significant differences in the recommendations by the advisory system (n = 210) compared to those of the physician intensivists to increase, maintain, or decrease PSV (p0.05). Physician intensivists agreed with 90.5% of all recommendations. The advisory system was very good at predicting intensivist decisions (r(2) = 0.90; p0.05) in setting PSV.The novel load-and-tolerance strategy of the advisory system provided automatic and valid recommendations for setting PSV to appropriately unload the respiratory muscles that were as good as the clinical judgment of physician intensivists.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS), the main cause of late mortality following lung transplantation, is defined as an irreversible decline in forced expiratory volume in 1 s (FEV1).Previous studies using azithromycin for BOS in lung transplant patients have demonstrated a potential reversibility of the decline in FEV1.OBJECTIVES: To examine whether initiating azithromycin reverses decline in FEV1in lung transplant recipients with established BOS of at least three months.METHODS: Pulmonary function tests were performed every three months in seven lung transplant recipients with established BOS of at least three months. FEV1was recorded at six and three months before initiation, at time of initiation, and three, six, nine and 12 months postazithromycin initiation. The primary end point was change in FEV1. During the study, no immunosuppressive medication changes or acute rejection episodes occurred.RESULTS: Mean time from transplant to azithromycin initiation was 64 months (range 17 to 117 months). Mean time from BOS diagnosis to azithromycin initiation was 22 months (range three to 67 months). Rate of FEV1decline from six months before azithromycin initiation, and rates of FEV1increase from initiation to three and 12 months post-treatment initiation, were not statistically significant (P=0.32, P=0.16 and P=0.18, respectively). Following a trend toward improvement in the first three months after treatment initiation, FEV1tended to stabilize.DISCUSSION: Although several studies address the possible benefit of maintenance azithromycin in lung transplant patients with BOS, the role of the drug remains unproven in these patients, and would best be addressed by a large randomized controlled trial.

After voluntary hyperventilation, normal humans do not develop a significant ventilatory depression despite low arterial CO2 tension, a phenomenon attributed to activation of a brain stem mechanism referred to as the "afterdischarge." Afterdischarge is one of the factors that promote ventilatory stability. It is not known whether physiological stimuli, such as hypoxia, are able to activate the afterdischarge in humans. To test this, breath-by-breath ventilation (VI) was measured in nine young adults during and immediately after a brief period (35-51 s) of acute hypoxia (end-tidal O2 tension 55 Torr). Hypoxia was terminated by switching to 100% O2 (end-tidal O2 tension of first posthypoxic breath greater than 100 Torr). Brief hypoxia increased VI and decreased end-tidal CO2 tension. In all subjects, termination of hypoxia was followed by a gradual ventilatory decay; hyperoxic VI remained higher than the normoxic baseline for several breaths and, despite the negative chemical stimulus of hyperoxia and hypocapnia, reached a new steady state without an apparent undershoot. We conclude that brief hypoxia is able to activate the afterdischarge mechanism in conscious humans. This contrasts sharply with the ventilatory undershoot that follows relief of sustained hypoxia, thereby suggesting that sustained hypoxia inactivates the afterdischarge mechanism. The present findings are of relevance to the pathogenesis of periodic breathing in a hypoxic environment. Furthermore, brief exposure to hypoxia might be useful for evaluation of the role of afterdischarge in other disorders associated with unstable breathing.

The contribution of distensibility and recruitment to the distinctive behavior of the pulmonary circulation is not known. To examine this question we developed a multibranched model in which an arterial vascular bed bifurcates sequentially up to 8 parallel channels that converge and reunite at the venous side to end in the left atrium. Eight resistors representing the capillary bed separate the arterial and venous beds. The elastic behavior of capillaries and extra-alveolar vessels was modeled after Fung and Sobin (Circ. Res. 30: 451-490, 1972) and Smith and Mitzner (J. Appl. Physiol. 48: 450-467, 1980), respectively. Forces acting on each component are modified and calculated individually, thus enabling the user to explore the effects of parallel and longitudinal heterogeneities in applied forces (e.g., gravity, vasomotor tone). Model predictions indicate that the contribution of distensibility to nonlinearities in the pressure-flow (P-F) and atrial-pulmonary arterial pressure (Pla-Ppa) relationships is substantial, whereas gravity-related recruitment contributes very little to these relationships. In addition, Pla-Ppa relationships, obtained at a constant flow, have no discriminating ability in identifying the presence or absence of a waterfall along the circulation. The P-F relationship is routinely shifted in a parallel fashion, within the physiological flow range, whenever extra forces (e.g., lung volume, tone) are applied uniformly at one or more branching levels, regardless of whether a waterfall is created. For a given applied force, the magnitude of parallel shift varies with proportion of the circulation subjected to the added force and with Pla.

To ascertain the relative contributions of vascular distensibility and nonhomogeneous behavior within the pulmonary circulation to the distinctive nonlinear relationship between inflow pressure (Pin) and flow [pressure-flow (P-F) relationship] and between Pin and outflow pressure (Pout) at constant flow (Pin-Pout relationship), we developed a multibranched model in which the elastic behavior of, and forces acting on, individual branches can be varied independently. The response of the multibranched model is described in the companion article (J. Appl. Physiol. 68: 1514-1527, 1990). Here we describe the methods used and the responses of single components of the larger model. Perivascular pressure is modeled as a function of intravascular and transpulmonary pressures (Pv and Ptp, respectively) and vessel length as a function of lung volume. These and the relationship between vascular area (A) and transmural pressure (Ptm) were modeled primarily from the dog data of Smith and Mitzner (J. Appl. Physiol. 48: 450-467, 1980). Vasomotor tone is modeled as a radial collapsing pressure (Pt) in the same plane as Ptm. In view of lack of information about the relationship between Pt and A for a given active state, different patterns were assumed that span a wide range of possible relationships. The P-F and Pin-Pout relationships of single vessels were very similar to those reported for the entire intact circulation. Of note, the slope of the Pin-Pout relationship in the low Pout range (0-5 Torr) was very low (less than 0.25) and increased gradually with Pout toward unity. Vasomotor tone caused an apparent parallel shift in the P-F relationship in the physiological flow range of the dog (2-8 l/min) regardless of the pattern used to model the Pt vs. A relationship; different patterns affected the P-F relationship only over the low flow range before the parallel shift was established.

In mechanically ventilated awake and sleeping humans, it has been shown that increasing inspiratory flow rate (V'I) exerted a reflex excitatory effect on respiratory output. Mechanoreceptors located in intercostal muscles or within the lung have been suggested as possible pathways that may mediate the excitatory effect of V'I. To test this, five patients with bilateral lung transplantation (LTP) and eight quadriplegics with spinal cord transection at the level of C6-C7 (QP) were studied. Patients were connected to a volume cycle ventilator in the assist volume-control mode and V'I was randomly changed. V'I pattern was square and all breaths were patient-triggered. V'I values of 30, 60 and 90 L x min(-1) were studied. Each level of V'I was sustained for 15 breaths. Airway pressures, end-tidal partial pressure of carbon dioxide (PCO2), airflows and volumes were measured breath by breath. Thirty seven trials in LTP and sixty in QP, where V'I was randomly changed between 30 and 90 L x min(-1), were analysed. In both groups of patients, minute ventilation increased and total breath duration decreased significantly as V'I increased. These changes were complete in the first breath after V'I transition, without evidence of adaptation of the response. The magnitude of the response did not differ between the two groups of patients and was comparable to that observed previously in conscious normal subjects. We conclude that the excitatory effect of inspiratory flow rate on breathing frequency persists in patients who have pulmonary or intercostal denervation. These results do not favour receptors located within the lung (below the resection lines) or in the intercostal muscles to mediate the response of breathing frequency to flow rate.

It has been shown in mechanically ventilated awake normal humans that increasing inspiratory flow rate (VI) exerts an excitatory effect on respiratory output. It is not known if this effect persists during sleep. To test this, seven normal adults were studied during wakefulness and non-rapid eye movement (non-REM) sleep. Subjects were connected through a nose mask to a volume-cycled ventilator in the assist/control mode, and VI was increased in steps (3 to 4 breaths each) from 30 to 70 L/min and then back to 30 L/min. VI pattern was square, and all breaths were subject-triggered. Forty-one trials during non-REM sleep and 10 during wakefulness were analyzed. Both during sleep and wakefulness minute ventilation increased and total breath duration (Ttot) decreased significantly in a graded and reversible manner as VI increased. These changes were complete in the first breath after VI transition. The response was significantly less during sleep than during wakefulness (p < 0.050; at 30 L/min Ttot, expressed as percent of that at 70 L/min, was 110.2 +/- 1.3% during sleep and 127.8 +/- 3.9% during wakefulness. During wakefulness, the rate of change in airway pressure before triggering the ventilator (dp/dt), an index of respiratory drive, increased significantly (p < 0.05) with increasing VI. During sleep dp/dt was not affected by VI changes. In four sleeping subjects the increase in VI was sustained for 1.5 to 2 min. There was no evidence for adaptation of the response; Ttot, averaged over the last three breaths, did not differ from that obtained with VI was sustained for only 3 to 4 breaths. We concluded that VI exerts an excitatory effect on respiratory output, mediated by a reflex neural mechanism, and the gain of this reflex is attenuated by sleep.

The effect of breathing pattern and level of ventilation on fluid filtration in the lung under edema forming conditions was studied in an in situ left upper lobe (LUL) canine preparation. LUL weight was continuously monitored. In Group 1, rate of edema formation (delta W/delta t) was measured In seven dogs at two vascular pressures (35 and 45 mm Hg) while the LUL was randomly ventilated under six conditions. At equivalent vascular pressures and mean airway pressures (Paw) (and hence, mean operating lung volume), increasing respiratory frequency (f) enhanced delta W/delta t. This was reversed when minute ventilation (VE) was returned to baseline by reducing tidal volume (VT), even when Paw were matched to baseline. Increasing VT also enhanced delta W/delta t whether VE was increased (J Appl Physiol 1988; 64:1900) or not (present study) and whether Paw was matched to baseline. In Group 2 delta W/delta t was measured at fixed VT and f while inspiratory/expiratory time ratio (TI/TE) was switched from 1:1 to 1:6. Shortening inspiratory time by increasing inspiratory flow rate had no effect on delta W/delta t. We conclude that increasing VE, whether by raising VT or f, promotes greater edema formation by mechanisms that are independent of vascular pressure or operating lung volume. Increasing VT appears to have an additional adverse effect over and above that of increased VE.

Pressure in the compliant middle segment of the pulmonary vascular bed (PM), as determined by arterial occlusion, was compared with pressure at the filtration site (effective filtration pressure, EFP), determined by the isofiltration technique, at very high (7–10 times normal) pulmonary flow in six in situ perfused canine left upper lobes. At these flow rates inflow and left atrial pressures averaged 41.9 +/- 1.3 and 2.5 +/- 0.5 (SE) mmHg, respectively. PM was 30.9 +/- 1.6 mmHg, and EFP was 32.3 +/- 1.9 mmHg with no significant difference between the two measurements by paired t test. The results indicate that the arterial occlusion technique yields a pressure that is equivalent to EFP even during very high pulmonary blood flow where the longitudinal distribution of resistance is quite different from that obtained during normal flow.

Dog left upper lobes (LUL) were perfused in situ via the left lower lobe artery. Lobe weight was continuously monitored. Increasing lobar flow from normal to 10 times normal had little effect on left atrial pressure, which ranged from 1 to 5 mmHg. There was a flow threshold (Qth) below which lobar weight was stable. Qth ranged from 1.1 to 1.55 l/min (mean 1.27) corresponding to four times normal LUL blood flow. Above Qth, step increases in lobar flow resulted in progressive weight gain at a constant rate that was proportional to flow. The effective pressure at the filtration site (EFP) at different flow rates was estimated from the static vascular pressure that resulted in the same rate of weight gain. From this value and from mean pulmonary arterial (PA) and left atrial (LA) pressures, we calculated resistance upstream (Rus) and downstream (Rds) from filtration site. At Qth, Rds accounted for 60% of total resistance. This fraction increased progressively with flow, reaching 83% at Q of 10 times normal. We conclude that during high pulmonary blood flow EFP is closer to PA pressure than it is to LA pressure, and that this becomes progressively more so as a function of flow. As a result, the lung accumulates water at flow rates in excess of four times normal despite a normal left atrial pressure.

The effects of raising tidal volume and positive end-expiratory pressure (PEEP) on rate of edema formation were studied in in situ canine left upper lobe preparations. Edema was induced by increasing blood flow to the left upper lobe (4–8 times normal). In the same animal, at equivalent flows and microvascular hydrostatic pressures, rate of edema formation observed with larger tidal volumes was significantly higher than that observed with smaller tidal volumes (0.73 +/- 0.29 vs. 0.58 +/- 0.30, P less than 0.001). Edema was also induced under static conditions (i.e., flow = 0) over a wide range of vascular pressures. Rate of edema formation was plotted against pressure and the best-fit linear regression was obtained. The slopes (g.min-1.mmHg-1.100 g-1) of the regression lines were significantly higher with larger tidal volumes compared with smaller tidal volumes [0.106 +/- 0.010 (SE) vs. 0.081 +/- 0.009, P less than 0.01]. The pressure intercepts were not different (16.1 +/- 1.6 vs. 15.7 +/- 1.8). When mean airway pressures were increased to levels equivalent to those obtained with larger tidal volumes, but by raising end-expiratory pressures, rate of edema formation dropped to levels below base line. We conclude that increasing the amplitude of cyclic changes in lung volume increases edema formation through mechanisms that are independent of changes in operating (i.e., mean) lung volume.

The effectiveness of Continuous positive airway pressure (CPAP) administration in improving blood oxygenation and the importance of the circuit capacity, by checking two different volumes of balloon reservoirs (a 3 l versus 23 l balloon), in reducing the work of breathing is presented. Twenty-five postoperative patients, after major gastrointestinal interventions were included in this study. Each patient being studied under three different conditions: Phase I: spontaneous breathing, Phase II: CPAP - 11 cmH2O, 3 l balloon reservoir; Phase III: CPAP - 11 cmH2O, 23 l balloon reservoir. All patients were intubated and were breathing room air. The results obtained clearly show a significant improvement in blood oxygenation due to CPAP, p less than 0.001. In addition, the work of breathing was considerably reduced utilizing a large capacity system with significant lower flow rates, p less than 0.001 and p less than 0.0001 respectively. Furthermore, rebreathing was prevented by maintaining continuous bubbling in the exit chamber and proved by having no change in PaCO2.

In this study, 8 years experience of early percutaneous peritoneal dialysis (PPD) in the treatment of acute necrotic hemorrhagic pancreatitis (ANHP) are presented. The introduction of methemalbuminemia and the presence of specific ascites rich in amylase, lipase and methemalbumin as early indicators of the presence of ANHP enabled us to confirm the diagnosis in 53 patients, after which early institution of PPD was possible. Thirty patients survived by PPD alone and 9 patients survived by the combination of PPD and surgery, giving an overall mortality rate of 26.4%. A better survival rate of patients having a high Ranson prognostic score was obtained. The introduction of computerized axial tomography (CAT), in 1980 into our hospital allowed us to use this technique for followup. This change and the fact that we were more experienced with PPD, divided our study into two periods: 1976 to 1979, 22 patients; 1980 to 1983, 31 patients. A more aggressive medical approach to treating ANHP was observed during the second period. Surgery was delayed compared to the first period and confined to treating late complications, such as infections, by drainage procedures. Despite the fact that the results were not statistically different, a trend towards a lower mortality rate (19.3%) in the second period compared to the first period (36%) was obtained.