Volume 165 Issue 9

Routine pulmonary function tests in young adolescents with asthma in general practice Peter H Hewson, Elizabeth A Tippett, Danny M Jones, Justin P Madden and Peter Higgs For editorial comment, see Sawyer and Bowes Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - ©MJA1996 Abstract Objective: To assess the value of performing routine pulmonary function tests by flow-loop spirometry in young adolescents with asthma. Design: A prospective clinical study comparing clinical assessment and patients' self- reporting of asthma severity with the results of pulmonary function tests. Setting: General practice in a small rural community of about 30 000 people. Patients: Young adolescents with asthma, aged 10-15 years, were enrolled in the study over a two-year period from July 1993 to June 1995 when they presented for either elective, interval assessments or with an acute exacerbation of asthma. Main outcome measures: Discrepancy between (i) the doctor's and the patient's perception of asthma control (six scale measures) and the consequent management plans, and (ii) the results of pulmonary function tests that indicated less than adequate airway function (i.e., forced expiratory volume in one second as a percentage of predicted vital capacity for height and sex [FEV 1 %] less than 65% or average flow rate over the middle 50% of forced vital capacity as a percentage of predicted normal value [FEF 25%-75% ] less than 65%). Results: Twenty-seven adolescents with asthma were assessed on a total of 37 occasions. The results of pulmonary function tests did not correlate with asthma symptoms and treatment in 11 of the 37 assessments (30%; 95% confidence interval [CI], 16%-47%). The 11 assessments were performed on eight patients. Conclusions: This small community-based study of adolescents with asthma supports the view that pulmonary function testing by flow-loop spirometry should be part of the routine assessment of acute and chronic asthmatics. Further study in a larger community is needed to clarify the frequency of over- and underestimation of asthma severity in this difficult age group. MJA 1996; 165: 469-472 Introduction Older children and adolescents often have difficulty assessing the severity of their asthma, 1 and consequently pulmonary function tests have been recommended for those with frequent or chronic asthma who are able to perform spirometry adequately. 2-4 Pulmonary function testing by flow-loop spirometry allows measurement of forced expiratory volume in one second as a percentage of the predicted vital capacity for height and sex (FEV 1 %), and forced mid expiratory flow (FEF 25%-75% : the average flow rate over the middle 50% of forced vital capacity). While peak flow monitoring and FEV 1 % have been used for decades as a measure of pulmonary function, forced mid expiratory flow is not as well known a measure, but is more sensitive than FEV 1 in detecting small airways obstruction. 2 Pulmonary function tests have been shown to be useful in adults, but there are few studies of their useful ness in children and young adolescents with asthma. One study found that 17% of apparently well children with asthma had a low forced expiratory volume in one second / vital capacity ratio (FEV 1 /FVC) and 54% had low forced mid expiratory flow (FEF 25%-75% ), suggesting that, without these tests, both patients and doctors were unable to detect mild degrees of broncho constriction, especially of the smaller airways. 5 To date, no study has described the use of pulmonary function tests as part of routine community medical practice in young adolescents. In fact, in some centres, spirometry tests are not yet done routinely in chronic asthmatics in this age group. We performed pulmon ary function tests in adolescents with asthma in an Australian country setting, comparing patients' and doctors' clinical assessment of asthma severity with the results of routinely performed pulmonary function tests. Methods This two-year study took place in Colac, Victoria (population, 14 000; regional population, 30 000) between July 1993 and June 1995. All young adolescents with asthma (recurrent wheeze responsive to bronchodilators) between the ages of 10 and 15 years pre senting to their general practitioner Monday to Friday either for an elective asthma management review, or because of an acute exacerbation of their asthma, were assessed by the general practitioner and included in the study. No adolescents were excluded from the study or refused to participate. Appointments for elective management reviews (interval assessments) had been made weeks in advance. An acute exacerbation of asthma was defined as an appreciably more severe wheeze and cough than usual (as assessed by the general practitioner). The severity of symptoms and the perception of asthma control were assessed by the general practitioner, giving day and night symptom scores (0-5), and a wheeze description, based on questioning of the patient. The doctor and the patient then separately graded asthma control as excellent, very good, fair, poor, or very poor. (The scoring system is given in the footnote to the Table). Forced expir atory volume in one second (FEV 1 ) and forced mid expiratory flow (FEF 25%-75% ) were measured -- on the same day if it was a daytime presentation (usually immediately after the clinical assessment) or the morning after if it was an evening presentation. An Alpha Vitalograph spirometer (Fisher & Paykel, Melbourne, Vic.) was used and the tests were conducted by the senior physiotherapist at Colac Hospital (E A T), who had attended the spirometry technician's course run by the Department of Respiratory Medicine, Alfred Hospital, Melbourne. The tests were repeated if the assessment was judged to be inadequate by the physiotherapist. The effect of bronchodilators on pulmonary function tests was determined in all patients, with recordings being taken 20 minutes (in one patient 25 minutes) after bronchodilator therapy. The pulmonary function tests were done without knowledge of the clinical status of the patient and the results were made available to the treating doctor if requested. The patients' previous home peak expiratory flow measurements were also recorded, as was peak flow measured with the spirometer. The results of the pulmonary function tests were considered not to correlate with asthma symptoms and treatment, and to be likely to lead to a change in asthma management, if: During an interval assessment: The patient complained of no, few or only moderate symptoms, the doctor felt asthma control was excellent, very good or reasonable, respectively, and did not change treatment, but FEV 1 % (normal, > >80%) or FEF 25%-75% (normal, > >65%) was less than 65%. The patient and the doctor thought control was poor, the dose of maintenance asthma therapy was increased, but pulmonary function tests revealed no evidence of bronchospasm. During assessment of an acute exacerbation: The patient and the doctor felt current asthma control was excellent or very good, no increase in dose of inhaled steroids was suggested and no oral corticosteroids were prescribed, but FEV 1 % or FEF 25%-75% was less than 65%. Results Twenty-seven adolescents with asthma (male : female ratio, 2 : 1) were assessed on a total of 37 occasions. On 22 occasions they were elective interval assessments and 15 were for an acute asthma exacerbation. Nineteen patients (70%) were monitoring peak flow at home. Twenty-nine (78%) of the pulmonary function tests were within two hours, four (11%) between two and four hours and four (11%) between four and 14 hours after the clinical assessment. Satisfactory spirometry measurements were achieved in all patients without difficulty (fewer than four repeats). Of the 22 interval assessments, 16 (73%) were in patients taking inhaled corticosteroids (in 11 of these the patients were taking more than 700 µg inhaled corticosteroids per day, and in five FEF 25%-75% values were less than 65%). In two (9%) interval assessments peak expiratory flows were less than 300 L/min (in only one of the assessments with FEF 25%-75% less than 65% were peak flows less than 300 L/min). Of the 15 acute exacerbation assessments, eight (53%) were in patients taking inhaled corticosteroids (in three of these the patients were taking more than 700 µg inhaled corticosteroids per day). In five (45%) acute exacerbation assessments peak expiratory flows were less than 300 L/min (four were unavailable). Details of the patients whose pulmonary function tests did not correlate with asthma symptoms and treatment are given in the Table. Overall, pulmonary function tests not correlating with clinical and patient assessment of asthma severity were found in 11 of 37 assessments (30%; 95% confidence interval [CI], 16%-47%). If only those tests performed within four hours of the clinical assessment are included, pulmonary function tests in 10 of 33 assessments (30%; 95% CI, 15%-46%) did not correlate with asthma severity. Pulmonary function tests in six of the 22 interval assessments (27%; 95% CI, 11%-50%) showed FEV 1 % or FEF 25%-75% to be less than 65% when management had not been changed after clinical assessment (Cases 1-6). During acute exacerbations, four of 15 assessments (27%; 95% CI, 8%-55%) showed FEV 1 % or FEF 25%-75% values to be less than 65% when no change in treatment had been made on clinical grounds (Cases 8-11). Tests in one patient (Case 7) showed normal pulmonary function after clinical assessment had suggested poor asthma control. Her pulmonary function tests were carried out within two hours of the clinical evaluation; her inhaled cortico steroid dose had been doubled. Discussion This community-based study of all young adolescent asthmatics presenting to their general practitioners in a country town found that in 30% of assessment opportunities the results of pulmonary function tests were likely to change management. This proportion was maintained even if slightly delayed pulmonary function tests (4-14 hours) were excluded. This result is comparable with previously published findings that 54% of apparently well asthmatics had lower than expected FEF 25%-75% values at follow-up, despite being asymptomatic. 5 At interval assessments in which management had not been changed and the results of pulmonary function tests were low, three of five adolescents (Table: assessments 1, 3-6) reported frequent wheeze. The other two thought their asthma was well controlled; however, their FEF 25%-75% values were 62% and 42%, respectively. In these patients peak flows, measured at home and by spirometry, were all above 300 L/min and this may have accounted for ALIGN=TOP the reluctance to change therapy. However, it has been shown previously that peak flow results can be misleading, and widely varying optimal values can be expected. 3 A low expectation of what can be achieved in frequently symptomatic patients may contribute to a less aggressive approach in adolescents with asthma. The rather frequent use of inhaled corticosteroids in relatively high doses in this small sample of asthmatics suggests that a more objective measure of asthma status should be used. Potential overuse of inhaled corticosteroids in these growing young people may not always safeguard those at risk of more severe asthma. Six of 11 patients (55%) taking more than 700 µg inhaled corticosteroids had FEF 25%-75% values less than 60%, suggesting that in these patients an even higher dose of inhaled corticosteroid may be required. More specific alterations to long term inhaled steroid use would be possible if pulmonary function tests were performed regularly. During assessments for acute exacerbation the rate of pulmonary function tests not correlating with symptoms was still high (27%) and the FEF 25%-75% was worryingly low in three patients in whom management was not altered (Table: assessments 8, 9, 10, and 11). These three adolescents all had frequent wheeze, but presumably were not distressed, with peak flows (measured at home and by spirometry) above 320 L/min. Pulmonary function tests gave an indication of small airways disease which they were not aware of or was not revealed by their peak flow measurements. Our study involved a small number of patients and the confidence intervals calculated suggest a larger study is necessary. Nevertheless, data on mortality in asthma indicate that underestimation of asthma severity can be extremely important. Robertson et al. found that about 35% of possibly preventable asthma deaths may have been related to medical practitioner underestimation of asthma severity. 6 The full implications of FEF 25%-75% values in the 55%-65% range is not yet certain. A long term follow-up of asymptomatic patients with values in this range has not yet been done. Most of our patients with low FEF 25%-75% values not correlating with symptoms had values below 55% (Table: 7 of 10 assessments). Thus, even if the implications of an FEF 25%-75% value between 55% and 65% is disputed, the frequency of the lower results suggests more aggressive treatment is required. This relatively small study of asthmatic adolescents in a small country town strongly supports the view that pulmonary function tests need to be part of the routine assessment of acute and chronic asthmatics. Acknowledgements We thank Professor P D Phelan, Department of Paediatrics, University of Melbourne, for his provocation, encouragement and support; and Mr Ross Gollan, Senior Lecturer, Department Mathematics and Statistics, Deakin University. References Sly PD, Landau LI, Weymouth R. Home recording of peak expiratory flow rates and perception of asthma. Am J Dis Child 1985; 139: 479-482. Landau LI. The value of lung function in guiding drug therapy in childhood asthma. Eur Respir Rev 1994; 4: 10-14. Phelan PD, Olinsky A, Robertson CF. Respiratory illness in children, 4th edition. Cambridge: Blackwell Scientific Publications, 1994; 152-156. Milner AD. Childhood asthma: diagnosis, treatment and management. London: Martin Dunitz, 1987; 18-38. Bye MR, Kerstein D, Barsh E. The importance of spirometry in the assessment of childhood asthma. Am J Dis Child 1992; 146: 977-981. Robertson CF, Rubinfeld AR, Bowes G. Deaths from asthma in Victoria: a 12-month survey. Med J Aust 1990; 152: 511-517.(Received 19 Sep 1995, accepted 4 Jul 1996) Authors' details 106 McKillop Street, Geelong, VIC 3220. Peter H Hewson, MD, FRACP, Consultant Paediatrician. Colac Hospital, Corangamite Street, Colac, VIC. Elizabeth A Tippett, DipPhys, Senior Physiotherapist. 2 Connor Street, Colac, VIC. Danny M Jones, MB BS, DA, DipRACOG, General Practitioner; Justin P Madden, MB BS, DA, DRCOG, General Practitioner; Peter Higgs, MB BS, General Practitioner. No reprints will be available. Correspondence: Dr P H Hewson. - - To top of article - ©MJA 1996 <URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Peter H Hewson · Elizabeth A Tippett · Danny M Jones · Justin P Madden · Peter Higgs

Research Urinary urge incontinence: randomised crossover trials of penthienate versus placebo and propantheline Graham M Coombes and Richard J Millard MJA 1996; 165: 473-476 Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Obstetrics & gynaecology and women's health Abstract Objective: To compare the efficacy of penthienate with that of propantheline and placebo for treatment of primary idiopathic detrusor instability. Design: Two prospective, randomised, crossover trials (double-blind for penthienate versus placebo and non-blinded for penthienate versus propantheline). Setting: Urology Clinic of Prince Henry Hospital, Sydney, NSW (an outpatient clinic of a tertiary referral hospital), in 1993-1994. Participants: Neurologically intact patients with urodynamically proven detrusor instability, urgency and urge incontinence, but no stress incontinence (20 participated in the penthienate/placebo trial and 23 in the penthienate/propantheline trial). Outcome measures: Cystometrography results before and after treatment; frequency and volumes of urine voided in weeks 1 and 4 of treatment; and patient scores for degree of continence, side effects, efficacy and acceptability of treatment. Interventions: Penthienate (5 mg), propantheline (15 mg) or placebo (all three times a day) for 4 weeks. Results: Penthienate produced significantly greater improvements than placebo in frequency (daytime, P = 0.002; and night-time, P = 0.02), incontinence scores (P = 0.002) and amplitude of unstable detrusor contractions, when present (P = 0.01), and significantly increased diurnal and nocturnal bladder capacity, both on cystometrography (P = 0.003) and by voiding-diary records (P < 0.001). It also increased residual urine volume over the baseline level, but not significantly. Side effects, especially dry mouth, were common with penthienate, and one patient developed urinary retention. Penthienate was significantly better than propantheline in improving cystometric capacity (P = 0.03), and reducing the amplitude of unstable detrusor contractions (P = 0.01), and was perceived as more effective by patients for frequency, nocturia and incontinence. Conclusions: Penthienate (5 mg three times a day) was objectively and subjectively significantly better than both placebo and propantheline (15 mg three times a day) for treatment of primary idiopathic detrusor instability. Introduction Detrusor instability is a common urologic problem, causing symptoms of urgency, frequency and urge incontinence. It is defined by the International Continence Society as the presence of detrusor contractions with pressure greater than 15 centimetres of water during the filling phase of cystometrography while the patient is trying to inhibit micturition.1 Although detrusor instability may result from neuropathy (e.g., after spinal injury and in multiple sclerosis, where it is best termed detrusor hyperreflexia), in most patients it is primary and idiopathic.2Many treatments have been used, including bladder training, biofeedback, anticholinergics, analgesics, muscle relaxants, tricyclic antidepressants and acupuncture.2-7 More invasive, surgical procedures, such as subtrigonal phenol injections, neuromodulation and bladder augmentation, are less commonly required. Success rates are variable, and depend partly on the cause of the instability, but are usually no higher than 70%.8,9 The anticholinergic propantheline bromide is used worldwide for detrusor instability and, along with oxybutynin, is among the most often studied anticholinergic agents. However, penthienate bromide, which was originally marketed in Australia for gastrointestinal spasm, has been in clinical use for detrusor instability at Prince Henry Hospital, Sydney, NSW, and, in our clinical experience, may be more effective than propantheline. It is a quaternary ammonium antimuscarinic that inhibits parasympathetic, postganglionic bladder smooth muscle receptors, has a short half-life and is optimally absorbed from the gastrointestinal tract on an empty stomach. However, its comparative efficacy has not been established. We therefore undertook randomised trials of penthienate versus placebo and penthienate versus propantheline in primary idiopathic detrusor instability. Methods Approval for the trials was given by the Eastern Sydney Area Health Service Ethics Committee. The trials were independent of drug company participation or sponsorship, apart from the manufacture and supply of placebo and penthienate tablets (for the first trial). Penthienate versus placebo The first trial was a prospective, randomised, double-blind crossover trial of penthienate versus placebo. Participants were 20 neurologically intact patients recruited from the outpatient Urology Clinic and Urodynamic Service of Prince Henry Hospital, Sydney, NSW. Inclusion criteria. These were: Age over 18 years; Presence of symptomatic urgency or urge incontinence; Detrusor instability (shown on medium-fill, room-temperature, videourodynamic studies); No history of neurologic disease, narrow-angle glaucoma or severe cardiac disease (American Heart Association Grade 3 or 4); No stress incontinence, bladder-outlet obstruction, significant postvoid residual urine (residuum greater than 10% of voided volume), current urinary tract infection or interstitial cystitis; No current gastrointestinal obstruction; No allergy or sensitivity to anticholinergic agents; Not pregnant; and Patient gave informed consent to active and placebo treatment. First phase. The trial began with a one-week run-in period in which patients kept charts of frequency and volume of urine voided. Informed consent was then obtained and patients were randomised in a double-blind fashion to placebo or penthienate. Codes were generated from randomisation tables in blocks of ten, and provided in sealed envelopes by the Pharmacy Department; neither patients nor investigators knew the code until after collection of all follow-up data. Patients received either placebo or penthienate (5 mg three times a day before meals) for four weeks. Dosage reduction was ethically necessary if the patient developed blurred vision, severe constipation, or excessive mouth dryness that interfered with nutrition. Placebo and penthienate tablets were made to the same size, shape and colour specifications by the manufacturer and stored in the refrigerator. Assessment. All patients were asked to keep records of frequency and volume of urine voided for two 72-hour periods in the first and fourth weeks of treatment. A visual analogue score for continence was also kept (from 1 [nil leakage], to 5 [wet all the time]) and episodes of incontinence were noted. Apart from keeping voiding diaries at the set times, patients were taught no formal bladder- training techniques. In the final (fourth) week of treatment, patients attended the outpatient clinic for assessment. History was taken and time/volume charts collected. Medium-fill room-temperature saline-filling cystometrography was performed by the urology registrar, and residual urine volume, flow rate, cystometric capacity and incidence and amplitude of any unstable detrusor contractions were recorded. Urodynamic methods, definitions and units conformed to the standards recommended by the International Continence Society.1In addition, patients scored side effects, efficacy of treatment and willingness to have that treatment in the future on a scale of 1-100. Second phase. After a five-day washout period, patients crossed to the other arm of the trial. As it was not considered ethical to subject patients to a further urodynamic study during this period (to prove stable disease course), treatment-period interaction could not be totally excluded. Again, treatment was for four weeks, with the same assessment as previously. Penthienate versus propantheline The second trial was an unblinded, prospective, randomised crossover trial of penthienate and propantheline in 23 patients with detrusor instability. Inclusion criteria, run-in period and randomisation were the same as those in the first trial, except that neither patients nor observers were blinded to the treatment. Patients received either penthienate (5 mg three times a day) or propantheline (15 mg three times a day) for four weeks. There was no placebo arm. All patients were then assessed as outpatients, with the same outcome measures as those in the first trial. After a five-day drug washout period, patients crossed over to receive the other medication for a further four weeks before reassessment. Statistical analyses Analysis of paired data was by the Wilcoxon matched-pairs signed-rank test. Unpaired group data were analysed with the Mann-Whitney U test. Results Penthienate versus placebo Patients comprised 16 women and four men, with median age 63.5 years (range, 36-85). Urological baseline characteristics are shown in Box 1. There were no significant differences in baseline data between those patients receiving placebo first and those receiving penthienate first. To investigate the possibility of a carryover effect of penthienate in patients who received placebo second, the data were analysed initially in groups according to which drug had been given first. In the placebo arm of the trial there were no significant differences in cystometric capacity, residual postvoid volume, amplitude of unstable detrusor contractions, flow rate, frequency, nocturia or subjective incontinence scores between patients who took placebo first and those who took it second. Thus, five days was adequate for washout of penthienate. Thereafter, data were analysed without regard to which drug was taken first. Continence and urodynamic characteristics after penthienate and placebo treatment are shown in Box 1. After penthienate treatment, there were increases over the baseline in daytime voiding interval, mean voided volume (daytime and night-time) and cystometric capacity, and decreases in night-time frequency and subjective incontinence score. Values for all these parameters were significantly "better" after penthienate than after placebo. The decrease in median incontinence score with penthienate was dramatic, from a baseline of 5 ("wet all the time") to 1 ("nil leakage"), compared with 4 for placebo. Ten of 20 patients taking penthienate became dry (incontinence score of 1, 50% cure rate), compared with only two patients taking placebo. The same 10 patients taking penthienate were also completely stable (detrusor pressure < 15 cm H2O) to a capacity of 500 mL on cystometrography. Among the other 10, the median amplitude of unstable detrusor contractions was reduced from 40 to 27 cm H2O. However, with placebo only four patients (20%) tested stable and the other 16 had unstable detrusor contractions, with a median pressure of 30 cm H2O. The difference between the penthienate and placebo groups in detrusor pressures in those patients who remained unstable was significant (P = 0.05). Residual urine volume increased from the baseline level in the penthienate group and decreased in the placebo group, but neither change was significant. However, the resulting difference between penthienate and placebo residual volumes was significant (P = 0.02). Urine flow rate increased significantly in both the penthienate and placebo group over the baseline level (P = 0.01), but did not differ significantly between the two groups. The increase in flow rate appeared to be related to the increase in voided volume, as there was no change in percentile performance on the Haylen Liverpool flow nomogram.10 Side effects of treatment were common with penthienate (Box 2). All patients mentioned a dry mouth, and in one elderly patient this led to difficulty swallowing, which necessitated reducing the penthienate dose. Although 11 of 20 patients taking placebo also mentioned mouth dryness, the scores for degree were significantly less than for penthienate. A patient taking penthienate complained of diarrhoea, but there was no evidence of faecal impaction to suggest spurious diarrhoea caused by decreased gastrointestinal motility. Another patient taking penthienate in the second phase of the trial developed chronic urinary retention (with a residual postvoid volume of 550 mL). This patient's results were excluded from the analysis. Patients' subjective impressions of treatment are also shown in Box 2. There was a significant preference for penthienate compared with placebo in both perceived efficacy and willingness for retreatment (P = 0.002). Penthienate was considered beneficial by 17 (85%), but placebo by only five (25%). Two patients preferred placebo to penthienate; their cystometric capacities and filling pressures on testing differed little between penthienate and placebo, but their voiding diaries showed greater daytime and night-time voided volumes during the penthienate arm. Penthienate versus propantheline Patients comprised 18 women and five men, with median age 63 years (range, 34-85). Propantheline was given first to 12 patients and penthienate to 11. Baseline characteristics are compared with those after propantheline and penthienate treatment in Box 3. Both penthienate and propantheline significantly increased daytime voiding interval, cystometric capacity and flow rate over baseline figures. However, the improvements in cystometric capacity were significantly greater with penthienate than with propantheline. Furthermore, penthienate, but not propantheline, significantly increased voided volume (both daytime and night-time) and decreased night-time frequency and the incidence of incontinence (by patient score). Consequently, daytime voided volume and incontinence score were significantly "better" for penthienate than for propantheline. The difference in incontinence score was dramatic -- 1.5 after penthienate (where 1 = "nil leakage"), but 5 ("wet all the time") after propantheline. Stable cystometrograms were seen in 13 of the 23 patients (56%) after penthienate, but in only 10 (43%) after propantheline. In the patients with residual unstable detrusor contractions, the amplitude of these contractions decreased with penthienate but increased with propantheline, which led to a significant difference between the two treatments (P = 0.01). Although residual urine volume increased over the baseline value with penthienate, the change was not significant. Similarly, although detrusor compliance (detrusor pressure at a given bladder volume, which measures bladder-wall stiffness) increased after penthienate but decreased after propantheline, none of the changes were significant and did not lead to significant differences between the two drug treatments. Side effects and subjective response to treatment are shown in Box 4. Mouth dryness was significantly worse with penthienate, but patients believed that it had significantly greater efficacy and were more willing to repeat penthienate treatment. Discussion Our trials showed a significantly greater response to penthienate than to placebo or propantheline treatment, both objectively and subjectively, in primary idiopathic detrusor instability. For drug therapy to be useful in this condition, it needs to be more effective than placebo, which can produce significant improvement11 (up to 43%, or as high as that of some active drug therapies).12 In addition, results should be at least as good as those that can be achieved with non-invasive therapies such as bladder training, without intolerable side effects. The Urology Clinic at Prince Henry Hospital has previously shown that bladder training and/or biofeedback gives up to 74% cure or improvement in symptoms of detrusor instability.5 In this study, we found that after penthienate there were objective improvements in bladder capacity, stability and amplitude of unstable detrusor contractions and 50%-56% of patients became objectively dry. There were also improvements in subjective criteria for continence after penthienate, with 85% feeling subjectively cured or improved. These subjective criteria were included to assess clinical worth from the patients' perspective, as statistical significance may not necessarily equate with clinical significance.4There have been no previous comparative trials of the relative efficacy of penthienate and propantheline for detrusor instability. We found that, in the doses studied (manufacturer's recommended starting doses), both produced some urodynamic and symptomatic improvements, but that penthienate was significantly better than propantheline in improving cystometric capacity and reducing the amplitude of unstable detrusor contractions, and was perceived as more effective by patients for frequency, nocturia and incontinence. Most recent studies on propantheline in detrusor instability have compared it with another anticholinergic, oxybutynin, which has been found to produce response rates of up to 60% and a median increase in cystometric capacity of 104 mL;13 it was more effective than propantheline in some studies,12,14 but not others.15 Similarly as for penthienate, the price of its therapeutic effect was a higher residual urine volume and higher rate of side effects.12 However, as we found for penthienate, the anticholinergic side effects were generally tolerable and, if the treatment was discontinued, short-lived. Nevertheless, in detrusor hyperreflexia caused by multiple sclerosis oxybutynin and propantheline treatment had to be discontinued because of side effects in 22% and 27% of patients, respectively.15 We conclude that penthienate bromide has a significant place in the management of detrusor overactivity. It has been our practice to use penthienate as first-line drug treatment in those patients with idiopathic detrusor instability not responsive to conservative measures such as bladder training and biofeedback. Unfortunately, it is currently unavailable in Australia as it is no longer manufactured locally. The side effects of anticholinergic treatment are well recognised and occurred with both penthienate and propantheline. With appropriate modifications of dosage (e.g., in the elderly, who are more likely to have side effects, and in those with neurogenic bladders and detrusor hyperreflexia caused by multiple sclerosis, who are more sensitive to penthienate), most patients can tolerate these side effects and still benefit from therapy. Treatment should start with the lowest therapeutic dose and be monitored closely to maximise patient compliance if long term use is considered. Acknowledgements Winthrop Laboratories manufactured and supplied the penthienate (Monodral) and placebo tablets for the first crossover trial. We thank Dorothy Wheeler, RN, and Marilynne Berg, RN, of the Urology Training Unit, Prince Henry Hospital, for their help in the follow-up studies. References Abrams P, Blaivas JG, Stanton SL, Andersen JT. The standardisation of terminology of lower urinary tract function. Scand J Urol Nephrol 1988; Suppl 114: 5-19. Tapp AJS, Cardozo LD, Versi E, Cooper D. The treatment of detrusor instability in controlled study postmenopausal women with oxybutynin chloride: a double blind placebo. Br J Obstet Gynaecol 1990; 97: 521-526. Blaivas JG, Labib KB, Michalik SK, Zayed AAH. Cystometric response to propantheline in detrusor hyperreflexia: therapeutic implications. J Urol 1980; 124: 259. Wein AJ. Pharmacologic treatment of incontinence. J Am Geriatr Soc 1990; 38: 317-328. Millard RJ, Oldenburg BF. The symptomatic, urodynamic and psychodynamic results of bladder re-education programs. J Urol 1983; 53: 565-566. Chang PL. Urodynamic studies in acupuncture for women with frequency, urgency and dysuria. J Urol 1988; 140: 563-566. Burgio KL, Engel BT. Biofeedback-assisted behavioural training for elderly men and women. J Am Geriatr Soc 1990; 38: 338-340. Koldewijn EL, Rijkhoff NJM, van Kerrebroeck PE, et al. Selective stimulation of sacral nerves for bladder control: a computer model. Neurourol Urodyn 1992; 11: 328-330. Mundy AR. Detrusor instability. Br J Urol 1988; 62: 393-397. Haylen BT, Ashby D, Sutherst JR, et al. Maximum and average urine flow rates in normal male and female populations -- the Liverpool nomograms. Br J Urol 1989; 64: 30-38. Benson H, Epstein MD. The placebo effect. JAMA 1975; 232: 1225. Thuroff JW, Bunke B, Ebner A, et al. Randomized, double blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol 1991; 145: 813-817. Moore KH, Hay DM, Imrie AE, et al. Oxybutynin Hydrochloride (3 mg) in the treatment of women with idiopathic detrusor instability. Br J Urol 1990; 66: 479-485. Gajewski JB, Awad SA. Oxybutynin versus propantheline in patients with multiple sclerosis and detrusor hyperreflexia. J Urol 1986; 135: 966-968. Holmes DM, Montz FJ, Stanton SL. Oxybutynin versus propantheline in the management of detrusor instability. A patient-regulated variable dose trial. Br J Obstet Gynaecol 1989; 96: 607-612. (Received 22 Jun, accepted 20 Jul 1996) Authors' details Department of Urology, Prince Henry Hospital, Sydney, NSW. Graham M Coombes, FRACS, Urology Registrar. Currently, Royal North Shore Hospital, Sydney, NSW; Richard J Millard, FRACS, FRCS, Associate Professor of Urology, University of NSW, Sydney, NSW. Reprints: Dr G M Coombes, 74 Osborne Road, Lane Cove, NSW 2066. 1: Continence and urodynamic characteristics before and after treatment with penthienate and placebo (median and range)*Baseline (n = 20)Penthienate (n = 19)†Placebo (n = 19)†P‡Daytime voiding interval (hours)2 (1-5)3 (2-6)2 (1-4)0.002Night-time frequency (times)2.5 (1-6)1 (0-5)2 (0-4)0.02Mean daytime voided volume (mL)200 (75-400)270 (125-400)168 (50-300)0.0002Mean night-time voided volume (mL)250 (50-650)300 (195-740)275 (50-700)0.02Incontinence score§5 (2-5)1 (1-5)4 (1-5)0.002Urodynamic testingCystometric capacity (mL)283 (150-450)500 (225-600)400 (200-500)0.003Amplitude of unstable detrusor contractions (cm H2O)¶40 (16-80)27 (16-40)30 (20-45)0.05Residual postvoid volume (mL)30 (0-160)40 (0-150)15 (5-50)0.02Flow rate (mL/s)14 (6-25)17 (10-30)20 (15-45)0.68Number of patients With stable cystometrogram**0104NA"Dry" (incontinence score of 1)0102NANA=not assessed. *Unless otherwise stated. †One patient was excluded because of chronic urinary retention. ‡ For difference between penthienate and placebo. § On analogue scale, with range 1 ("nil leakage") to 5 ("wet all the time"). ¶ n = 10 for penthienate and n = 16 for placebo, after exclusion of subjects with stable cystometrogram. ** Detrusor pressure < 15 cm H2O on filling cystometrography to a capacity of 500 mL. Back to text2: Side effects and subjective patient impressions of penthienate and placebo PenthienatePlaceboDry mouthNumber of patients20 (100%)11 (55%)Mean score (range)*65 (25-95)25 (0-80)Nasal dryness2 (10%)0Constipation/lower abdominal pain1 (5%)0Upper abdominal pain1 (5%)0Blurred vision1 (5%)0Chronic urinary retention1 (5%)0Mean subjective efficacy (range)*80 (10-95)23 (0-95)Number of patients Improved17 (85%)5 (25%) Willing to repeat treatment12 (60%)5 (25%)* Subjective score on scale of 0-100. Patient had diagnosed hiatus hernia, but no documented peptic ulcer or reflux oesophagitis. Back to text3: Continence and urodynamic characteristics before and after treatment with penthienate and propantheline (median and range)*Baseline (n = 23)Penthienate (n = 23)Propantheline (n = 23)P †Daytime voiding interval (hours)2 (1-5)3 (2-6)3 (2-4)0.53Night-time frequency (times)2 (1-6)1 (0-5)2 (1-6)0.07Mean daytime voided volume (mL)200 (75-400)260 (125-400)200 (125-450)0.001Mean night-time voided volume (mL)250 (50-650)300 (195-740)325 (230-550)0.17Incontinence score‡5 (2-5)1.5 (1-5)5 (1-5)0.001Urodynamic testingCystometric capacity (mL)280 (150-450)500 (225-600)470 (275-550)0.03Amplitude of unstable detrusor contractions (cm H2O)40 (15-80)27 (16-40)50 (20-75)0.01Residual postvoid volume (mL)25 (0-160)37 (0-150)17.5 (0-100)0.1Flow rate (mL/s)15 (6-29)20 (10-50)20 (15-35)0.48Compliance (mL/cmH2O)70 (12-210)100 (23-600)55 (14-166)0.08Number with stable cystometrogram§01310NANA=not assessed. * Unless otherwise stated. † For difference between penthienate and propantheline. ‡ On analogue scale, with range 1 ("nil leakage") to 5 ("wet all the time"). § Detrusor pressure < 15 cm H2O on filling cystometrography to a capacity of 500 mL. Back to text 4: Side effects and subjective patient impressions of penthienate and propanthelinePenthienate PropanthelineP*Mean score for subjective efficacy† (range)83 (10-95)38 (5-90)0.002Mean score for mouth dryness† (range)73 (25-45)55 (30-90)0.05Mean score for constipation† (range)5 (0-50)7 (0-75)0.73Number of patients "dry" (incontinence score, 1)1310 NANumber of patients improved1913NANumber of patients willing to repeat treatment1211 NANA=not assessed. * By Wilcoxon matched-pairs signed-rank test. † Subjective score on scale of 0-100. Back to text

Graham M Coombes · Richard J Millard

Position Statement Asthma in pregnancy and lactation A position paper for the Thoracic Society of Australia and New Zealand Christine F McDonald and Jonathan G W Burdon MJA 1996; 165: 485-488 Introduction - Literature search - Effects of pregnancy on asthma - Effects of asthma on pregnancy - Management of asthma in pregnancy - Pharmacological therapy - Labour - Breastfeeding - Patient education - Monitoring - References - Author's Details - - More articles on Respiratory medicine This position statement was developed as a consensus view between the two authors and was subsequently reviewed by the Education and Research Sub-Committee of the Thoracic Society of Australia and New Zealand, whose membership comprises six respiratory physicians with a broad range of interests in research and clinical respiratory medicine. This Committee also sought the opinion of an external reviewer with expertise in the subject. The following conclusions were reached: Physiological changes which occur during pregnancy may affect asthma control. Regular monitoring (monthly or every six weeks) of asthmatic women should occur throughout pregnancy. Regular therapy, including the use of inhaled steroids, is recommended. Well-controlled asthma should have no adverse effects on pregnancy, labour or breastfeeding. Medicines used to control asthma carry less risk to the mother and baby than a severe attack of asthma. Good asthma management will result in a birth outcome similar to that experienced by women without asthma. Introduction Pregnant women with asthma should be reassured that their asthma medication carries less risk to the fetus than a severe asthma attack. Inadequately treated asthma can cause maternal and fetal hypoxaemia, which leads to complications during pregnancy and poorer birth outcomes. Here, we outline the effects of asthma on pregnancy (and vice versa) and the management of asthma during pregnancy and the postpartum period. Literature search We searched the literature, using the MEDLINE database, for the period 1985-1995 and the keywords "asthma" and "pregnancy". Standard textbooks on asthma were also reviewed. A total of 146 papers were identified and other papers contained within their references were also reviewed. Thirty-three papers were found suitable. Effects of pregnancy on asthma Although bronchial hyperresponsiveness lessens during mid-pregnancy,1 studies reporting changes in asthma severity during pregnancy show widely differing results.2-5 Overall, the data indicate that the clinical severity of asthma during pregnancy improves in about 30% of women, remains stable in about 50% and worsens in about 20%.6Factors responsible for the variation in asthma severity during pregnancy include an increase in circulating free cortisol,7,8 a decrease in bronchomotor tone and an increase in serum concentrations of cyclic adenosine monophosphate.8 These changes would normally improve the asthma, but in pregnancy other competing factors, including exposure to fetal antigens and alterations in cell-mediated immunity, may worsen asthma symptoms.8 Asthma may be further complicated by sinusitis and rhinitis, which occur in about 35% of pregnant women, but vascular dilatation and congestion of the mucosa of the upper respiratory tract (vasomotor rhinitis of pregnancy) does not involve the lower airways.9 The physiological respiratory changes which occur during pregnancy may affect asthma control (Box). Changes in blood gases secondary to acute asthma will be superimposed on the physiological respiratory alkalosis of pregnancy. Therefore, a normal or elevated PCO2 associated with acute asthma will indicate respiratory compromise of greater severity in pregnancy than in the non-pregnant state. The dyspnoea of pregnancy must be differentiated from dyspnoea caused by asthma. Indeed, patients who develop asthma during pregnancy may wrongly attribute dyspnoea to the pregnancy, which can lead to undermedication and severe maternal and fetal hypoxaemia. It is difficult to predict which women will experience worsening of their asthma during pregnancy, but the severity of the condition before pregnancy,2,8 and an absence of the expected decrease in IgE concentration during pregnancy,8,13 should alert the clinician to this possibility. If asthma is going to worsen, it will usually do so between 24 and 36 weeks' gestation. Symptoms are likely to be less troublesome in the peripartum period. In most women, asthma severity returns to the prepregnant state within three months of delivery,1,5 but in rare cases it may be worse than before the pregnancy. Effects of asthma on pregnancy The fetus exists in a precarious state of oxygenation and is dependent for its oxygen supply on maternal arterial oxygen content, venous return and cardiac output, and uterine artery and placental bloodflow. Compensating mechanisms of the fetus to combat potentially adverse conditions of oxygenation include a haemoglobin level of at least 16 g/dL and a P50 of 22 mmHg (indicating a left shift in the oxyhaemoglobin dissociation curve). Poorly controlled asthma or severe asthma attacks further threaten the fetus because of increased maternal hypoxaemia and diminution of uterine artery bloodflow secondary to hypocapnic vasoconstriction. These women have an increased incidence of low birthweight and premature babies, neonatal hypoxia, complications during labour, and perinatal and maternal mortality.14-17 Hyperemesis gravidarum, maternal haemorrhage and pre-eclampsia are more common in this group.14 For these reasons, it has been argued that a pregnancy complicated by asthma should be regarded as a high risk pregnancy.16 However, the babies of most asthmatic women (i.e., those with well controlled asthma) show no difference in birthweight, Apgar scores or rates of congenital malformation when compared with those of non-asthmatic mothers.5,15,16 Management of asthma in pregnancy The management of asthma during pregnancy is similar to that at any other time: treatment should be aggressive, with the aim of eliminating symptoms and restoring and maintaining normal lung function. Guidelines for asthma management have been published by the National Asthma Campaign and are highly recommended.18 Cooperation between the respiratory physician and obstetrician is important throughout pregnancy for women with severe asthma. Pharmacological therapy Care should be taken with pharmacological therapy during pregnancy, particularly in the first trimester, when the risk of congenital defects is greatest. Fortunately, the medicines currently used in the treatment of asthma have been found in practice to have a good safety profile during pregnancy. The drug categories listed here are those of the Australian Drug Evaluation Committee's categorisation of risk of drug use in pregnancy.19 Bronchospasm relaxants β2-Agonists (category A): There is no evidence of a teratogenic risk with the commonly used inhaled β2-agonists salbutamol, terbutaline and fenoterol. Intravenous salbutamol may be used to delay the onset of labour in some circumstances and there is a theoretical risk that oral β2-agonists could also have this effect. Delayed labour does not occur with bronchodilators administered by metered-dose inhaler or wet nebulisation. Ipratropium bromide (category B1): Although there is less experience with this drug, it appears to be safe for use during pregnancy, as it is poorly absorbed when administered by the inhaled route and has not been identified as imparting an increased risk of fetal malformations. Salmeterol (category B3): These newer long-acting agents have not been tested extensively in pregnant women. Theopyllines (category A): The use of theophyllines remains controversial. They may aggravate the nausea and reflux suffered by some pregnant women and can cause transient neonatal tachycardia and irritability.20,21 Teratogenicity has been shown in animals,22,23 and there are occasional case reports of cardiovascular abnormalities in humans.24 However, larger human studies have not shown any significant increase in fetal abnormalities.25,26 It has been suggested that theophyllines be withheld during the first trimester.26 If they are used, serum theophylline levels should be measured as drug metabolism may alter during pregnancy. Preventive inhalations and aerosols Sodium cromoglycate (category A): This drug appears to have no adverse fetal effects. Nedocromil sodium (category B1): Animal studies have not shown any teratogenic effects, but, as with all new drugs, care should be exercised, especially in the first trimester. Inhaled corticosteroids Beclomethasone and budesonide (category B3): These are the mainstay of treatment in moderate to severe asthma and both appear to have a good safety profile in pregnancy. Although beclomethasone is a known animal teratogen, its use in pregnant women has not been associated with teratogenicity. The largest human experience of inhaled corticosteroids is with beclomethasone and it is therefore the inhaled steroid of choice in pregnancy.9 Less information is available on the use of budesonide in pregnancy as it is a newer drug. If moderate to severe asthma is well controlled with budesonide, the risks of destabilising the condition by changing from budesonide to beclomethasone must be weighed against the potential benefits of using a medicine which has been more extensively studied. Fluticasone (category B3): Experience with this drug in pregnancy is more limited. Oral corticosteroids (Category A) These are sometimes necessary for severe asthma in pregnancy but usually only for short periods. An increased risk of cleft palate and placental abnormalities has been reported in animals given huge doses of oral steroids.27,28 These abnormalities have not been reported in humans, and the results of animal studies should not deter the practising clinician from using oral corticosteroids if required. Methotrexate and other steroid-sparing agents have an occasional role in the treatment of some individuals with severe resistant asthma. However, these drugs are contraindicated in women of childbearing age who are trying to conceive or who are pregnant. Labour There is no increase in the induction of labour, use of forceps or emergency caesarean sections in women with asthma, but elective caesarean sections are more common. Women with very severe asthma may be advised to have an elective caesarean section at a time when their asthma control is good. Close cooperation between the respiratory physician, obstetrician and anaesthetist is particularly important at this time. Symptoms of asthma during labour are generally easily controlled with standard asthma therapy. Acute asthma attacks in labour are rare, but prostaglandin F2alpha (Dinoprost, UpJohn) and ergometrine cause bronchoconstriction. Their use in the induction of labour, the initiation of the third stage of labour and for placental separation should be avoided.29 There is no evidence that oxytocin causes bronchoconstriction. Breastfeeding Breastfeeding should be continued in women with asthma as breast milk confers some immunity to infection to the baby, especially to respiratory and gastrointestinal infections. Breast milk may contain very small amounts of the drugs used to treat asthma, but, in general, these are not known to be harmful to the infant. Corticosteroids are about 90% protein bound in the blood and are not secreted into breast milk in any significant quantity. However, the manufacturers of budesonide have recommended discontinuation of this drug during lactation because of an absence of information regarding its transmission into breast milk. The decision to alter a successful medication regimen that is controlling the mother's asthma must be weighed against any potential detrimental effects to the infant from continuation of the drug. Although less than 1% of maternal theophylline is transferred to the infant,30 it has been suggested that women breastfeed their baby before taking this drug to minimise its side effects.31 It is recommended that tetracycline antibiotics and iodine-containing mixtures be avoided in pregnant and lactating women as they may cause dental discoloration and goitre in the baby. Patient education Environmental trigger factors which cause deterioration in asthma control or may lead to acute asthma attacks must be avoided and pregnant women should be urged to stop smoking. Mothers should be advised about the importance of avoiding exposure to allergens and environmental tobacco smoke in the first years of their child's life to reduce the potential for later asthma development.32 Monitoring Women with asthma should be reviewed at least every four to six weeks (and more frequently if needed) so that early changes in respiratory function can be detected and treated expeditiously. Although formal spirometry may be indicated from time to time, lung function can be easily monitored at home with a peak flow meter.33 The doctor should formulate an asthma action plan with the patient, to be put into effect if her condition deteriorates.33If a woman with asthma is closely monitored, pregnancy outcomes approaching those of the general population can be expected.34 Well-controlled asthma should have no adverse effect on pregnancy, labour or breastfeeding. References Juniper EF, Daniel EE, Roberts RS, et al. Improvement in airway responsiveness and asthma severity during pregnancy. A prospective study. Am Rev Respir Dis 1989; 140: 924-931. Williams DA. Asthma and pregnancy. Acta Allergol 1967; 22: 311-323. Turner ES, Greenberger PA, Patterson R. Management of the pregnant asthmatic patient. Ann Intern Med 1980; 93: 905-919. Greenberger PA, Patterson R. Management of asthma during pregnancy. N Engl J Med 1985; 312: 897-902. Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, post-partum and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988; 81: 509-517. Burdon JGW, Goss G. Asthma and pregnancy. Aust N Z J Med 1994; 24: 3-4. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 1981; 139: 492-498. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976; 37: 164-168. National Heart, Lung and Blood Institute. Report of the Working Group on Asthma and Pregnancy. Executive Summary: Management of asthma during pregnancy. J Allergy Clin Immunol 1994; 93: 139-162. Prowse CM, Gaensler EA. Respiratory and acid-base changes during pregnancy. Anesthesiology 1965; 26: 381-392. Rees GB, Pipkin KB, Symonds EM, et al. A longitudinal study of respiratory changes in normal human pregnancy with cross sectional data on subjects with pregnancy-induced hypertension. Am J Obstet Gynecol 1990; 162: 826-830. Gee JBL, Packer BS, Millen JE, et al. Pulmonary mechanics in pregnancy. J Clin Invest 1967; 46: 945-952. Gazioglu K, Kaltreider NL, Rosen M, et al. Pulmonary function during pregnancy in normal women and patients with cardiopulmonary disease. Thorax 1970; 25: 445-450. Hernandez E, Angell CS, Johnson JW. Asthma in pregnancy: current concepts. Obstet Gynecol 1980; 55: 739-743. Gordon M, Niswander KR, Berendes H, et al. Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynecol 1970; 106: 421-429. Bahna SL, Bjerkedal T. The course and outcome of pregnancy in women with bronchial asthma. Acta Allergol 1972; 27: 397-406. Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986; 78: 349-353. National Asthma Campaign. Asthma Management Handbook. Melbourne: National Asthma Campaign Ltd, 1993. Australian Drug Evaluation Committee. Medicines in Pregnancy. 3rd ed. Commonwealth Department of Health and Family Services, 1996. 20. Yeh TF, Pildes RS. Transplacental aminophylline toxicity in a neonate [letter]. Lancet 1977; 1: 910. Labovitz E, Spector S. Placental theophylline transfer in pregnant asthmatics. JAMA 1982; 247: 786-788. Gilbert EF, Bruyere HJ, Ishikawa S, et al. The effect of methylxanthines on catecholamine-stimulated and normal chick embryos. Teratology 1977; 16: 47-52. Ishikawa S, Gilbert EF, Bruyere HJ, et al. Aortic aneurysms associated with cardiac defects in theophylline-stimulated chick embryos. Teratology 1978; 18: 23-30. Park JM, Schmer V, Myers TM. Cardiovascular anomalies associated with prenatal exposure to theophylline. South Med J 1990; 83: 1487-1488. Schatz M. Asthma during pregnancy: interrelationships and management. Ann Allergy 1992; 68: 123-133. Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest 1995; 107: 642-647. Fainstat T. Cortisone-induced congenital cleft palate in rabbits. Endocrinology 1954; 55: 502-508. Blackburn WR, Kaplan HS, McKay DG. Morphologic changes in the developing rat placenta following prednisolone administration. Am J Obstet Gynecol 1963; 92: 234-246. Math AA, Hedqvist P. Effect of prostaglandins F2 and E2 on airway conductance in healthy subjects and asthmatic patients. Am Rev Respir Dis 1975; 111: 313-320. Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics 1979; 57: 518-525. Berkowitz R, Coustan DR, Mochizuki TK. Handbook for prescribing medications during pregnancy. 2nd ed. Boston: Little, Brown and Co, 1986. Peak JK. Prevention of asthma. Eur Respir J 1996; 9: 1545-1555. The Thoracic Society of Australia and New Zealand. Peak flow meter use in asthma management. Med J Aust 1996; 164: 727-730. Stenius-Aarniala B, Piilrila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988; 43: 12-18. Authors' details Department of Respiratory Medicine, Austin and Repatriation Medical Centre, Heidelberg, VIC. Christine F McDonald, PhD, FRACP, Consultant Respiratory Physician. Department of Respiratory Medicine, St Vincent's Hospital, Melbourne, VIC. Jonathan G W Burdon, MD, FRACP, Consultant Respiratory Physician. Reprints: Dr J G W Burdon, Director, Department of Respiratory Medicine, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, VIC 3065. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Physiological respiratory changes in pregnancy Dyspnoea Dyspnoea is experienced by 60%-70% of women at some time during pregnancy,10 most commonly in the first or second trimester. Mechanical factors do not seem to play a major role in its pathogenesis because it frequently occurs before any increase in abdominal girth. Early pregnancy: Dyspnoea may be caused by rising circulating maternal progesterone levels, which result in a progressive increase in minute ventilation of up to 40% by the end of the first trimester, largely as a result of increases in tidal volume.11 Late pregnancy: Dyspnoea later in pregnancy is (likely to be) caused by a combination of the hyperventilation of pregnancy and restriction due to uterine enlargement. The latter leads to a small reduction in both residual volume and functional residual capacity, while total lung capacity is maintained by an increase in inspiratory capacity.12,13 Changes in peak flow rates and forced expiratory volume in one second (FEV1) are small and of no clinical significance.1,13 Respiratory alkalosis Maternal gas exchange is mildly disordered as a result of the increase in minute ventilation.11 A slight rise in arterial oxygen tension, a change in carbon dioxide tension and pH changes are common and indicate a mild respiratory alkalosis. The changes in arterial blood gas tensions occur despite increases in oxygen consumption and carbon dioxide production in the last few months of pregnancy.11 Back to text

Christine F McDonald

Menorrhagia: a clinical update Carl E Wood Almost every woman experiences episodes of abnormal or excessive menstrual bleeding MJA 1996; 165: 510-514 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - Assessment of blood loss - Causes - Diagnosis - Management - Drug therapy - Surgery - References - Authors' details - - ©MJA1996 Introduction Menorrhagia is defined as a blood loss of 80 mL or more per period. Population studies show that the typical menstrual blood loss is 30-40 mL, and that 90% of women have losses of less than 80 mL. 1 Menorrhagia is still one of the more common reasons for women to be referred to a gynaecologist, and is the main presenting symptom in 38% of Australian women having hysterectomies. 2 Box 1 summarises the stages in clinical assessment and management of menorrhagia. 1: Assessment and management of menorrhagia Assessment of blood loss Women seeking treatment for menorrhagia often do not have greater blood losses than average. In a population study, 26% of women with normal menstrual loss ( < 60 mL) considered their periods heavy, while 40% of those with heavy losses ( > > 80 mL) considered their periods to be moderate or light. 1 In one study, over half the women referred for endometrial ablation complaining of heavy periods had menstrual blood losses of less than 80 mL. 3 Social embarrassment, inconven ience, costs of sanitary protection, the safety of using tampons, and interference with sexual activity all make coping with menstruation difficult. An approximate assessment of blood loss can be made from a pad and tampon count. 4 If blood loss does not appear excessive, then counselling on how best to manage menstrual loss may avoid unnecessary drug treatment or surgical intervention. Causes The volume of blood lost at menstruation is controlled by local uterine vascular tone, haemostasis, and regeneration of endometrium. Studies of patients with menorrhagia have shown a greater endometrial concentration of the vasodilator prostaglandin E (PGE), 5,6 and a relationship between total prostaglandin (PGE, PGI 2 and PGF 2 a ) concentration and average blood loss. 6 Increased endometrial fibrinolysis may be of importance, 7 as suggested by reduction in mean menstrual blood loss in women taking fibrinolytic inhibitors (e.g., tranexamic acid). 8 The wide variety of causes of menorrhagia are shown in Box 2. The frequency of the organic causes in a normal population is not known. Anovulation may be associated with menorrhagia close to menarche and to menopause. It may be particularly important when prolonged menstrual cycles occur, as oestrogen in the absence of progesterone may cause endometrial hyperplasia, atypical hyperplasia and eventually carcinoma. Progesterone alone or progesterone associated with the oral contraceptive pill prevents such changes. Management of women with menorrhagia may be more effective if psychosocial factors (depression, work difficulties, heavy smoking [> 20 per day], excessive alcohol intake, and sexual problems) 9,10 are taken into consideration. Diagnosis The main diagnostic procedures for menorrhagia include: Dilatation and curettage Outpatient endometrial sampling Hysteroscopy Vaginal ultrasonography. Dilatation and curettage (D&C) involves a general anaesthetic and a one-day stay in hospital; it is not cost effective for diagnosing endometrial malignancy in women under 40 years (who have a low prevalence of serious uterine conditions and endometrial cancer). 11 The potential benefits need to be weighed up against the risks (general anaesthesia and possible uterine perforation and laceration of the cervix). 12 Moreover, a significant proportion of endometrial lesions are not detected by D&C, 12,13 and its usefulness as a diagnostic tool has been repeatedly questioned. 12,14,15 Endometrial sampling and hysteroscopy: Endometrial sampling (the passage of intrauterine catheters which scrape or brush the endometrial surface) or hysteroscopy (which enables targeted biopsy of abnormal endometrium) have high levels of patient acceptability, lower complication rates, usually do not require inpatient admission and general anaesthesia, and are as accurate and cost effective as D&C. 15-17 Vaginal ultrasound: Ultrasound diagnosis markedly increases the accuracy of clinical diagnosis and assists in treatment choice (including avoidance of surgery) and selection of patients most suited to endometrial resection, intrauterine resection of polyps and fibromyomas, open, vaginal or laparoscopic myomectomy, adenomyomectomy and hysterectomy. 18 Management Drug therapy Over the last decade, a wide variety of drugs have been used for the treatment of menorrhagia (Box 3). Medical treatment avoids major surgery, but has associated side effects and is generally only effective for the duration of treatment. Thirty-one randomised controlled trials of drug therapy with objective measurement of menstrual blood loss have been published. The one controlled study, comparing tranexamic acid (1 g given four times daily on Days 1-4 of menstruation) and norethisterone taken on Days 9-26, showed tranexamic acid to be more effective and with no significant side effects. Although isolated case reports of thrombotic episodes with tranexamic acid exist, a Scandinavian study of 238 000 treatments with this drug over 19 years showed no increased thrombotic events compared with those in an age-matched general population. 22 The possibility of minor subclinical thrombosis with long term use can be excluded only by a follow-up study. In women with a pretreatment blood loss of 80-200 mL per cycle, 92% had their blood loss reduced to less than 80 mL per cycle with tranexamic acid. Those with a menstrual blood loss of more than 250 mL per cycle did not achieve a normal blood loss and required surgery. 23 A comparison of the drugs used in all the controlled trials indicates that a norgestrel-releasing intrauterine device (IUD), 28,30 danazol, 20,28 and tranexamic acid 24,30 are most effective in reducing menstrual blood loss, while mefenamic acid, 20,28 the oral contraceptive pill and progestogens are usually less effective. A recent study has shown tranexamic acid to be more effective (54% reduction in blood loss) than mefenamic acid (20% reduction), whereas ethamsylate (a clotting agent) was ineffective. 31 (The hormone-releasing IUD is not registered for use in Australia or the United Kingdom as treatment for menorrhagia.) Danazol's serious side effects (menopausal symptoms and mild androgenic effects) make it unacceptable for long term use and it is also relatively expensive. Tranexamic acid has few side effects and offers the advantage of alleviating menstrual pain. Surgery Abdominal hysterectomy v. endometrial resection Randomised controlled trials have been performed comparing abdominal hysterectomy with less invasive surgical intervention for menorrhagia. 32,33 Abdominal hysterectomy requires longer theatre times and six or seven days' hospital stay, whereas endometrial resection (ablation) is a day-stay or overnight procedure. Abdominal hysterectomy has a higher complication rate (45%) compared with transcervical endometrial resection (0-15%). Complications include uterine perforation, fluid overload, haemorrhage and cervical stenosis. Reported mortality rates for abdominal hysterectomy are two to five times higher than those for endometrial resection (0.06%-0.16% v. 0.03%), and major complication rates are five to twelve times higher (1%-2.5% v. 0.2%). 34 Resumption of normal activities after abdominal hysterectomy takes two to three months versus two to three weeks for resection. Endometrial resection results in 13%-64% of women having no menstrual bleeding and 62%-77% having reduced menstrual loss. After endometrial resection 6%-23% of women require reoperation for continued bleeding, with the higher rates being reported in studies with a longer follow-up. 32,33 The probability of requiring a hysterectomy four years after endometrial resection has been estimated to be 12%. 35 Some form of sterilisation or contraception is needed after endometrial resection. Pregnancy is unlikely, but if it occurs the risk of complications is higher. Hysterectomy is preferable if the patient has a large uterus, severe endometriosis, a desire for amenorrhoea or certain cure, or there is an increased risk of uterine cancer (family history, marked obesity, polycystic ovaries and diabetes). Endometrial resection can be used if a woman is unfit for hysterectomy. It also avoids possible ovarian dysfunction and the psychological effects of hysterectomy. Endometrial resection has a 47% cost advantage over hysterectomy because of shorter theatre time and hospital stay, but the cost advantage diminishes with time to 29% because of the need for repeat surgery. 36 Myomectomy The number of abdominal myomectomies performed in Australia has been estimated at 1500 per year; most are for menorrhagia in women wishing to retain the uterus. 2 After myomectomy, recurrence rates of 5%-27%, retreatment rates of 10%, and fertility rates of 40%-59% have been reported. 37 Some abdominal myomectomies may be replaced by laparoscopic or laparoscopic-minilaparotomy procedures, as fibroids up to 14 cm in diameter in uteri up to the size of a uterus in a 24 weeks' pregnant woman have been removed by these methods. 29,38 The safety of the laparoscopic technique has been established, with the only serious complication among 214 patients in three studies being one postoperative haemorrhage requiring reoperation. 29,38,39 Abdominal v. laparoscopic myomectomy The average hospital stay for abdominal myomectomy is four to five days, compared with one to three days for the laparoscopic procedure. 29,40 The cost of laparoscopic myomectomy ($2217) is lower than that of abdominal myomectomy ($3825). 2 Laparoscopic myomectomy involves a shorter hospital stay, with probable associated advantages of reduced pain, reduced risk of wound complications, earlier return to normal activity, and reduced costs. 40 Myoma reduction has been performed by laser or electro coagulation. A volume reduction varying from 10% to 80% has been achieved with fibromyoma up to 10 cm in diameter. Follow-up so far has been limited to three years and there has been little or no regrowth. 37,41 Results of further studies may establish its role in the treatment of menorrhagia. Hysterectomy Compared with abdominal hysterectomy, vaginal hysterectomy is associated with less pain and morbidity, shorter hospital stays and faster recovery periods. 42 However, analysis of Australian hospital morbidity data indicates that at least some of these benefits do not always accrue. 2 It is more difficult to perform and its use to date for menorrhagia and, in particular, myomas is limited. Only 25% of hysterectomies are performed vaginally in Australia. 2 Techniques for laparoscopic hysterectomy are still developing. 43,44 Results indicate that, compared with abdominal hysterectomy, postoperative pain is reduced and hospital stays (one to four days) and recovery periods (one to four weeks) are shorter. A meta-analysis of 29 reports involving 3189 patients having laparoscopic hysterectomy 45 showed lower febrile morbidity and incidence of blood transfusion, but similar serious complication rates, to both vaginal and abdominal hysterectomies. Seven controlled trials comparing laparoscopic with abdominal procedures showed reduced time in hospital, shorter convalescence and similar complication rates. 45,46 Like vaginal hysterectomy, laparoscopic hysterectomy, with its reduced recovery period, does benefit patients, their families and employers. In conclusion, the diversity of possible surgical treatments indicates the need for flexibility in choosing techniques to resolve an individual patient's problem, and the possible advantage for gynaecologists to learn the new hysteroscopic and laparoscopic techniques for removal of the endometrium, polyps, myomas, adenomyomas and the uterus (Box 4). References Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss -- a population study. Acta Obstet Gynecol Scand 1966; 45: 320-351. Hirsch NA. Technologies for the treatment of menorrhagia and uterine myomas. Canberra: Australian Institute of Health and Welfare, 1993. (Health Technology Series No. 10.) Deeny M, Davis JA. Assessment of menstrual blood loss in women referred for endometrial ablation. Eur J Obstet Gynaecol 1994; 57: 179-180. Higham JM, O'Brien PMS, Shaw RW. Assessment of menstrual loss using a pictorial chart. Br J Obstet Gynaecol 1990; 97: 734-739. Smith SK, Abel MH, Kelly RW, Baird DT. Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding. Br J Obstet Gynaecol 1981; 88: 434-442. Cameron IT, Leask R, Kelly RW, Baird DT. Endometrial prostaglandins in women with abnormal menstrual bleeding. Prostaglandins Leukot Med 1987; 29: 249-258. Albrechtson OK. The fibrinolytic activity of the human endometrium. Acta Endocrinol 1956; 23: 219-229. Ylikorkala O, Viinikka L. Comparison between antifibrinolytic and antiprostaglandin treatment in the reduction of increased blood loss in women with intrauterine contraceptive devices. Br J Obstet Gynaecol 1983; 90: 78-83. Wood C. The association of psycho-social factors and gynaecological symptoms. Aust Fam Physician 1978; (7 April): 471-478. Lumley J, Wood C. Female reproductive system. In: Krupinski J, Stoller W, editors. North west region health and social survey. Melbourne: Heinemann, 1971: 52-63. Coulter A, Klassen A, MacKenzie IZ, McPherson K. Diagnostic dilatation and curettage: is it used appropriately? BMJ 1993; 306: 236-239. MacKenzie IZ, Bibby JG. Critical assessment of dilatation and curettage of 1029 women. Lancet 1978; 2: 566-568. Vessey M, Clarke J, MacKenzie I. Dilatation and curettage in young women. Health Bull 1979; 39: 59-62. Strovall T, Solomon S, Ling F. Endometrial sampling before hysterectomy. Obstet Gynecol 1989; 73: 405-409. Goldberg G, Tsalacopoulos G, Davey D. A comparison of endometrial sampling with the Accurette and Vabra aspirator and uterine curettage. S Afr Med J 1982; 61: 114-116. MacKenzie I. Routine outpatient diagnostic uterine curettage using a flexible plastic aspiration curette. Br J Obstet Gynaecol 1985; 92: 1291-1296. Gillespie A, Nichols A. The value of hysteroscopy. Aust N Z J Obstet Gynaecol 1994; 34: 85-87. Wood C, Hurley VA, Leoni M. The value of vaginal ultrasound in the management of menorrhagia. Aust N Z J Obstet Gynaecol 1993; 33: 198. Fraser IS, McCarron G. Randomised trial of 2 hormonal and 2 prostaglandin-inhibiting agents in women with a complaint of menorrhagia. Aust N Z J Obstet Gynaecol 1991; 31: 66-70. Dockeray CJ, Sheppard BL, Bonnar J. Comparison between mefenamic acid and danazol in the treatment of established menorrhagia. Br J Obstet Gynaecol 1989; 96: 840-844. Bonnar J. Dysfunctional uterine bleeding. Presention at the Royal Society of Medicine, London, Feb 1994. London: The Royal Society, 1994. Rybo G. Tranexamic acid therapy effective treatment in heavy menstrual bleeding. Clinical update on safety. Ther Adv 1991; 4: 1-8. Preston JT, Cameron IT, Adams EJ, Smith SK. Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia. Br J Obstet Gynaecol 1995; 102: 401-406. Vermylen J, Verhaegen-Declereq ML, Verstraete M, Fierens F. A double blind study of the effect of tranexamic acid in essential menorrhagia. Thromb Diath Haemorrh 1968; 20: 583-587. Fraser IS. Treatment of menorrhagia. Baillieres Clin Obstet Gynaecol 1989; 3: 391-402. Fraser IS. Prostaglandins, prostaglandin inhibitors and menstrual disorders part II: menorrhagia and premenstrual syndrome. Healthright 1988; 8: 31-35. Fraser IS, McCarron G, Markham R. Objective measurement of menstrual blood loss in women with a complaint of menorrhagia associated with pelvic disease or coagulation disorder. Obstet Gynecol 1986; 68: 630-633. Cameron IT, Leask R, Kelly RW, Baird DT. The effects of danazol, mefenamic acid, norethisterone and a progesterone-impregnated coil on endometrial prostaglandin concentrations in women with menorrhagia. Prostaglandins 1987; 34: 99-110. Nezhat C, Nezhat F, Silfer SL, et al. Laparoscopic myomectomy. Int J Fertil 1991; 36: 275-280. Milsom I, Anderson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol 1991; 164: 879-883. Bonnar J, Sheppard BL. Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid. BMJ 1996; 313: 579-582. Gannon M, Holt E, Fairbank J, et al. A randomised trial comparing endometrial resection and abdominal hysterectomy for the treatment of menorrhagia. BMJ 1991; 303: 1362-1364. Dwyer N, Hutton J, Stirrat G. Randomised controlled trial comparing endometrial resection with abdominal hysterectomy for the surgical treatment of menorrhagia. Br J Obstet Gynaecol 1993; 110: 237-243. Macdonald R, Phipps J, Singer A. Endometrial ablation -- a safe procedure. Gynaecol Endosc 1992; 1: 7-9. Broadbent M, Magos AL. Endometrial resection follow up: late onset of pain. Br J Obstet Gynaecol . In press. Sculpher MJ, Bryan S, Dwyer N, et al. An economic evaluation of transcervical endometrial resection versus abdominal hysterectomy for the treatment of menorrhagia. Br J Obstet Gynaecol 1993; 100: 244-252. Wood C, Maher P, Hill D. Myoma reduction by electrocautery. Gynaecol Endoscopy 1994; 3: 163-165. 38. Wood C, Maher P. Removal of fibromyomata by laparoscopic surgery after preoperative GnRH analogue -- an alternative to abdominal hysterectomy and myomectomy. Aust N Z J Obstet Gynaecol 1996. In press. Maher P, Wood C, Hill D. Endoscopic minilaparotomy. Aust N Z J Obstet Gynaecol 1995; 35: 76-78. Tavmergan E, Tavmergan EN, Turker S. Preliminary results of 100 pelviscopic myomectomies. 4th Congress of the European Society for Gynaecological Endoscopy, Brussels. 6-9 December. Gynaecol Endosc 1995; 4 Suppl I: 68. Goldfarb HA. Electrocoagulation of myomas [abstract]. Fourth Biennial Meeting of the International Society of Gynaecologic Endoscopists, London, Apr 26-29, 1995. London: ISGE, 1995. Kovac SR, Christie SJ, Bindbeutel GA. Abdominal versus vaginal hysterectomy: a statistical model for determining physician decision making and patient outcome. Med Decis Making 1991; 11: 19-28. Wood C, Maher P, Hill D. Replacement of abdominal hysterectomy by the laparo vaginal technique -- its success and limitations. Aust N Z J Obstet Gynaecol 1994; 34: 71-74. Jones IS, Flynn M, Hall B, et al. Laparoscopic assisted vaginal hysterectomy -- an audit plus a word of caution. J Obstet Gynaecol 1995; 21: 119-125. Garry R, Phillips G. How safe is the laparoscopic approach to hysterectomy.? Gynaecol Endoscopy 1995; 4: 77-79. Wood C, Maher P. Laparoscopic hysterectomy. In: Wood C, Maher P, editors. Hysterectomy. London: Bailliere Tyndall, 1996. In press. Author's details Melbourne Gynoscopy Centre, Melbourne, VIC. Carl E Wood, FRACOG, Professor, Department of Obstetrics and Gynaecology, Monash University. Reprints: Professor C E Wood, Melbourne Gynoscopy Centre, 284 High Street, Ashburton, VIC 3147. - - To top of article - ©MJA 1996 <URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Carl E Wood