Joy Conway

Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease

Acute exacerbations of chronic obstructive airways disease (COAD) are a common cause of admission to hospital, and have a high mortality. Nasal intermittent positive pressure ventilation (NIPPV) has been used successfully in patients with respiratory failure due to neuromuscular and skeletal disorders, but the outcome of treatment in patients with COAD is less well known. We carried out a prospective randomised controlled trial of conventional treatment versus conventional treatment plus NIPPV, in 60 patients with acute ventilatory failure due to exacerbations of COAD. For the NIPPV group there was a rise in pH, compared with a fall in the controls (mean difference of change between the groups 0.046 [95% CI 0.06-0.02, p < 0.001]), and a larger fall in PaCO2 (mean difference in change between the groups 1.2 kPa [95% CI 0.45 to 2.03, p < 0.01]). Median visual analogue scores over the first 3 days of admission showed less breathlessness in the NIPPV group (2.3 cm [range 0.1-5.5]) than in the control group (4.5 cm [range 0.9-8.8]) (p < 0.025). Survival rates at 30 days were compared for intention-to-treat and efficacy populations. In the efficacy mortality comparison, mortality in the NIPPV group was reduced: 1/26 vs 9/30 (relative risk = 0.13, CI = 0.02-0.95, p = 0.014). This effect was less in the intention-to-treat analysis: 3/30 vs 9/30 (relative risk = 0.33, CI = 0.10-1.11, p = 0.106). In patients with acute ventilatory failure due to COAD who received NIPPV there was a significant rise in pH, a reduction in PaCO2 and breathlessness, and reduced mortality.

Acupuncture versus placebo for the treatment of chronic mechanical Neck pain: A randomized, controlled trial

Context Chronic neck pain is a common, disabling condition and is difficult to treat. Because traditional therapies, such as physical therapy and nonsteroidal anti-inflammatory drugs, have limited effectiveness and can have adverse effects, many patients seek alternative therapies, such as acupuncture. Contribution This randomized, controlled trial of acupuncture versus sham transcutaneous electrical stimulation for patients with chronic mechanical neck pain identified no clinically significant benefit of acupuncture over placebo with respect to pain, function, or analgesic use. Implications Acupuncture did not lead to clinically significant improvement in chronic mechanical neck pain when compared with placebo. The Editors Chronic mechanical neck pain can be caused by dysfunction of a variety of structures within the neck (1-3) but specifically excludes systemic problems such as rheumatoid arthritis. It is usually associated with unspecified degenerative changes (cervical spondylosis) that include osteoarthritis. Neck pain presents a substantial problem and may be responsible for as many days of work absenteeism as low back pain (4). Osteoarthritis is the most common of the chronic diseases and affects most people older than 65 years of age (5). It is degenerative and progressive in nature (1-3, 6). Because there is no cure for cervical spondylosis, treatment tends to center on symptom relief (7, 8). If the condition is symptomatic and symptoms are left untreated, this manifests as increasing episodic pain, stiffness, or both, and patients may then experience a spiral of increasing dysfunction (9). Two systematic reviews of conventional conservative physical therapy suggest that little evidence supports the efficacy of such intervention (8, 10). Nonsteroidal anti-inflammatory drugs, the mainstay of pharmacologic treatment, are associated with a wide spectrum of serious and well-documented adverse reactions (5). There has been a huge increase in the use of complementary and alternative medicine in both the United States and the United Kingdom (11, 12). Acupuncture is the most frequently used type of complementary and alternative medicine therapy for the treatment of osteoarthritis (13). Despite little sound evidence of efficacy (14), approximately 1 million people seek complementary and alternative medicine treatment annually in the United States (15). Two systematic reviews of acupuncture in neck pain (4, 16) suggest that there has been insufficient research in this area and that the published studies are of poor quality. Therefore, we conducted a rigorous evaluation to test whether western-style acupuncture performs better than placebo for treatment of chronic mechanical neck pain. We defined western acupuncture as a conventional diagnosis followed by individualized acupuncture treatment using a combination of prescriptive tender, local, and distal points. This is in contrast to a traditional Chinese approach, which would formulate an individualized diagnosis based on traditional Chinese theories of meridians and energy (or qi). Methods Study Design and Patient Selection We designed a randomized, single-blind, placebo-controlled trial using a pragmatic treatment regimen. The study was conducted in the outpatient departments of Southampton General Hospital and Salisbury District Hospital in the United Kingdom. Between 1999 and 2001, patients were referred by rheumatologists or family physicians or from physiotherapy waiting lists. Appropriate ethical approval was obtained from the Southampton and South West Hampshire Joint Research Ethics Committee. Patients were 18 to 80 years of age, had chronic (>2 months) mechanical neck pain, and had a pain score of more than 30 mm on a visual analogue scale (VAS) for 5 of 7 pretreatment days (possible score on this VAS ranges from 0 to 100 mm). We excluded pregnant patients; those with a history of fracture or surgery to the neck, cervical congenital abnormality, uncontrolled low back pain, contraindication to acetaminophen, systemic illness (for example, rheumatoid arthritis), or ongoing neck-related litigation or disability claims; and those with current or recent manual neck treatment or steroid use (oral or local injection). Sample Size Previous studies suggested a 50% to 75% improvement using acupuncture for patients with chronic pain, compared with 30% for placebo treatment (17). We used these findings as the basis for our power calculation. At 5% significance and 90% power, 53 patients were required in each group to detect a 30% difference in response between active and placebo treatments. Interventions Informed consent was obtained along with a full medical history, neurologic examination, cervical radiography, and laboratory investigations (full blood count, erythrocyte sedimentation rate, and liver function tests). We told patients that we were comparing 2 types of intervention: 1) acupuncture with needles and 2) treatment with a machine designed to stimulate acupuncture points through skin electrodes. The patients were informed that the treatment might or might not prove to be effective and that there was a 50% chance that they would be assigned to a placebo but were not told what the placebo was. Blinding was not broken until 1 year after treatment. One practitioner performed all interventions. Acupuncture We used single-use, sterile, silver-handle, prepacked needles without guide tubes. Sizes used were 13 mm 0.25 mm, 25 mm 0.25 mm, and 40 mm 0.25 mm. We based point selection on individualized western acupuncture techniques by using a list of points previously reported as being effective in neck pain (18, 19) and by reaching a consensus according to our own clinical and teaching practice (Appendix Table). The specific points for each individual were defined at each treatment session, depending on the patients pain distribution and palpation of the neck and thorax to determine ah-shi points, or local tender points, for acupuncture. At least 1 distal point was used. Point location and depth of insertion were as described in traditional texts (19). Six points on average, per side if pain was bilateral, were used on each patient, and deqi (a term used to describe acupuncture needle sensation) was obtained on each needle. Twenty-minute treatment sessions were given. The patient was checked every 6 or 7 minutes to ascertain whether deqi was still present, and needles were manipulated again if required. Placebo There is considerable debate about the ideal placebo for acupuncture studies (20). To enhance the rigor of our study, we chose to use a previously well-validated placebo (17, 21-23) that could not have a specific physiologic effect. The Noma FM-4 electroacupuncture stimulator (Noma Ltd., Southampton, United Kingdom) was used. It has 4 channels, allowing pseudostimulation of up to 8 acupuncture points simultaneously, and emits visual and audio signals. Reusable electrodes (Body Clock Health Care Ltd., London, United Kingdom) were fixed to the surface of the patients skin and were connected to the stimulator through decommissioned cables. The cables were severed inside the output plug, so that no current could reach the patient. Examination and point selection were the same as with real acupuncture for each treatment. Point location and treatment variables were changed during subsequent treatment sessions if patients felt they were not progressing. Patients were told that the machine could stimulate acupuncture points through high-frequency, low-intensity stimulation and therefore would not produce any sensation. If patients reported sensation, the therapist adjusted the unit for comfort (although since this was a sham procedure, such adjustment made no real difference). Patients in both groups were instructed to use acetaminophen alone for pain relief and were not given or permitted any other form of treatment, including exercises or stretches, during the study and for 2 months after treatment ended. Patients were treated twice per week for 4 weeks. The therapist had taken an Acupuncture Association of Chartered Physiotherapists accredited course on western acupuncture techniques and had 7 years of experience practicing acupuncture. Randomization Randomization lists for Southampton General Hospital and Salisbury District Hospital were generated by using a computer program, Randomlogue, produced by Southampton University Department of Medical Statistics, Southampton, United Kingdom. Sealed envelopes containing the individual randomization codes, numbered consecutively with sex and age strata, were then prepared (sex strata were male and female, and age strata were 18 to 49 years and 50 to 80 years) Patients were strictly allocated across 4 strata for either of the study hospitals according to the next available envelope number. Data Collection Before randomization, patients were instructed to use a daily pain diary (on a VAS) to record pain and acetaminophen use for 7 consecutive days. After a week, the pain diaries were examined, and if the inclusion criteria (which were unknown to the patients) were satisfied, randomization occurred. Patients completed the various questionnaires before treatment and at 1 and 8 weeks after treatment. Pain continued to be recorded either weekly or daily throughout treatment and up to 8 weeks after treatment. Additional questionnaires and pain evaluation were also completed at 6 and 12 months after treatment. Figure 1 shows a flow chart of the trial. Figure 1. Study flow with outcome assessments. Outcomes The VAS score for pain 1 week after treatment, recorded daily for 7 consecutive days, was the primary outcome. Pain was recorded on a scale of 0 mm (indicating no pain) to 100 mm (indicating worst pain imaginable). A significant outcome for acupuncture was considered to be a 30% difference in VAS score between groups 5 weeks after randomization (1 week after treatment), taking into account baseline pain. Secondary Outcomes

Inhaled synthetic surfactant abolishes the early allergen-induced response in asthma

Allergen-induced inhibition of pulmonary surfactant in asthma may promote airway oedema and consequently potentiate the severity of the asthmatic response. A randomised, single-blind, cross-over study of an inhaled synthetic phospholipid dry-powder surfactant (Pumactant) was conducted in atopic, asthmatic subjects with previously documented early and late asthmatic responses (EAR and LAR) to an inhaled allergen. This was conducted to evaluate the role of exogenous surfactant administration on EAR and LAR. A total of seven subjects had complete evaluable data and received the full dose of Pumactant. Asthmatic subjects inhaled two separate doses of 400 mg Pumactant prior to an allergen exposure. The first dose was administered 8 h in advance and the second dose 30 min in advance. The dosage occurred through a purpose-built administration device. This was followed by a standard bronchial-provocation test, and forced expiratory volume in one second (FEV1) was measured at regular intervals over a 10-h period. Pumactant was well tolerated and, surprisingly, abolished the EAR but not the LAR in all seven subjects. The mean area under the curve between 0–2 h (EAR) following bronchial provocation test was 0.08 for the Pumactant treatment group (PT) and 13.29 for the no treatment (NT) group. The maximum drop in FEV1 for EAR was 4.19% and 23.98% in the PT and the NT group, respectively. The demonstration of inhibition of the early asthmatic response by exogenous surfactant, provides the first evidence that pulmonary surfactant dysfunction may also contribute to the very early asthmatic response to allergen. Exogenous surfactant administration could serve as a useful adjunct in controlling the early allergen-induced symptoms in patients with allergic asthma.

The use of combined single photon emission computed tomography and X-ray computed tomography to assess the fate of inhaled aerosol

BACKGROUND Gamma camera imaging is widely used to assess pulmonary aerosol deposition. Conventional planar imaging provides limited information on its regional distribution. In this study, single photon emission computed tomography (SPECT) was used to describe deposition in three dimensions (3D) and combined with X-ray computed tomography (CT) to relate this to lung anatomy. Its performance was compared to planar imaging. METHODS Ten SPECT/CT studies were performed on five healthy subjects following carefully controlled inhalation of radioaerosol from a nebulizer, using a variety of inhalation regimes. The 3D spatial distribution was assessed using a central-to-peripheral ratio (C/P) normalized to lung volume and for the right lung was compared to planar C/P analysis. The deposition by airway generation was calculated for each lung and the conducting airways deposition fraction compared to 24-h clearance. RESULTS The 3D normalized C/P ratio correlated more closely with 24-h clearance than the 2D ratio for the right lung [coefficient of variation (COV), 9% compared to 15% p < 0.05]. Analysis of regional distribution was possible for both lungs in 3D but not in 2D due to overlap of the stomach on the left lung. The mean conducting airways deposition fraction from SPECT for both lungs was not significantly different from 24-h clearance (COV 18%). Both spatial and generational measures of central deposition were significantly higher for the left than for the right lung. CONCLUSIONS Combined SPECT/CT enabled improved analysis of aerosol deposition from gamma camera imaging compared to planar imaging. 3D radionuclide imaging combined with anatomical information from CT and computer analysis is a useful approach for applications requiring regional information on deposition.

In silico modeling of asthma

The incidence of asthma is increasing throughout the world, especially among children, to the extent that it has become a medical issue of serious global concern. Appropriately, numerous pharmacologic drugs and clinical protocols for the treatment and prophylaxis of the disease have been reported. From a scientific perspective, a review of the literature suggests that the targeted delivery of an aerosol would, in a real sense, enhance the efficacy of an inhaled medicine. Therefore, in accordance with published data we have developed a mathematical description of disease-induced effects of disease on airway morphology. A morphological algorithm defining the heterogeneity of asthma has been integrated with a computer code that formulates the behavior and fate of inhaled drugs. In this work, predicted drug particle deposition patterns have been compared with SPECT images from experiments with healthy human subjects (controls) and asthmatic patients. The asthma drug delivery model simulations agree with observations from human testing. The results indicate that in silico modeling provides a technical foundation for addressing effects of disease on the administration of aerosolized drugs, and suggest that modeling should be used in a complementary manner with future inhalation therapy protocols.

Humidification as an adjunct to chest physiotherapy in aiding tracheo-bronchial clearance in patients with bronchiectasis

Humidification of inspired air or oxygen is frequently utilized by respiratory physiotherapists to relieve sputum retention. Cold water, jet nebulizing humidifiers are in widespread use but there has been no previous attempt to investigate the efficacy of this treatment. We have performed a single-blind, cross-over study to quantify the effect of humidification as an adjunct to chest physiotherapy. Seven patients with bronchiectasis completed the trial, with a mean (range) age of 51 years (41-64 years) and mean (range) percent of predicted FEV1 of 46% (29-76%). On 2 days, separated by 1 week, subjects were randomly allocated to humidification or no humidification as a precursor to an optimal chest physiotherapy regimen. A radio-aerosol of human serum albumin millimicrospheres labelled with 99mTechnetium was used to measure sputum clearance by serial gamma camera images. Serial measurements of sputum weight and FEV1 were also recorded. Humidification (30 min) was followed by postural drainage (20 min) with the subject using the forced expiration technique to assist clearance. When humidification was combined with physiotherapy there was a significant increase in total wet weight of sputum (P less than 0.05) with a median (range) increase of 6 g (-9-15.5 g); and a significant increase in total radiolabel clearance (P less than 0.05) with a median (range) increase of 8.7% (1-13%), compared to physiotherapy alone. This study demonstrates that the use of cold water, jet nebulizing humidifiers significantly increases tracheo-bronchial clearance above that of an optimal physiotherapy regimen alone in bronchiectasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cospray-dried unfractionated heparin with L-leucine as a dry powder inhaler mucolytic for cystic fibrosis therapy

Accumulation of inspissated secretions that are difficult to clear and congest the airways is a feature of lung disease in patients with cystic fibrosis (CF). These secretions restrict airflow, harbour infection and limit the delivery of inhaled drugs including gene therapy vectors to the underlying target cells. Unfractionated heparin (UFH) has mucolytic properties suggesting that it may be a useful therapeutic agent for lung disease in these patients. For the pulmonary delivery of UFH to patients with CF, the dry powder inhaler has potential advantages over systems using nebulised suspensions. However, spray-dried particles in the appropriate size range (1-5 microm) may absorb atmospheric moisture, causing aggregation. UFH has been cospray-dried with L-leucine (1%, w/w) to produce particles that are less cohesive than UFH alone and show good aerosolisation performance. Rheological analysis has shown that spray-dried UFH and UFH cospray-dried with L-leucine significantly (p < 0.05) reduce the elasticity and yield stress of CF sputum. The superior physical properties of UFH/L-leucine indicate this is the preferred formulation for development as an inhaled mucolytic.

Evaluation of the accuracy and precision of lung aerosol deposition measurements from planar radionuclide imaging using simulation

Planar images of known, theoretical distributions of radioaerosol in the lung have been simulated using lung models derived from magnetic resonance studies on human subjects. Total lung activity was evaluated from the simulated images together with the absolute penetration index (PI) and a relative value expressed as a fraction of that in a simulated ventilation image. The accuracy and precision of these measurements were calculated by comparison with the true values used in the simulation. Total activity was assessed with systematic errors within 5% and precision within 6.5%. Measured PIs varied only slowly with true PI and inter-model variation masked changes between measurements on the different distributions. The relative PI reduced inter-model variation and provided significant differences between all the distributions. PI was significantly affected by misalignment of the lung region of interest. The conducting airways deposition fraction (CADF) used in the simulation correlated linearly with the fractional activity in a central lung region, allowing CADF to be estimated with a precision of 21%.

A Comparison of Planar Scintigraphy and SPECT Measurement of Total Lung Deposition of Inhaled Aerosol

Planar gamma camera imaging of inhaled aerosol deposition is extensively used to assess the total deposition in the lung. However, validation of the measurements is not straightforward, as gold standard measurements of lung activity against which to compare are not readily available. Quantitative SPECT imaging provides an alternative method for comparison. Four different methods for planar image quantification are compared. Two attenuation correction techniques, thickness measurement and transmission measurement, have been combined with two scatter correction techniques, reduced attenuation coefficient and line-source scatter function convolution subtraction. Each technique has been applied to 10 studies of aerosol deposition of a fine aerosol (mass median aerodynamic diameter 1.8 microm) and 10 studies using a coarse aerosol (mass median aerodynamic diameter 6.5 microm). The total activity in the right lung for each measurement has been compared to the value determined from SPECT imaging on the same subjects. When the thickness measurement and transmission techniques were applied with scatter compensation using a reduced attenuation coefficient, activity was systematically overestimated by 5% in both cases. The corresponding random errors (coefficient of variation) were 8.6% and 6.6%. Separate scatter correction reduced these systemic errors significantly to -1.5% and 2.7%, respectively. The random errors were not affected. All techniques provided assessment of total lung activity with an accuracy and precision that differed by less than 10% compared to the SPECT values. Planar gamma camera imaging provides a good method of assessing total lung deposition of inhaled aerosol.

HUMAN LUNG MORPHOLOGY MODELS FOR PARTICLE DEPOSITION STUDIES

Knowledge of human lung morphology is of paramount importance in calculating deposition patterns of inhaled particulate matter (PM) to be used in the definition of ambient air quality standards. Due to the inherently complex nature of the branching structure of the airway network, practical assumptions must be made for modeling purposes. The most commonly used mathematical models reported in the literature that describe PM deposition use Weibels model A morphology. This assumes the airways of the lung to be a symmetric, dichotomously branching system. However, computer simulations of this model, when compared to scintigraphy images, have shown it to lack physiological realism (Martonen et al., 1994a). Therefore, a more physiologically realistic model of the lung is needed to improve the current PM dosimetry models. Herein, a morphological model is presented that is based on laboratory data from planar gamma camera and single-photon emission computed tomography (SPECT) images. Key elements of this model include: The parenchymal wall of the lung is defined in mathematical terms, the whole lung is divided into distinct left and right components, a set of branching angles is derived from experimental measurements, and the branching network is confined within the discrete left and right components (i.e., there is no overlapping of airways). In future work, this new, more physiologically realistic morphological model can be used to calculate PM deposition patterns for risk assessment protocols.