Intravenous aminoglycoside usage and monitoring of patients with cystic fibrosis in Australia. What's new?

BACKGROUND: The aim of this study was to determine the current situation regarding aminoglycoside use and monitoring in patients with cystic fibrosis (CF) throughout Australia. METHODS: A questionnaire was sent out to all CF units. Information gathered included patient characteristics, aminoglycoside use, dosing, therapeutic drug-monitoring methods, toxicity monitoring and incidence of occurrence. RESULTS: Responses were obtained from 27 of the 28 units identified. Tobramycin was the aminoglycoside of choice. All but three centres were using once-daily dosing for aminoglycoside administration. Initial dosing in tobramycin-naïve patients was based on bodyweight (range 7-12 mg/kg). Patients being readmitted were mainly prescribed the dose that they had received on their previous admission. All units gave i.v. doses by infusion with five units using bolus dosing as well. The method of therapeutic drug monitoring varied greatly. A computer programme was used by 15 units. Toxicity monitoring usually coincided with therapeutic drug monitoring. Nephrotoxicity was reported as having occurred in 13 units and ototoxicity in 15 units. The highest incidence of toxicity was ototoxicity in 20% of patients in one CF unit. CONCLUSION: Aminoglycoside dosing regimens have changed since the last survey was carried out in 1999. There has been an increase in the use of once-daily dosing from 54 to 88% of units. The reporting of both ototoxicity and renal toxicity has also increased (from 27 to 75% and from 19 to 65%, respectively). Standardization of management protocols for antibiotic use and patient monitoring may help reduce the risk of cumulative toxicity to aminoglycosides in CF patients.

Rituximab use in systemic lupus erythematosus pneumonitis and a review of current reports.

Rituximab is a chimeric monoclonal antibody specific for human CD20 that causes selective transient depletion of the CD20+ B-cell subpopulation. We report the first case of systemic lupus erythematosus (SLE) pneumonitis resistant to conventional treatments that responded well to rituximab and review current reports on the use of rituximab in SLE.

Density dependence of maximal flow is lung volume dependent during bronchoconstriction.

We examined the changes in maximum expiratory flow (Vmax) and the density dependence of maximum expiratory flow (delta Vmax) during histamine-induced bronchoconstriction in dogs. Histamine acid phosphate solution was nebulized into the airways of six dogs to produce predominantly peripheral airway obstruction. Vmax air, Vmax with the dogs breathing 80% He-20% O2 (delta Vmax), and airway sites of flow limitation (choke points) were examined at four lung volumes (VL), which ranged from 51 to 23% of the control vital capacity (VC). The findings were interpreted in terms of the wave-speed theory of flow limitation. At all VL, Vmax air decreased during bronchoconstriction by approximately 30% compared with the control value. Resistances peripheral to a 0.3-cm-diam airway were increased about threefold with histamine, whereas resistances between 0.6-cm-diam bronchi and main-stem bronchi increased just slightly. Airway diameters were measured in the air-dried lung at 20 cmH2O transpulmonary pressure. Our results showed that only at 44% VC did delta Vmax decrease in all experiments after histamine to indicate peripheral obstruction (mean: 68.5 to 45%). At 23% VC, delta Vmax increased slightly, from 22 to 28%. At 23 and 36% VC, substantial differences in the wave-speed variables between air and HeO2 were present before bronchoconstriction, so that delta Vmax was low in some dogs, although peripheral airway obstruction was not evident. When bronchoconstriction was produced, delta Vmax at 23% VC could not be decreased further and even increased in four of six dogs. Thus changes in delta Vmax at given lung volume may not reflect the predominant site of airflow obstruction during bronchoconstriction.

Expiratory flow limitation in dogs with regional changes in lung mechanical properties.

We examined maximum expiratory flow (Vmax) in two canine preparations in which regional changes in lung mechanical properties were produced. In one experiment serial bronchial obstructions were made to determine whether flow-limiting sites (choke points, CP) would occur in series. With the right lung tied off, constrictions were placed at the left lower lobar bronchus (LLL) and left main-stem bronchus. On deflation from total lung capacity, the obstructed LLL and nonobstructed left upper lobe (LUL) emptied into the obstructed left main-stem bronchus. Although a CP common to both lobes was identified at the main-stem obstruction, which limited total Vmax, we questioned whether there was also a CP at the lobar obstruction that fixed LLL flow. In that case the rate of LLL emptying would not be dependent on the presence of the common (i.e., central) CP and thus the flow contribution of the LUL. We found that when the LUL was removed, the LLL increased its rate of emptying. Thus a lobar CP did not fix LLL flow and CP did not occur in series. In a second experiment emphysema was produced in the left lung to reduce lung recoil, whereas the right lung was normal. CP were identified at approximately lobar bronchi of each lung, and the lungs were emptied at different rates. A CP common to both lungs was not identified. Our results indicate that in localized lung disease, if flows from the different regions are high enough, then wave speed is reached in proximal airways, and a CP occurs centrally rather than peripherally. On the other hand, if flows are low, then wave speed is reached peripherally and a CP common to all lung regions does not occur.

Forced expiration and HeO2 response in canine peripheral airway obstruction.

We examined the effect of peripheral airway obstruction on parameters of maximum expiratory flow (Vmax) in a canine model of bronchiolitis obliterans (B). B was produced by the repeated intrabronchial instillations of a 1% nitric acid solution in seven dogs (group B). In seven control dogs (group C), a normal saline solution was used. During forced vital capacity deflation, Vmax on air, the relative increase in Vmax on 80% He-20% O2 (delta Vmax), and airway sites of flow limitation "choke points" (CP) were determined at multiple lung volumes (VL). The findings were interpreted in terms of the wave-speed theory of flow limitation. Wave-speed parameters were identified with a pressure-measuring device positioned in the airway. Compared with the findings for group C, Vmax decreased substantially at the lower VL (less than 50% vital capacity) in group B, whereas there were no changes in delta Vmax at any VL. CP were identified in central airways in both groups but were slightly more upstream in group B. Our analysis indicated that the reduction in Vmax in group B was due to an increase in upstream frictional pressure losses (Pfr) that caused a relative reduction in the pressure head, so that choking occurred in slightly upstream airways. delta Vmax did not change in group B because with CP identified in central airways, Pfr were density dependent, and significant differences in head loss on the two gas mixtures did not occur. Choking therefore occurred with similar wave-speed variables on the two gas mixtures, and delta Vmax was maintained.

Mechanism of reduced maximum expiratory flow in dogs with compensatory lung growth.

We examined the mechanism of the reduced maximum expiratory flow rates (Vmax) in a dog model of postpneumonectomy compensatory lung growth. During forced expiration, a Pitot-static tube was used to locate the airway site of flow limitation, or choke point, and to measure dynamic intrabronchial pressures. The factors determining Vmax were calculated and the results analyzed in terms of the wave-speed theory of flow limitation. Measurements were made at multiple lung volumes and during ventilation both with air and with HeO2. Five of the puppies had undergone a left pneumonectomy at 10 wk of age, and 5 littermate controls had undergone a sham operation. All dogs were studied at 26 wk of age, at which time compensatory lung growth had occurred in the postpneumonectomy group. Vmax was markedly decreased in the postpneumonectomy group compared with control, averaging 42% of the control flow rates from 58 to 35% of the vital capacity (VC). At 23% of the VC, Vmax was 15% less than control. Choke points were more peripheral in the postpneumonectomy dogs compared with controls at all volumes. The total airway pressure was the same at the choke-point airway in the postpneumonectomy dogs as that in the same airway in the control dogs, suggesting that the airways of the postpneumonectomy dogs displayed different bronchial area-pressure behavior from the control dogs. Despite the decreased Vmax on both air and HeO2, the density dependence of flow was high in the postpneumonectomy dogs and the same as controls at all lung volumes examined.

Pulmonary gas exchange during exercise in highly trained cyclists with arterial hypoxemia.

The causes of exercise-induced hypoxemia (EIH) remain unclear. We studied the mechanisms of EIH in highly trained cyclists. Five subjects had no significant change from resting arterial PO(2) (Pa(O(2)); 92.1 +/- 2.6 Torr) during maximal exercise (C), and seven subjects (E) had a >10-Torr reduction in Pa(O(2)) (81.7 +/- 4.5 Torr). Later, they were studied at rest and during various exercise intensities by using the multiple inert gas elimination technique in normoxia and hypoxia (13.2% O(2)). During normoxia at 90% peak O(2) consumption, Pa(O(2)) was lower in E compared with C (87 +/- 4 vs. 97 +/- 6 Torr, P < 0.001) and alveolar-to-arterial O(2) tension difference (A-aDO(2)) was greater (33 +/- 4 vs. 23 +/- 1 Torr, P < 0. 001). Diffusion limitation accounted for 23 (E) and 13 Torr (C) of the A-aDO(2) (P < 0.01). There were no significant differences between groups in arterial PCO(2) (Pa(CO(2))) or ventilation-perfusion (VA/Q) inequality as measured by the log SD of the perfusion distribution (logSD(Q)). Stepwise multiple linear regression revealed that lung O(2) diffusing capacity (DL(O(2))), logSD(Q), and Pa(CO(2)) each accounted for approximately 30% of the variance in Pa(O(2)) (r = 0.95, P < 0.001). These data suggest that EIH has a multifactorial etiology related to DL(O(2)), VA/Q inequality, and ventilation.

Corticosteroid induced osteoporosis. Guidelines for treatment.

BACKGROUND: Last year, Australian Family Physician published 'Guidelines for Management of Postmenopausal Osteoporosis', which were developed by Osteoporosis Australia. Recently, significant advances in our understanding of the treatment of corticosteroid osteoporosis have occurred. OBJECTIVE: The following guidelines, also developed by Osteoporosis Australia, and supported by the National Asthma Campaign, are to help general practitioners identify those patients at risk of this problem and to provide information about current treatment strategies. DISCUSSION: Corticosteroids are widely used and effective agents for the control of many inflammatory diseases. Corticosteroid osteoporosis is a common problem associated with the long term high dose use of these medications.

Asthma and irreversible airflow obstruction.

To determine whether asthma alone can cause irreversible airflow obstruction 42 men and 47 women with chronic asthma (mean duration 22 (SD 13) years) without evidence of other disease likely to cause irreversible airflow obstruction were treated with theophylline orally and a beta agonist both orally and by inhalation for four weeks. After two weeks of treatment the FEV1 was less than 85% of the predicted normal value (%P) in 48 patients and these individuals then received prednisolone 0.6 mg/kg/day for two weeks. Duration and severity of asthma and smoking history were quantified by questionnaire; 38 patients were current smokers or ex-smokers. FEV1 was measured at 0, 2, and 4 weeks. The mean difference between the best FEV1 during the study and the predicted normal value was 0.29 l (p less than 0.001); FEV1 %P decreased with age (r = -0.30, p less than 0.01) and with the duration (r = -0.47, p less than 0.001) and severity (r = -0.55, p less than 0.001) of asthma. Similar findings were noted when the results for non-smokers and those whose asthma started in adult life were analysed separately. We conclude that asthma alone can cause irreversible airflow obstruction and that the degree of obstruction is a function of the duration and severity of previous asthma. The results suggest the possibility that irreversible airflow obstruction in asthma may be preventable by minimising the degree of persistent asthma.

Pulmonary disease from occupational exposure to an artificial aluminium silicate used for cat litter.

All available workers engaged in bagging an artificial crystalline aluminium silicate--the kiln-dried residue from the calcining and water extraction of alunite (a hydrated sulphate of aluminium and potassium) that is currently classified as a nuisance dust--were studied after a complaint of respiratory and systemic symptoms, including arthritis, by an employee of the factory, who showed physiological and radiographic evidence of diffuse pulmonary fibrosis and in whom lung biopsy showed diffuse fibrosis with granulomas. Inhalation challenge produced a transient decrease in transfer factor and transfer factor standardised for alveolar volume. Twenty-five subjects were known to have been exposed at some time to the dust of alunite-residue. Of the 17 who could be contacted, all agreed to attend for respiratory questionnaire and occupational history, pulmonary function testing (spirometry, lung volumes, gas transfer), and posteroanterior chest radiograph. Six subjects considered that occupational exposure to the dust was responsible for respiratory symptoms. Three subjects had abnormality of the chest radiograph consistent with pulmonary fibrosis. The mean percentage of predicted transfer factor standardised for effective alveolar volume was 71.1% in subjects with abnormal chest radiographs and 86.6% in subjects with normal radiographs (p = 0.10). There was a trend in the correlation between the percentage of predicted transfer factor standardised for effective alveolar volume and total dust exposure (sum of the products of grade of severity of each exposure period and duration of each exposure period in months) (r = 0.40 p = 0.10). This study suggests that there may be a relation between inhalation of the dust of this form of aluminium silicate and pulmonary fibrosis.

Irreversible airflow obstruction. Evolution in asthma.

To determine whether asthma can cause irreversible airflow obstruction (IAO) 89 subjects with uncomplicated asthma received intensive treatment for four weeks. FEV1 was measured at 0, two and four weeks; pulmonary elasticity and flow resistance was measured in 46 of the subjects at four weeks. Severity of asthma and cigarette consumption were ascertained by a questionnaire. The mean difference between the predicted and highest FEV1 during treatment was 0.29 L (P less than 0.001). The highest FEV1% predicted correlated (P less than 0.001) with the duration and severity of asthma in the entire group, in the 51 nonsmokers, and in the 47 subjects with the adult onset of asthma. Pulmonary resistance, but not elastic recoil, correlated with the duration and severity of asthma (P less than 0.01). The results show that chronic asthma can cause narrowed airways and IAO, and suggest that this may be prevented by improved control of asthma.

Pulmonary function tests in the detection of small airway obstruction in a canine model of bronchiolitis obliterans.

We compared parameters of maximal expiratory flow with other tests used in the detection of small airways obstruction (SAD) in a canine model of bronchiolitis obliterans. Bronchiolitis was produced by instilling a 1% solution of nitric acid into the airways of 8 dogs (Group N). In 5 control dogs, a normal saline solution was instilled (Group C). Plethysmographic lung volumes, oscillatory airway resistance (RL), and tests for SAD were examined after bronchiolitis was produced. To evaluate peripheral airway function, the single-breath nitrogen washout curve was used to obtain the slope of phase III and to estimate the lung volume at which a terminal increase in N2 concentration was observed (closing capacity). Maximal expiratory flow-volume curves while the dogs breathed air and 80:20 helium:oxygen (HeO2) were performed to obtain the air flow rate at 50% vital capacity (V50), the corresponding HeO2 flow rate (delta Vmax), and the lung volume at which air and HeO2 flow rates were equal (Viso). After injury, the histologic aspects of the lung in Group N showed acute and chronic inflammation of the small airways. The RL did not change in Group N, despite a relative increase in peripheral airway resistance, which when measured increased about 4 times. Compared with Group C, significant increases in closing capacity and Viso and significant decreases in V50 were observed in Group N. Although predicted to decrease in SAD, delta Vmax did not change. We conclude that delta Vmax is relatively insensitive to SAD. Possible mechanisms resulting in reduced V50 but maintained delta Vmax in this model were further examined in terms of the concepts outlined by the wave-speed theory of flow limitation.

Effect of previous volume history on airway closure.

We studied the effect of volume history on airway closure in six healthy males ranging from 32 to 67 yr of age. The method used was to compare the regional distribution of 133Xe boluses distributed according to N2O uptake during open-glottis breath-hold maneuvers with the regional distribution of boluses of intravenously injected 133Xe. Measurements were made at two lung volumes, one close to residual volume (RV) and the other just below closing volume. The required volume was reached either by expiring from total lung capacity or by inspiring from RV. Although there was considerable airway closure in the basal regions of the lungs at both lung volumes studied, the degree of airway closure was not dependent on the previous volume history. We conclude that the airways concerned with closure have a volume-pressure hysteresis similar to that of the lung parenchyma. Furthermore in normal humans the volume-pressure hysteresis of the lung is not secondary to airway closure.

Dynamic lung function in dogs with compensatory lung growth.

Nine puppies underwent left pneumonectomy at 10 wk of age while nine sex-matched littermates had a sham operation, and all animals were studied at 25 wk of age. Postpneumonectomy dogs demonstrated compensatory growth in that lung weight and total lung capacity (TLC) were the same as those of control animals when normalized for body weight. In postpneumonectomy dogs all lobes of the remaining right lung increased in weight, but this was most notable in the cardiac lobe which grew across the mediastinum. Subdivisions of lung volume were normal in postpneumonectomy animals except for residual volume (RV): RV/TLC was increased when compared with control animals. In intact dogs static pressure-volume curves of the lung and respiratory system did not differ between groups, and the static pressure-volume curves of excised lungs were closely similar. Maximum expiratory flow was sharply reduced in postpneumonectomy dogs, averaging 40% of flow in control dogs over the lower 50% of the vital capacity. In both groups the fractional increase in maximal expiratory flow during HeO2 breathing was substantial and similar. Regional compliances, resistances, and perfusion distribution were examined using 133Xe. Regional compliance and perfusion were reduced in the left hemithorax of postpneumonectomy dogs while regional resistances were increased.

Nocardia asteroides isolated from three patients with cystic fibrosis.

Over a 7-year period, three patients with cystic fibrosis had multiple sputum specimens that were smear- and culture-positive for Nocardia asteroides. Two of the patients had received long-term, low-dose inhalational corticosteroid therapy. Although all three patients were treated with cotrimoxazole, resulting in eradication of the organism from the sputum, there was no change in their clinical state, radiological findings, or pulmonary function. The isolation of Nocardia asteroides from the respiratory tract of cystic fibrosis patients is an unusual finding. Its presence does not necessarily imply disease, and in these three cases, it most likely represented colonisation. The clinical significance of Nocardia spp. isolated from the respiratory tract of cystic fibrosis patients needs to be considered in the context of the individual clinical picture.

Determinants of adherence in adults with cystic fibrosis.

Cystic fibrosis (CF) is now as much a disease of adults as of children and adolescents. An important focus of recent research has been the impact of the complex, expensive, and time consuming routine of self-care and medical treatment that is required by adults with CF to maintain health. A growing concern for medical and allied health teams is the issue of patient adherence to prescribed health management plans. A summary of the particular medical and treatment context of CF is followed by a review of adherence measurement issues and the determinants of adherence to treatment regimens in people with CF, primarily adults. Evidence for factors which influence adherence decisions of people with CF is examined. The medical and psychological aspects of this complex problem have not been adequately addressed because of difficulties with definition and measurement. Only a small proportion of the variance in adherence has been accounted for in the literature. New measurement technologies and new theoretical directions offer promise for a better understanding of this complex and important issue and may result in more effective intervention strategies to improve adherence.

Pulmonary disease from exposure to an artificial aluminium silicate: further observations.

A cross sectional analysis of the relation between exposure to an artificial aluminium silicate (alunite residue) and pulmonary function changes has been made in 32 subjects, 17 of whom had been previously reported and in whom there was suggestive evidence of a dose response relation between gas transfer and total silicate exposure. Longitudinal data were also available for nine subjects. No dose effect relation was observed in either analysis and only one of the three subjects previously observed to have an abnormal chest radiograph (the index subject) had deteriorated appreciably. Respirable particles of alunite residue were injected intratracheally into Syrian hamsters. No evidence of pulmonary toxicity was seen as judged by bronchoalveolar lavage measurements of the concentrations lactic dehydrogenase, albumin, and the lambda fraction of gold, and the numbers of macrophages, polymorphonuclear cells, and red blood cells (alpha-quartz and ferrous oxide were used as positive and negative controls). These results do not support a significant toxic effect of this aluminium silicate on the lungs.

Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptake.

A group of 15 competitive male cyclists [mean peak oxygen uptake, VO2peak 68.5 (SEM 1.5 ml x kg(-1) x min(-1))] exercised on a cycle ergometer in a protocol which began at an intensity of 150 W and was increased by 25 W every 2 min until the subject was exhausted. Blood samples were taken from the radial artery at the end of each exercise intensity to determine the partial pressures of blood gases and oxyhaemoglobin saturation (SaO2), with all values corrected for rectal temperature. The SaO2 was also monitored continuously by ear oximetry. A significant decrease in the partial pressure of oxygen in arterial blood (PaO2) was seen at the first exercise intensity (150 W, about 40% VO2peak). A further significant decrease in PaO2 occurred at 200 W, whereafter it remained stable but still significantly below the values at rest, with the lowest value being measured at 350 W [87.0 (SEM 1.9) mmHg]. The partial pressure of carbon dioxide in arterial blood (PaCO2) was unchanged up to an exercise intensity of 250 W whereafter it exhibited a significant downward trend to reach its lowest value at an exercise intensity of 375 W [34.5 (SEM 0.5) mmHg]. During both the first (150 W) and final exercise intensities (VO2peak) PaO2 was correlated significantly with both partial pressure of oxygen in alveolar gas (P(A)O2, r = 0.81 and r = 0.70, respectively) and alveolar-arterial difference in oxygen partial pressure (P(A-a)O2, r = 0.63 and r = 0.86, respectively) but not with PaCO2. At VO2peak PaO2 was significantly correlated with the ventilatory equivalents for both oxygen uptake and carbon dioxide output (r = 0.58 and r = 0.53, respectively). When both P(A)O2 and P(A-a)O2 were combined in a multiple linear regression model, at least 95% of the variance in PaO2 could be explained at both 150 W and VO2peak. A significant downward trend in SaO2 was seen with increasing exercise intensity with the lowest value at 375 W [94.6 (SEM 0.3)%]. Oximetry estimates of SaO2 were significantly higher than blood measurements at all times throughout exercise and no significant decrease from rest was seen until 350 W. The significant correlations between PaO2 and P(A)O2 with the first exercise intensity and at VO2peak led to the conclusion that inadequate hyperventilation is a major contributor to exercise-induced hypoxaemia.

Arterial hypoxaemia in endurance athletes is greater during running than cycling.

The effect of both training discipline and exercise modality on exercise-induced hypoxaemia (EIH) was examined in seven runners and six cyclists during 5 min high intensity treadmill and cycle exercise. There were no significant interactions between training discipline, exercise modality and arterial P(O(2)) (Pa(O(2))) when subject groups were considered separately but when pooled there were significant differences between exercise modalities. After min 2 of exercise arterial hydrogen ion concentration, minute ventilation, alveolar P(O(2)) (PA(O(2))) and Pa(O(2)) were all lower with treadmill running with the largest differential for the latter occurring at min 5 (treadmill, 80.8+/-1.8; cycle, 90.2+/-2.5, mmHg, N=13, P< or = 0.05). At every min of exercise, the differences in Pa(O(2)) between the ergometers were strongly associated with similar differences in PA(O(2)) and alveolar to arterial P(O(2)) (PA(O(2))-Pa(O(2))). It is concluded that the greater EIH with treadmill running is a consequence of the combined effect of a reduced lactic acidosis-induced hyperventilation and greater ventilation-perfusion inequality with this exercise mode.