- Email: [email protected]
Airflow Limitation—Reversible or Irreversible?
26
Pharmacological adaptive responses during drug therapy and in disease are not uncommon.l1 The classic example is tolerance to the analgesic effects of morphine and the problems of addiction and withdrawal in patients with opioid dependence. In cardiovascular therapeutics haemodynamic tolerance may occur during chronic treatment of severe heart failure with the vasodilator hydralazinel2 and pharmacological adaptive responses may be encountered to chronic digitalis therapy, although there is continuing controversy about the clinical importance of this effect during the treatment of heart failure.13 Pharmacological adaptation may well underly the therapeutic action of certain drugs-eg, antidepressant agents bring about many adaptive changes in brain function which some see as the mechanism by which they produce their therapeutic effect. Indeed, electroconvulsive therapy, as gleaned from the results of animal experimentation, produces neuropharmacological adaptive responses very similar to those of the antidepressant drugs.14 It is likely that at least part of the long-term hypotensive action of &bgr;-adrenergic blockers is due to pharmacological and physiological adaptation to cardiovascular &bgr;-blockade. An important consequence of the pharmacological adaptive response is the withdrawal syndrome. Opioid withdrawal is best known, but alcohol withdrawal producing delirium tremens, and the benzodiazepine withdrawal syndrome are both well °
documented and their mechanisms may not be dissimilar .15 Withdrawal from &bgr;-blockers can produce a transient increase in sympathetic nervous system activity, and clonidine withdrawal may result in a serious hypertensive rebound. Pharmacological adaptation may also produce adverse effects, of which tardive dyskinesia due to chronic neuroleptic therapy is an important example. Chronic "prophylactic" drug therapy is now commonplace, for instance in hypertension, mental illness, diabetes mellitus, peptic, ulceration, and ischaemic heart disease. New therapeutic approaches to chronic illness will probably require long-term drug administration in conditions such as Alzheimer’s disease. There is much to learn about the importance of pharmacological adaptation in chronic drug therapy with respect to its influence on efficacy and the occurrence of adverse reactions and withdrawal syndromes. New treatments will bring new problems to light, for some of these adaptive responses will be difficult to predict. 12. Packer M, Meller J, Medina N, Yushak
M, Gorlin R. Hemodynamic characterization of tolerance to long-term hydralazine therapy in severe chronic heart failure. N Engl J Med 1982, 306: 57-62. 13. Aronson JK, Ford AR, Grahame-Smith DG. Techniques for studying the pharmacodynamic effects of cardiac glycosides on patients’ own erythrocytes during glycoside therapy. Klin Wochenschr 1981; 59: 1323-32. 14. Grahame-Smith DG. The neuropharmacological effects of electroconvulsive shock and their relationship to the therapeutic effect of electroconvulsive therapy in depression. In: Usdin E, et al. Frontiers in biochemical and pharmacological research in depression. New York: Raven, 1984: 327-43. 15. Cowen PJ, Nutt DJ. Abstinence symptoms after withdrawal of tranquillising drugs: is there a common neurochemical mechanism? Lancet 1982; ii: 360-62.
Airflow Limitation—Reversible Irreversible?
or
KNOWING the reversibility of airflow obstruction is important for clinicians and for research, but how should the response be expressed?l,2In particular, it is not clear whether or in what circumstances the response should be expressed in absolute terms, as a percentage of baseline or in relation to the capacity for response (predicted value minus baseline value), nor is it clear where, if anywhere, the arbitrary dividing line between "reversible" and "irreversible" airflow obstruction should be placed. These issues are important since the terms reversible and irreversible are often used to place patients into diagnostic categories such as asthma or chronic obstructive lung disease, with, in some circumstances, implications for prognosis or management. When trying to decide how bronchodilator responsiveness should be expressed, two questions need to be considered. The first is which method of expressing the response best distinguishes a true response to a bronchodilating drug from the inherent variability in the measurement of airflow. The second and more difficult task is to determine which method is giving the most relevant information-relevance depends on the circumstances of the test and may differ between clinical, pharmacological, and epidemiological studies. Two reports by Tweeddale and colleagues3,4 centre on the first question. These workers assessed short-term variability in the measurement of forced expiratory volume in 1 second (FEV 1) in the absence of any drug. They studied a group of 67 subjects with either normal lung function or a restrictive disorder (FEV1 1.1-6.3 litres) and a group of 150 patients with airflow obstruction (FEV, 0-5-47 litres); FEV1 was determined as the best of three readings according to specified criteria on two occasions 20 min apart. The findings were similar in the two groups. There was no significant change in mean FEV1 between the two measurements, and thus no evidence of a learning effect. More relevant to the question of reversibility, the difference in litres between the two measurements was independent of the initial FEV 1; consequently the difference, when expressed as a percentage of initial FEV p increased progressively as FEV1 decreased. These findings suggest that repeatability of FEV measurements should be considered in absolute terms rather than as a percentage of the initial value. These studies were unable to separate the component parts of the
variability-instrument error, patient technique, or true change in airway calibre-but they give a 1. Editorial. Assessment of airflow obstruction. Lancet 1986; ii. 1255-56. 2. Eliasson O, Degraff AC The use of criteria for reversibility and obstruction to define patient groups for bronchodilator trials. Am Rev Respir Dis 1985; 132: 858-64. 3. Tweeddale PM, Merchant S, Leslie M, Alexander F, McHardy GJR. Short term variability in FEV,: relation to pretest activity, level of FEV1, and smoking habits. Thorax 1984; 39: 928-32. 4. Tweeddale PM, Alexander F, McHardy GJR Short term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects. Thorax 1987; 42: 487-90.
27
which the response to a be assessed. Tweeddale et al calculated that, after a drug, a minimum change in FEV1 in the two groups of 190 and 160 ml, respectively, would have been necessary to be more than 95 % confident that an observed change was not due to measurement variability. These workers proceeded to measure the response to 200 µg of salbutamol or 500 ng of terbutaline in the patients with airflow obstruction. The change in FEV after the bronchodilator ranged from - 450 to + 950 ml, with the distribution skewed towards an increase in FEV1. They then assessed two methods of separating "responders" from "non-responders". When responders were defined as those showing an increase in FEVI above the upper 95% confidence interval for natural variability in these subjects (160 ml), patients with a high initial FEV were more likely to be responders. When responders were defined as those showing an increase in FEV of 15 % or more, patients with a low FEV were more likely to be responders. Thus the two methods of expressing the response to a bronchodilator identified different
composite
measure
bronchodilator
against
can
subjects. Tweeddale et al did not look at the repeatability of bronchodilator testing, although this issue is also important. In the large intermittent positive-pressure breathing study in the USA,s the FEV1 response to measured in 985 subjects isoprenaline (250 µg) with chronic obstructive lung disease (COLD) at 3-monthly intervals for nearly 3 years. There was no significant change in the mean response to isoprenaline over this period (a 15 % increase in FEV1) but the within subject variability in response was large-approximately two-thirds of the initial response to isoprenaline. Variability was greatest in patients with a low FEVI, as would be predicted from the Tweeddale study. The mean increase in FEV1 of 15% in these patients with COLD and in whom asthma was specifically excluded is incidentally identical to the figure quoted in an official statement by the American Thoracic Society as being typical of asthma.6This observation accords with several recent studies and surveys in which the change in FEV as a percentage of baseline showed little difference between patients diagnosed as asthma and those diagnosed as chronic bronchitis or COLD.2,7 The change in FEV expressed in absolute terms or as a percentage of predicted, a measure of potential capacity for response, was however able to separate the two groups in one large survey.2 The way in which bronchodilator responses are analysed depends ultimately on the question being was
5. Anthonisen NR, Wright
EC, and the IPPB Trial Group. Bronchodilator response in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 133: 814-19. 6 American Thoracic Society Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136: 225-44. 7. Wardman AG, Binns V, Clayden AD, Cooke NJ. The diagnosis and treatment of adults with obstructive airways disease in general practice. Br J Dis Chest 1986; 80: 19-26.
asked of the test. Use of an absolute change in response to a bronchodilator appears to be better able to separate a true change from chance variation, but if, for example, expressing the response as a percentage of baseline value is a better predictor of clinical outcome (eg, long-term decline in FEVI, or response to corticosteroids) than other methods it may be the more appropriate way to express the results. There is little information in this area, although a study of 129 patients with COLD found that change in FEV was a poor predictor of prognosis when expressed in absolute terms and a much better predictor when related to the capacity to respond as measured by
predicted FEV1 *8 Thus the question of how to express the reversibility of airflow obstruction is far from resolved. Fortunately, this dilemma is seldom important in the clinical setting, where confidence ’
about the true nature of a response to a bronchodilator can be increased by repeat testing, and where the patient’s subjective response is often helpful. Until more answers are available one has to conclude that, outside the immediate clinical setting, the relevance of one of the most commonly used tests of pulmonary function is poorly understood.
DIALYSIS ARTHROPATHY
long-term survivors on haemodialysis have a disabling joint disease commonly known as dialysis arthropathy.9-11 It is characterised by the deposition in bones and synovia of a hitherto unknown type of amyloid composed predominantly of &bgr;2-microglobulin,12-15 and is distinct from the joint problems associated with hyperparathyroidism described in the early days of haemodialysis16 and from any other type of joint disease. The increased incidence of carpal tunnel syndrome, often associated with amyloid deposition, has been recognised in long-term haemodialysis patients for some years. Indeed, most patients on dialysis for more than 15 years have had the disorder; 10,17-19 the first episode seldom occurs before the MANY
severe
and
DS, Gimeno F, van der Weele LT, Sluiter HJ. Assessment of ventilatory vanables in survival prediction of patients with chronic airflow obstruction: the importance of reversibility. Eur J Respir Dis 1985; 67: 360-68. 9. Brown EA, Gower PE. Joint problems in patients on maintenance haemodialysis. Clin Nephrol 1982; 18: 247-50. 10 Brown EA, Arnold IR, Gower PE. Dialysis arthropathy complication of long-term treatment with haemodialysis. Br Med J 1986; 292: 163-66. 11. Munoz-Gomez J, Gomez-Perez R, Llopart-Buisan E, Sole-Argues M. Clinical picture of the amyloid arthropathy in patients with chronic renal failure maintained on haemodialysis using cellulose membranes. Ann Rheum Dis 1987; 46: 573-79 12. Bardin T, Kuntz D, Zingraff J, Voisin MC, Zelmar A, Lansaman J. Synovial amyloidosis in patients undergoing long-term haemodialysis. Arthritis Rheum 8. Postma
1985; 28: 1052-58. 13. Orfila C, Goffinet F, Durroux F, et al
Haemodialysis-associated amyloidosis and beta2, microglobulin deposits in long-term haemodialysis patients. Nephrol Dial Transpl 1987; 2: 448. 14. Sethi D, Woodrow DF, Brown EA, et al. Beta2 microglobulin derived amyloid and iron in dialysis arthropathy. Nephrol Dial Transp 1987; 2: 449. 15. Nakazawa R, Hamaguchi K, Hasaka E, Shishido H, Yokoyama T Synovial amyloidosis of &bgr;2-microglobulin type in patients undergoing long-term haemodialysis Nephron 1987; 44: 379-80. 16. Massry SG, Bluestone R, Klinenberg JR, Cobum JW. Abnormalities of the musculoskeletal system in haemodialysis patients. Sem Arthritis Rheum 1975; 4: 321-49. 17. Schwarz A, Keller F, Syfert S, Poll W, Molzahn M, Distler A. Carpal tunnel syndrome: a major complication in long-term haemodialysis patients. Clin Nephrol 18.
1984; 22: 133-37. Jain UK, Cestero RUM, Baum J. Carpal tunnel syndrome maintenance hemodialysis JAMA 1979; 242: 2868-69.
in
patients
undergoing
Pharmacological adaptive responses during drug therapy and in disease are not uncommon.l1 The classic example is tolerance to the analgesic effects of morphine and the problems of addiction and withdrawal in patients with opioid dependence. In cardiovascular therapeutics haemodynamic tolerance may occur during chronic treatment of severe heart failure with the vasodilator hydralazinel2 and pharmacological adaptive responses may be encountered to chronic digitalis therapy, although there is continuing controversy about the clinical importance of this effect during the treatment of heart failure.13 Pharmacological adaptation may well underly the therapeutic action of certain drugs-eg, antidepressant agents bring about many adaptive changes in brain function which some see as the mechanism by which they produce their therapeutic effect. Indeed, electroconvulsive therapy, as gleaned from the results of animal experimentation, produces neuropharmacological adaptive responses very similar to those of the antidepressant drugs.14 It is likely that at least part of the long-term hypotensive action of &bgr;-adrenergic blockers is due to pharmacological and physiological adaptation to cardiovascular &bgr;-blockade. An important consequence of the pharmacological adaptive response is the withdrawal syndrome. Opioid withdrawal is best known, but alcohol withdrawal producing delirium tremens, and the benzodiazepine withdrawal syndrome are both well °
documented and their mechanisms may not be dissimilar .15 Withdrawal from &bgr;-blockers can produce a transient increase in sympathetic nervous system activity, and clonidine withdrawal may result in a serious hypertensive rebound. Pharmacological adaptation may also produce adverse effects, of which tardive dyskinesia due to chronic neuroleptic therapy is an important example. Chronic "prophylactic" drug therapy is now commonplace, for instance in hypertension, mental illness, diabetes mellitus, peptic, ulceration, and ischaemic heart disease. New therapeutic approaches to chronic illness will probably require long-term drug administration in conditions such as Alzheimer’s disease. There is much to learn about the importance of pharmacological adaptation in chronic drug therapy with respect to its influence on efficacy and the occurrence of adverse reactions and withdrawal syndromes. New treatments will bring new problems to light, for some of these adaptive responses will be difficult to predict. 12. Packer M, Meller J, Medina N, Yushak
M, Gorlin R. Hemodynamic characterization of tolerance to long-term hydralazine therapy in severe chronic heart failure. N Engl J Med 1982, 306: 57-62. 13. Aronson JK, Ford AR, Grahame-Smith DG. Techniques for studying the pharmacodynamic effects of cardiac glycosides on patients’ own erythrocytes during glycoside therapy. Klin Wochenschr 1981; 59: 1323-32. 14. Grahame-Smith DG. The neuropharmacological effects of electroconvulsive shock and their relationship to the therapeutic effect of electroconvulsive therapy in depression. In: Usdin E, et al. Frontiers in biochemical and pharmacological research in depression. New York: Raven, 1984: 327-43. 15. Cowen PJ, Nutt DJ. Abstinence symptoms after withdrawal of tranquillising drugs: is there a common neurochemical mechanism? Lancet 1982; ii: 360-62.
Airflow Limitation—Reversible Irreversible?
or
KNOWING the reversibility of airflow obstruction is important for clinicians and for research, but how should the response be expressed?l,2In particular, it is not clear whether or in what circumstances the response should be expressed in absolute terms, as a percentage of baseline or in relation to the capacity for response (predicted value minus baseline value), nor is it clear where, if anywhere, the arbitrary dividing line between "reversible" and "irreversible" airflow obstruction should be placed. These issues are important since the terms reversible and irreversible are often used to place patients into diagnostic categories such as asthma or chronic obstructive lung disease, with, in some circumstances, implications for prognosis or management. When trying to decide how bronchodilator responsiveness should be expressed, two questions need to be considered. The first is which method of expressing the response best distinguishes a true response to a bronchodilating drug from the inherent variability in the measurement of airflow. The second and more difficult task is to determine which method is giving the most relevant information-relevance depends on the circumstances of the test and may differ between clinical, pharmacological, and epidemiological studies. Two reports by Tweeddale and colleagues3,4 centre on the first question. These workers assessed short-term variability in the measurement of forced expiratory volume in 1 second (FEV 1) in the absence of any drug. They studied a group of 67 subjects with either normal lung function or a restrictive disorder (FEV1 1.1-6.3 litres) and a group of 150 patients with airflow obstruction (FEV, 0-5-47 litres); FEV1 was determined as the best of three readings according to specified criteria on two occasions 20 min apart. The findings were similar in the two groups. There was no significant change in mean FEV1 between the two measurements, and thus no evidence of a learning effect. More relevant to the question of reversibility, the difference in litres between the two measurements was independent of the initial FEV 1; consequently the difference, when expressed as a percentage of initial FEV p increased progressively as FEV1 decreased. These findings suggest that repeatability of FEV measurements should be considered in absolute terms rather than as a percentage of the initial value. These studies were unable to separate the component parts of the
variability-instrument error, patient technique, or true change in airway calibre-but they give a 1. Editorial. Assessment of airflow obstruction. Lancet 1986; ii. 1255-56. 2. Eliasson O, Degraff AC The use of criteria for reversibility and obstruction to define patient groups for bronchodilator trials. Am Rev Respir Dis 1985; 132: 858-64. 3. Tweeddale PM, Merchant S, Leslie M, Alexander F, McHardy GJR. Short term variability in FEV,: relation to pretest activity, level of FEV1, and smoking habits. Thorax 1984; 39: 928-32. 4. Tweeddale PM, Alexander F, McHardy GJR Short term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects. Thorax 1987; 42: 487-90.
27
which the response to a be assessed. Tweeddale et al calculated that, after a drug, a minimum change in FEV1 in the two groups of 190 and 160 ml, respectively, would have been necessary to be more than 95 % confident that an observed change was not due to measurement variability. These workers proceeded to measure the response to 200 µg of salbutamol or 500 ng of terbutaline in the patients with airflow obstruction. The change in FEV after the bronchodilator ranged from - 450 to + 950 ml, with the distribution skewed towards an increase in FEV1. They then assessed two methods of separating "responders" from "non-responders". When responders were defined as those showing an increase in FEVI above the upper 95% confidence interval for natural variability in these subjects (160 ml), patients with a high initial FEV were more likely to be responders. When responders were defined as those showing an increase in FEV of 15 % or more, patients with a low FEV were more likely to be responders. Thus the two methods of expressing the response to a bronchodilator identified different
composite
measure
bronchodilator
against
can
subjects. Tweeddale et al did not look at the repeatability of bronchodilator testing, although this issue is also important. In the large intermittent positive-pressure breathing study in the USA,s the FEV1 response to measured in 985 subjects isoprenaline (250 µg) with chronic obstructive lung disease (COLD) at 3-monthly intervals for nearly 3 years. There was no significant change in the mean response to isoprenaline over this period (a 15 % increase in FEV1) but the within subject variability in response was large-approximately two-thirds of the initial response to isoprenaline. Variability was greatest in patients with a low FEVI, as would be predicted from the Tweeddale study. The mean increase in FEV1 of 15% in these patients with COLD and in whom asthma was specifically excluded is incidentally identical to the figure quoted in an official statement by the American Thoracic Society as being typical of asthma.6This observation accords with several recent studies and surveys in which the change in FEV as a percentage of baseline showed little difference between patients diagnosed as asthma and those diagnosed as chronic bronchitis or COLD.2,7 The change in FEV expressed in absolute terms or as a percentage of predicted, a measure of potential capacity for response, was however able to separate the two groups in one large survey.2 The way in which bronchodilator responses are analysed depends ultimately on the question being was
5. Anthonisen NR, Wright
EC, and the IPPB Trial Group. Bronchodilator response in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 133: 814-19. 6 American Thoracic Society Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136: 225-44. 7. Wardman AG, Binns V, Clayden AD, Cooke NJ. The diagnosis and treatment of adults with obstructive airways disease in general practice. Br J Dis Chest 1986; 80: 19-26.
asked of the test. Use of an absolute change in response to a bronchodilator appears to be better able to separate a true change from chance variation, but if, for example, expressing the response as a percentage of baseline value is a better predictor of clinical outcome (eg, long-term decline in FEVI, or response to corticosteroids) than other methods it may be the more appropriate way to express the results. There is little information in this area, although a study of 129 patients with COLD found that change in FEV was a poor predictor of prognosis when expressed in absolute terms and a much better predictor when related to the capacity to respond as measured by
predicted FEV1 *8 Thus the question of how to express the reversibility of airflow obstruction is far from resolved. Fortunately, this dilemma is seldom important in the clinical setting, where confidence ’
about the true nature of a response to a bronchodilator can be increased by repeat testing, and where the patient’s subjective response is often helpful. Until more answers are available one has to conclude that, outside the immediate clinical setting, the relevance of one of the most commonly used tests of pulmonary function is poorly understood.
DIALYSIS ARTHROPATHY
long-term survivors on haemodialysis have a disabling joint disease commonly known as dialysis arthropathy.9-11 It is characterised by the deposition in bones and synovia of a hitherto unknown type of amyloid composed predominantly of &bgr;2-microglobulin,12-15 and is distinct from the joint problems associated with hyperparathyroidism described in the early days of haemodialysis16 and from any other type of joint disease. The increased incidence of carpal tunnel syndrome, often associated with amyloid deposition, has been recognised in long-term haemodialysis patients for some years. Indeed, most patients on dialysis for more than 15 years have had the disorder; 10,17-19 the first episode seldom occurs before the MANY
severe
and
DS, Gimeno F, van der Weele LT, Sluiter HJ. Assessment of ventilatory vanables in survival prediction of patients with chronic airflow obstruction: the importance of reversibility. Eur J Respir Dis 1985; 67: 360-68. 9. Brown EA, Gower PE. Joint problems in patients on maintenance haemodialysis. Clin Nephrol 1982; 18: 247-50. 10 Brown EA, Arnold IR, Gower PE. Dialysis arthropathy complication of long-term treatment with haemodialysis. Br Med J 1986; 292: 163-66. 11. Munoz-Gomez J, Gomez-Perez R, Llopart-Buisan E, Sole-Argues M. Clinical picture of the amyloid arthropathy in patients with chronic renal failure maintained on haemodialysis using cellulose membranes. Ann Rheum Dis 1987; 46: 573-79 12. Bardin T, Kuntz D, Zingraff J, Voisin MC, Zelmar A, Lansaman J. Synovial amyloidosis in patients undergoing long-term haemodialysis. Arthritis Rheum 8. Postma
1985; 28: 1052-58. 13. Orfila C, Goffinet F, Durroux F, et al
Haemodialysis-associated amyloidosis and beta2, microglobulin deposits in long-term haemodialysis patients. Nephrol Dial Transpl 1987; 2: 448. 14. Sethi D, Woodrow DF, Brown EA, et al. Beta2 microglobulin derived amyloid and iron in dialysis arthropathy. Nephrol Dial Transp 1987; 2: 449. 15. Nakazawa R, Hamaguchi K, Hasaka E, Shishido H, Yokoyama T Synovial amyloidosis of &bgr;2-microglobulin type in patients undergoing long-term haemodialysis Nephron 1987; 44: 379-80. 16. Massry SG, Bluestone R, Klinenberg JR, Cobum JW. Abnormalities of the musculoskeletal system in haemodialysis patients. Sem Arthritis Rheum 1975; 4: 321-49. 17. Schwarz A, Keller F, Syfert S, Poll W, Molzahn M, Distler A. Carpal tunnel syndrome: a major complication in long-term haemodialysis patients. Clin Nephrol 18.
1984; 22: 133-37. Jain UK, Cestero RUM, Baum J. Carpal tunnel syndrome maintenance hemodialysis JAMA 1979; 242: 2868-69.
in
patients
undergoing