Nausherwan K. Burki

A Novel Extracorporeal CO2 Removal System: Results of a Pilot Study of Hypercapnic Respiratory Failure in Patients With COPD

BACKGROUND Hypercapnic respiratory failure in patients with COPD frequently requires mechanical ventilatory support. Extracorporeal CO2 removal (ECCO2R) techniques have not been systematically evaluated in these patients. METHODS This is a pilot study of a novel ECCO2R device that utilizes a single venous catheter with high CO2 removal rates at low blood flows. Twenty hypercapnic patients with COPD received ECCO2R. Group 1 (n = 7) consisted of patients receiving noninvasive ventilation with a high likelihood of requiring invasive ventilation, group 2 (n = 2) consisted of patients who could not be weaned from noninvasive ventilation, and group 3 (n = 11) consisted of patients on invasive ventilation who had failed attempts to wean. RESULTS The device was well tolerated, with complications and rates similar to those seen with central venous catheterization. Blood flow through the system was 430.5 ± 73.7 mL/min, and ECCO2R was 82.5 ± 15.6 mL/min and did not change significantly with time. Invasive ventilation was avoided in all patients in group 1 and both patients in group 2 were weaned; PaCO2 decreased significantly (P < .003) with application of the device from 78.9 ± 16.8 mm Hg to 65.9 ± 11.5 mm Hg. In group 3, three patients were weaned, while the level of invasive ventilatory support was reduced in three patients. One patient in group 3 died due to a retroperitoneal bleed following catheterization. CONCLUSIONS This single-catheter, low-flow ECCO2R system provided clinically useful levels of CO2 removal in these patients with COPD. The system appears to be a potentially valuable additional modality for the treatment of hypercapnic respiratory failure.

Mechanisms of Dyspnea

The mechanisms and pathways of the sensation of dyspnea are incompletely understood, but recent studies have provided some clarification. Studies of patients with cord transection or polio, induced spinal anesthesia, or induced respiratory muscle paralysis indicate that activation of the respiratory muscles is not essential for the perception of dyspnea. Similarly, reflex chemostimulation by CO₂ causes dyspnea, even in the presence of respiratory muscle paralysis or cord transection, indicating that reflex chemoreceptor stimulation per se is dyspnogenic. Sensory afferents in the vagus nerves have been considered to be closely associated with dyspnea, but the data were conflicting. However, recent studies have provided evidence of pulmonary vagal C-fiber involvement in the genesis of dyspnea, and recent animal data provide a basis to reconcile differences in responses to various C-fiber stimuli, based on the ganglionic origin of the C fibers. Brain imaging studies have provided information on central pathways subserving dyspnea: Dyspnea is associated with activation of the limbic system, especially the insular area. These findings permit a clearer understanding of the mechanisms of dyspnea: Afferent information from reflex stimulation of the peripheral sensors (chemoreceptors and/or vagal C fibers) is processed centrally in the limbic system and sensorimotor cortex and results in increased neural output to the respiratory muscles. A perturbation in the ventilatory response due to weakness, paralysis, or increased mechanical load generates afferent information from vagal receptors in the lungs (and possibly mechanoreceptors in the respiratory muscles) to the sensorimotor cortex and results in the sensation of dyspnea.

Chronic eosinophilic pneumonia: a review

Chronic eosinophilic pneumonia (CEP) is a disease of unknown cause. The hallmark of CEP is eosinophil accumulation in the lungs. While the triggering factor is unknown, eosinophil accumulation in the lungs is now believed to be secondary to the actions of eosinophil-specific chemoattractants, including eotaxin and regulated upon activation, normal T-cell expressed and secreted (RANTES), and IL-5 released from Th2 lymphocytes in the lungs. There is a female preponderance in CEP, with a peak incidence in the 5th decade; the onset is insidious with weight loss, cough, and dyspnea. An atopic history is common, but asthma is not a prerequisite for the development of CEP. Airways obstruction may develop during the course of CEP, but may also result from CEP. The chest x-ray usually shows bilateral peripheral shadows, which may be migratory. Peripheral eosinophilia is usual. Standard treatment of CEP is with oral steroids, usually with dramatic resolution of symptoms and radiographic changes; however, relapses are common when the daily steroid dose is reduced below 15 mg. Current data suggest that when treatment is stopped, relapse is common in the majority of patients (>80%) followed for a sufficiently long period of time. Some recent reports suggest that treatment with inhaled steroids may be of some value in this condition.

The pulmonary effects of intravenous adenosine in asthmatic subjects

BackgroundWe have shown that intravenous adenosine in normal subjects does not cause bronchospasm, but causes dyspnea, most likely by an effect on vagal C fibers in the lungs [Burki et al. J Appl Physiol 2005; 98:180-5]. Since airways inflammation and bronchial hyperreactivity are features of asthma, it is possible that intravenous adenosine may be associated with an increased intensity of dyspnea, and may cause bronchospasm, as noted anecdotally in previous reports.MethodsWe compared the effects of placebo and 10 mg intravenous adenosine, in 6 normal and 6 asthmatic subjects.ResultsPlacebo injection had no significant (p > 0.05) effect on the forced expiratory spirogram, heart rate, minute ventilation (Ve), or respiratory sensation. Similarly, adenosine injection caused no significant changes (p > 0.05) in the forced expiratory spirogram; however, there was a rapid development of dyspnea as signified visually on a modified Borg scale, and a significant (p < 0.05) tachycardia in each subject (Asthmatics +18%, Normals + 34%), and a significant (p < 0.05) increase in Ve (Asthmatics +93%, Normals +130%). The intensity of dyspnea was significantly greater (p < 0.05) in the asthmatic subjects.ConclusionThese data indicate that intravenous adenosine does not cause bronchospasm in asthmatic subjects, and supports the concept that adenosine-induced dyspnea is most likely secondary to stimulation of vagal C fibers in the lungs. The increased intensity of adenosine-induced dyspnea in the asthmatic subjects suggests that airways inflammation may have sensitized the vagal C fibers.

Spirometry and flow-volume curves in healthy, normal Pakistanis

Previous studies have indicated that lung volumes in healthy, normal Pakistani adults are smaller than measurements reported in comparable healthy European populations; in order to confirm these findings and to examine the relationship of maximal expiratory flow rates to lung volumes, we studied 250 non-smoking healthy subjects (116 men and 114 women) between the ages of 18 and 65 years. The population sample was drawn from urban and rural areas of Pakistan, with low levels of air pollution. The results indicate that the forced vital capacity (FVC) and forced expired volume in 1 second (FEV1) were lower in the Pakistani population compared to European populations and North American populations of European descent. These data are in conformity with previous studies; however, in Pakistani men the effects of age on FVC and FEV1 were slight so that, after the fourth decade, the FVC and FEV1 values are very comparable between the European and Pakistani populations. Amongst Pakistani women, on the other hand, FVC and FEV1 remained lower than in their European counterparts throughout adult life. Maximal expiratory flow rates amongst the men did not correlate with age, and these values were very similar to those reported in age-matched European populations. In women, however, there was a significant correlation of maximal flow rates with age and height, and the maximal expiratory flows were decreased compared to European populations. These data indicate that in Pakistani men pulmonary mechanics may be different to their European counterparts, allowing for higher maximal expiratory flows at any given lung volume.

Blockade of airway sensory nerves and dyspnea in humans

Evidence has accumulated from previous studies that vagal fibers in the lungs are involved in the genesis of dyspnea. In a series of human studies, based on our previous animal data (J Physiol 1998; 508:109-18; J Appl Physiol 1998; 84:417-24; J Appl Physiol 2003; 95:1315-24) we established that intravenous adenosine has a dyspnogenic effect (J Appl Physiol 2005; 98:180-5; Respir Res 2006; 7:139; Pulm Pharmacol Ther 2008; 21:208-13), strongly implicating a role for vagal C-fibers in the genesis of dyspnea. We have now analyzed the relative effects of blockade of vagal C-fibers by two methods and routes of delivery: by inhibition of the sodium channel and interruption of action potential conduction in the nerve by inhaled local anesthetic (lidocaine), and by blockade by systemic theophylline, a known, nonselective adenosine receptor antagonist. Both techniques significantly (p < 0.05) attenuated the dyspneic response to intravenous adenosine. However, the attenuation was significantly (p < 0.05) greater with pretreatment with systemic theophylline (mean change in response, DeltaAUC -44%) versus pretreatment with inhaled lidocaine (mean change in response, DeltaAUC -11.8%). These differences in the results of airway sensory nerve blockade probably reflect different populations of C fiber receptors and may explain conflicting results of previous studies of dyspnea and airway anesthesia.

Long-term oral bronchodilator therapy of asthma with pirbuterol.

We studied the effects of an oral β2 selective bronchodilator, pirbuterol, in 12 male asthmatic patients over periods ranging from 6 to 23 months (mean, 13.8). Each patient was evaluated initially by physical examination, urinalysis, blood analysis, and pulmonary function tests. Patients were examined at regular intervals thereafter. Patients remained off all bronchodilator therapy for 12 hr before each visit. Blood analysis, urinalysis, and pulmonary function tests were performed and the pulmonary function tests were repeated approximately 2 hr after an oral dose of pirbuterol. We found no significant changes in the baseline resistance or in the bronchodilator response to pirbuterol during the course of the study, but there was a significant decrease in the functional residual capacity (FRC). The reduction in FRC could be due to the prolonged reduction in airways resistance with continuous therapy. We found no increase in the bronchodilator response to pirbuterol during oral prednisone therapy. There were no significant changes in serum potassium. Side effects attributable to pirbuterol, nervousness and tremor, occurred in only 2 patients and were easily controlled.

Pulmonary Function in the Elderly: Response to Theophylline Bronchodilation

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P <.05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P > .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.

Effects of acute prolonged exposure to high-altitude hypoxia on exercise-induced breathlessness.

The direct effects of hypoxia on exercise-induced breathlessness are unclear. Increased breathlessness on exercise is known to occur at high altitude, but it is not known whether this is related to the hypoxia per se, or to other ventilatory parameters. To examine the role of high-altitude hypoxia in exercise-induced breathlessness, studies were performed in 10 healthy, normal subjects at sea level and after acute exposure to an altitude of 4450 m. Although the perception of hand weights did not alter between sea level and high altitude, the intensity of exercise-induced breathlessness increased significantly at high altitude. This was associated with a higher minute ventilation and respiratory frequency for any given exercise level, whereas tidal volume was not significantly altered from sea level values. The increased intensity of breathlessness with exercise did not change significantly over the 5 days at high altitude. These results suggest that the increased intensity of exercise-induced breathlessness at high altitude is not related to peripheral mechanisms or the pattern of ventilation, or to the level of hypoxia per se, but to the level of reflexly increased ventilation.

Effects of Therapeutic Doses of Albuterol on β2-Adrenergic Receptor Density and Metabolic Changes

β2-Agonist drugs at inhaled supratherapeutic doses or when given orally or parenterally alter peripheral lymphocyte β2-adrenoceptor density (βAR) and have demonstrable metabolic effects. However, it is not known whether these changes occur at therapeutic inhaled doses. We therefore studied the effects of therapeutic doses of inhaled albuterol in five asthmatic subjects (mean age 23.0 ±2.4 years) and six normal subjects (mean age 28.3 ± 3.3 years). Subjects were studied in a randomized, double-blind protocol in which each subject received either inhaled albuterol (270 μg four times daily) for 2 weeks followed by placebo or vice versa in two sequential 2-week periods separated by a 2-week washout period. In the asthmatics, baseline FEV1 increased significantly (p < 0.05) after 2 weeks of inhaled albuterol treatment compared to the initial visit and after 2 weeks of placebo (mean FEV1: 3.2 L ± 0.7 L, 2.9 L ± 0.5 L, and 3.0 L ± 0.7 L, respectively). Baseline peripheral lymphocyte βAR was not significantly different (p > 0.05) between the asthmatic (mean: 757 ± 176) and normal subjects (mean: 732 ± 251). However, in neither group was there any significant change (p > 0.05) in βAR or plasma potassium, insulin, or glucose, either acutely or after 2 weeks of albuterol therapy. The present study confirms that there is no difference in peripheral lymphocyte βAR between asthmatic and normal subjects and also shows that at therapeutic doses of inhaled albuterol, there are no significant changes in βAR or metabolic effects.