Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline.

Alpha-1 antitrypsin (A1AT) functions primarily to inhibit neutrophil elastase, and deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). Severe A1AT deficiency occurs in one in 5000 to one in 5500 of the North American population. While the exact prevalence of A1AT deficiency in patients with diagnosed COPD is not known, results from small studies provide estimates of 1% to 5%. The present document updates a previous Canadian Thoracic Society position statement from 2001, and was initiated because of lack of consensus and understanding of appropriate patients suitable for targeted testing for A1AT deficiency, and for the use of A1AT augmentation therapy. Using revised guideline development methodology, the present clinical practice guideline document systematically reviews the published literature and provides an evidence-based update. The evidence supports the practice that targeted testing for A1AT deficiency be considered in individuals with COPD diagnosed before 65 years of age or with a smoking history of <20 pack years. The evidence also supports consideration of A1AT augmentation therapy in nonsmoking or exsmoking patients with COPD (forced expiratory volume in 1 s of 25% to 80% predicted) attributable to emphysema and documented A1AT deficiency (level ≤11 µmol/L) who are receiving optimal pharmacological and nonpharmacological therapies (including comprehensive case management and pulmonary rehabilitation) because of benefits in computed tomography scan lung density and mortality.

Comparison and reliability of two non-invasive acetylene uptake techniques for the measurement of cardiac output.

Comparison and reliability of two non-invasive acetylene uptake techniques for the measurement of cardiac output. Thirteen trained male cyclists performed CO2 rebreathing (CO2RB) at intensities from rest to 200 W, and open-circuit acetylene uptake (OpCirc) and single-breath acetylene uptake (SB) at intensities from rest to 300 W, with all procedures using 50 W increments. Oxygen consumption VO2 cardiac output Q and heart rate (HR), were measured at each stage, and the values for each variable were compared within each intensity to determine reliability of the measuring device. Both the OpCirc and SBs were shown to be reliable measures of cardiac output (r = 0.95 and 0.92, respectively) with decreasing coefficients of variation (CV) as intensity increased, and were similar to published data. The Q-VO2 relationship using the SB diverged from the regression line for OpCirc and CO2RB. Linear regression of the Q--VO2 relationship for CO2RB was y = 6.18 x VO2 + 2.59 for OpCirc was y = 6.12 x VO2 + 2.98 and for SB was y = 5.05 x VO2 + 3.76. The OpCirc and SBs were both shown to be reliable techniques for measuring cardiac output, comparable to previously reported cardiac output measurements, and suitable for use in exercise testing. However, the SB, requiring a constant, slow exhalation rate, made the procedure difficult to perform at higher exercise intensities.

Effects of vagal denervation on cardiorespiratory and behavioral responses in the newborn lamb.

Recently, Wong et al. (Wong KA, Bano A, Rigaux A, Wang B, Bharadwaj B, Schurch S, Green F, Remmers JE, and Hasan SU, J Appl Physiol 85: 849-859, 1998) demonstrated that fetal lambs that have undergone vagal denervation prenatally do not establish adequate alveolar ventilation shortly after birth. In their study, however, vagal denervation was performed prenatally and the deleterious effects of vagal denervation on breathing patterns and gas exchange could have resulted from the prenatal actions of the neurotomy. To quantify the relative roles of pre- vs. postnatal vagal denervation on control of breathing, we studied 14 newborn lambs; 6 were sham operated, and 8 were vagally denervated below the origin of the recurrent laryngeal nerve. Postoperatively, all denervated animals became hypoxemic and seven of eight succumbed to respiratory failure. In vagally denervated lambs, expiratory time increased, whereas respiratory rate, minute ventilation, and lung compliance decreased compared with the sham-operated animals. In the early postoperative period, the frequency of augmented breaths was lower but gradually increased over time in the denervated vs. sham-operated group. The dynamic functional residual capacity was significantly higher than the passive functional residual capacity among the sham-operated group compared with the denervated group. No significant differences were observed in the prevalence of various sleep states and in the amount of total phospholipids or large- and small-aggregate surfactants between the two groups. We provide new evidence indicating that intrauterine actions of denervation are not required to explain the effects of vagal denervation on postnatal survival. Our data suggest that vagal input is critical in the maintenance of normal breathing patterns, end-expiratory lung volume, and gas exchange during the early neonatal period.

Comparison of intramuscular betamethasone and oral prednisone in the prevention of relapse of acute asthma.

OBJECTIVE: To compare the relapse rate after a single intramuscular injection of a long acting corticosteroid, betamethasone, with oral prednisone in patients discharged from the emergency department (ED) for acute exacerbations of asthma. PATIENTS AND METHODS: Patients with acute exacerbations of asthma who were suitable for discharge from the ED were enrolled in a double-blind, randomized, placebo controlled pilot study. At discharge, patients were randomly assigned to receive either intramuscular betamethasone 12 mg and placebo capsules, or a placebo intramuscular injection and prednisone 50 mg daily for seven days. At days 7 and 21, patients were contacted by telephone to determine relapse. Relapse was defined as an unscheduled visit to a physician for treatment of continuing or worsening symptoms of asthma. RESULTS: One hundred and seventy-one patients were enrolled, of whom 87 were randomly assigned to the betamethasone group and 84 to the prednisone group. Baseline characteristics were matched evenly between the groups, with the exception of asthma duration (15.5 versus 21.2 years, respectively) and use of inhaled corticosteroids (46% versus 64.3% respectively) (P<0.05). Using intention-to-treat analysis, the relapse rates for betamethasone and prednisone at day 7 were 14.9% (13 of 87 patients) and 25% (21 of 84 patients), respectively (P=0.1), and at day 21, the rates were 36.8% (32 of 87 patients) and 31% (26 of 84 patients), respectively (P=0.4). There were no differences in symptom score, peak flows and adverse effects between the two groups at days 7 and 21. CONCLUSIONS: A single dose of intramuscular betamethasone 12 mg was safe and as efficacious as prednisone in preventing the relapse of acute asthma. There was a trend toward a reduced relapse rate at seven days. In select ED patients discharged for acute asthma, intramuscular betamethasone may be an effective alternative to prednisone.

Alpha1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society.

OBJECTIVE: To prepare new guidelines for the Canadian Thoracic Society (CTS) regarding severe alpha1-antitrypsin (AAT) deficiency and AAT replacement therapy. MATERIALS AND METHODS: Previously published guidelines and the medical literature about AAT deficiency and AAT replacement were reviewed. The prepared statement was reviewed and approved by the CTS Standards and Executive Committees. RESULTS: Three studies evaluated AAT replacement. The National Heart, Lung and Blood Institute's AAT Registry was a nonrandomized comparison of patients receiving and not receiving AAT replacement, and evaluated the decline in forced expiratory volume in 1 s (FEV1) in 927 subjects. The rate of FEV1 decline was significantly less in those receiving AAT treatment (66 +/- SE 5 mL/year versus 93 +/- SE 11 mL/year; P=0.03) only in the subgroup with FEV1 35% to 49% predicted. In another study comparing 198 German patients receiving weekly AAT infusions and 97 untreated Danish patients, the mean annual decline in FEV1 was significantly less in treated patients only in the subgroup with FEV1 31% to 65% predicted (62 mL versus 83 mL, P=0.04). Neither of these studies was a randomized, controlled study and, thus, cannot be taken as proof of efficacy. A randomized, double-blind, placebo controlled trial of monthly replacement therapy over three years in 56 exsmokers with severe AAT deficiency and moderate emphysema showed a trend (P=0.07) favouring slower progression of emphysema by computed tomography scan in the group receiving AAT replacement. CONCLUSIONS: AAT replacement therapy has not been proven definitively to be clinically effective in reducing the progression of disease in AAT-deficient patients, but there is a possible benefit to selected patients. A placebo controlled, randomized clinical trial of AAT replacement therapy is required. The authors recommend reserving AAT replacement therapy for AAT-deficient patients with impaired FEV1 of 35% to 50% predicted who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV1, and participation of all AAT-deficient subjects in the Canadian AAT Registry.

Interaction between postural and respiratory control of human intercostal muscles.

To study the interaction between postural and respiratory control of intercostal muscles, we used electromyography of intercostal muscles of the lateral chest wall in conscious humans. Bipolar fine-wire electrodes were placed in external and internal intercostal muscles in the midaxillary line of four subjects who sat on a bench and breathed through a pneumotachograph. They were instructed to hold their breath at end expiration, rotate their thorax to the right or left, and then hold the rotation while resuming breathing. Holding a rotation induces steady tonic activity in either internal or external intercostal muscles, depending on the direction of the rotation. The degree of rotation was varied from one run to the next, resulting in varied levels of tonic postural activity. When breathing resumes, internal intercostal muscles have their activity almost completely suppressed with each inspiration independently of whether the tonic postural tone is small or large. External intercostal muscles show inspiratory increases in activity superimposed on the postural tone, which apparently amplifies the effect of respiratory input to their motoneurons.

Respiratory physiology in upper abdominal surgery.

This article describes the pathophysiology of the respiratory system after upper abdominal surgery, emphasizing the role of respiratory muscle dysfunction. The history of current techniques to measure respiratory muscle function are reviewed. The authors describe the postoperative pattern of breathing, speculate on the physiologic mechanisms responsible and discuss the data supporting the role of reflexes arising from the abdomen and the shift of neural output to different respiratory muscles. Finally, the authors review the impact of "closed" surgical interventions such as laparoscopic cholecystectomy.

Multipatient use of prefilled disposable oxygen humidifiers for up to 30 days: patient safety and cost analysis.

BACKGROUND: Prefilled disposable oxygen humidification units have been shown to decrease the likelihood of contamination when compared to reusable oxygen humidification units. However, prefilled disposable humidifiers are expensive when used for single patients, especially in areas of high turnover, and it is not known whether these units need to be routinely changed before they are empty. The number of patients safely using a prefilled disposable humidifier has not been documented in previously reported work. Are patients at risk of nosocomial infections due to cross-contamination when prefilled disposable oxygen humidifiers are applied to multi-patient use? What are the cost benefits of multiple patient use of prefilled disposable oxygen humidifiers? When local practice or physician preference dictates the use of humidification for low-flow oxygen, these questions need to be answered. METHODS & MATERIALS: Data were collected over two time periods to address changes due to seasonal variations and include area of use, number of patients, and quantitative cultures for aerobic microorganisms (including Legionella). Each disposable humidifier was monitored for a period of 1 month or until only 1 inch of water remained. Costs of using reusable humidifiers and prefilled humidifiers and therapist/nurse time to initiate therapy with both units were compared. During this period, 60 reusable humidifiers were also cultured for aerobic microorganisms and Legionella. RESULTS: We report results on 1,311 of the 1,315 disposable prefilled oxygen humidifiers used. We saw no significant growth in any of the prefilled disposable humidifiers for periods of up to 30 days, with > 100 humidifiers having been used by > 20 patients. CONCLUSIONS: Our results show that prefilled disposable oxygen humidifiers can be used without cross-contamination, on multiple patients, for a period of 1 month. The use of prefilled humidifiers in this way represents a substantial cost saving when compared to reusable humidifiers.

Intercostal muscles are used during rotation of the thorax in humans.

To test the idea that the lateral intercostal muscles may be more suited to aid in rotational than respiratory movements of the thorax, we inserted bipolar fine-wire electrodes in external and internal intercostal muscles in the right midaxillary line in nine sitting subjects and examined the pattern of contraction of these muscles during voluntary axial rotations of the thorax (30-35 degrees), resting breathing, and CO2-induced hyperpnea. The right external intercostal muscles were strongly recruited in rotations to the left but were not active in rotations to the right. In contrast, the right internal intercostal muscles were active in rotations to the right but not in rotations to the left. Rotations completed in 1 or 2 s were associated with an early burst of electromyographic activity, followed by a low plateau that persisted while the rotation was held. Rotations made very gradually over 5-10 s were associated with gradually rising electromyographic activity. The amplitude of activity recorded during 30-35 degrees rotations was equivalent to that measured when minute ventilation was increased by CO2 to 50 l/min. We conclude that the lateral intercostal muscles have a major role in producing axial rotations of the thorax.

Pulmonary function tests: are they really necessary?

Pulmonary function tests and clinical evaluation can complement one another, but neither can take the place of the other. The tests can provide objective, reproducible assessment of a patient's pulmonary status. Pulmonary function tests can support clinical diagnoses, quantify the severity and variability of the disorder, and can assist early intervention by indicating problems likely to arise later in the course of the disease.

Inhibition of breathing associated with gallbladder stimulation in dogs.

The effect of mechanical stimulation of the gallbladder on breathing was studied in anesthetized spontaneously breathing dogs. Measurements of tidal volume, breathing frequency, rib cage and abdominal diameter, transdiaphragmatic pressure, and electrical activity of the diaphragm were made while traction or compression was applied to the gallbladder for periods of 30 s. Both forms of mechanical stimulation produced similar changes, including large decreases in tidal volume, respiratory rate, electrical activity of the diaphragm, and transdiaphragmatic pressure swings. Inspiratory rib cage expansion was little affected, but abdominal expansion was greatly reduced, and swings in gastric pressure were reduced more than swings in pleural pressure, indicating a selective decrease in diaphragmatic activity. Recovery of all measured parameters returned toward control values, despite continued traction or compression. Some inhibition persisted after the stimulus was withdrawn. The very brief interval between stimulus and response suggested that the mechanism was a neural reflex. The afferents involved are unknown but are not purely vagal in nature, since qualitatively similar results were seen in animals after vagotomy. The alteration in breathing frequency indicates that at least part of the reflex is supraspinally mediated. The change in pattern of breathing closely resembles that seen in subjects after abdominal surgery and supports the theory that reflex inhibition of breathing contributes to postoperative pulmonary complications seen in those subjects.

Effect of lung volume on breath holding.

The mechanism by which large lung volume lessens the discomfort of breath holding and prolongs breath-hold time was studied by analyzing the pressure waves made by diaphragm contractions during breath holds at various lung volumes. Subjects rebreathed a mixture of 8% CO2-92% O2 and commenced breath holding after reaching an alveolar plateau. At all volumes, regular rhythmic contractions of inspiratory muscles, followed by means of gastric and pleural pressures, increased in amplitude and frequency until the breakpoint. Expiratory muscle activity was more prominent in some subjects than others, and increased through each breath hold. Increasing lung volume caused a delay in onset and a decrease in frequency of contractions with no consistent change in duty cycle and a decline in magnitude of esophageal pressure swings that could be accounted for by force-length and geometric properties. The effect of lung volume on the timing of contractions most resembled that of a chest wall reflex and is consistent with the hypothesis that the contractions are a major source of dyspnea in breath holding.

Diaphragm function and respiratory response after upper abdominal surgery in dogs.

Decreased diaphragm activity has been demonstrated after cholecystectomy in humans (Am. Rev. Respir. Dis. 127: 431-436, 1983). To investigate the mechanism(s) of postoperative diaphragm dysfunction we have established a dog model. Three groups of mongrel dogs were studied under general anesthesia: six dogs received no surgery (control); nine dogs underwent upper abdominal surgery (cholecystectomy); and six dogs underwent lower abdominal surgery (pseudoappendectomy). Diaphragm function was assessed by changes in transdiaphragmatic pressure swings, the ratio of changes in gastric to esophageal pressure swings, and the ratio of changes in abdominal to rib cage diameters during quiet tidal breathing. In the upper abdominal surgery group there were significant postoperative decreases in all parameters of diaphragm function and an increase in minute ventilation and respiratory frequency. However, there were no significant postoperative changes in the parameters of diaphragm function in the control or lower abdominal surgery groups. These studies establish that general anesthesia is not responsible for the reduced diaphragm activity seen postoperatively and that diaphragm function is not affected by lower abdominal surgery in dogs.

Diaphragm function after upper abdominal surgery in humans.

Patients undergoing upper abdominal surgery characteristically develop changes in lung function and are liable to develop atelectasis in the lower lobes. We studied 15 patients to assess lung function and, in particular, diaphragm function in patients undergoing cholecystectomy. Postoperatively, forced expiratory volume in one second and vital capacity decreased in all patients. The alveolar-arterial oxygen difference widened in the 10 patients in whom it was measured. Chest roentgenograms demonstrated patchy atelectasis in 9 of the 10 patients in whom films were obtained. There was a significant reduction in tidal volume with no change in minute ventilation immediately postoperatively. Diaphragm function was assessed by: changes in transdiaphragmatic pressure swings during quiet tidal breathing, the ratio of changes in gastric to esophogeal pressure swings, and the ratio of changes in abdominal to rib cage diameters. The results showed a significant decrease in changes in transdiaphragmatic pressure and the ratio of changes in gastric to esophogeal pressure swings in the postoperative period. In the 4 patients studied with magnetometers, there was a reduction in the ratio of changes in abdominal to rib cage diameters in all patients. These data indicate reduced diaphragm activity in the postoperative period, with a shift from predominantly abdominal to rib cage breathing. There was a reversal toward normal function by 24 h. This reduction in diaphragm function may be responsible for the atelectasis, reduced vital capacity, and hypoxemia in postoperative patients.

Shape and regional volume in immersed lung lobes.

We froze 10 isolated canine lower lobes by immersing them in chlorothene (sp gr 1.4) at -20 degrees C. In six instances the contralateral lower lobe was frozen over dry ice. The lobes were then sliced horizontally, and the volume and weight of each slice were measured so that expansion (specific volume) and the amount of tissue (weight) could be assessed as a function of distance down the lung. Lobes frozen under chlorothene at low [35% total lung capacity (TLC)] and medium [60% TLC] volumes demonstrated a gradient of regional expansion that was about half that predicted on the basis of pleural surface pressure. Lobes frozen under chlorothene at high volumes [80% TLC] did not demonstrate a significant gradient of regional expansion. These results demonstrated tissue interdependence. When lobes frozen under chlorothene were compared with contralateral lobes frozen over dry ice, substantial differences in shape were evident. Chlorothene-frozen lobes had greater vertical height, and a smaller fraction of their weight was present in dependent regions: lobes frozen in chlorothene had half as much tissue over the lower 40% of their vertical height as did lobes frozen over dry ice. We demonstrated two mechanisms by which relative homogeneity of regional expansion was maintained in response to differences in pleural pressure, tissue interdependence and tissue movement from more compressed to less compressed regions.

Static lung function in puppies after pneumonectomy.

We performed left pneumonectomy on eight puppies at 9 wk of age; seven littermates underwent a sham operation and functioned as controls. All were studied at 20 wk of age, at which time the remaining lung in the animals with pneumonectomy had the same volume, weight, and surface areas as both lungs of the controls. Total lung capacity (TLC) was the same in controls and postpneumonectomy dogs, but in the latter, the ratio of functional residual capacity to TLC (FRC/TLC) and that of residual volume to TLC (RV/TLC) were larger. Lung pressure-volume curves also differed, postpneumonectomy dogs demonstrating slightly greater recoil at lung volumes below TLC. Therefore, the increased FRC and RV of postpneumonectomy animals could not be ascribed to changes in lung recoil and must have been caused by increased chest wall recoil perhaps related to differences in shape between lung and chest wall. Studies of regional lung function revealed reduced aerated lung in the left hemithorax of the postpneumonectomy dogs and increased FRC/TLC and RV/TLC at the left base. The abnormal distribution of regional volumes did not account entirely for the increase in overall FRC and RV. Comparison of excised lung pressure-volume curves in those measured in intact animals revealed better agreement in postpneumonectomy dogs than in controls.