- Email: [email protected]
Characteristics and Prognostic Value of Morning Dipping of Peak Expiratory Flow Rate in Stable Asthmatic Subjects
Characteristics and Prognostic Value of Morning Dipping of Peak Expiratory Flow Rate in Stable Asthmatic Subjects· Vincenzo BeUia, M.D.; Fabio Cibella, M.D.; Giovanni Migliara, M.D.; Giuseppe Peralta, M.D.; and Giovanni Bonsignore, M.D., F.C.C.~t
Characteristics and prognostic relevance of morning dip of peak expiratory.Row rate (PEFR) were evaluated in stable asthmatic subjects. Among 246 outpatients monitored four times daily for two weeks, 38 (group A) showed a significant difference between morning reading of PEFR and each of the others; they were compared to 38 randomly selected patients (group B) not showing morning dip in PEFR. Less frequent seasonal course, extrinsic pathogenesis, and sensitization to mites characterized group A; starting airftow limitation was more severe in those with morning dip, but no
H orne monitoring ofbronchial asthma with portable peak Howmeters has allowed the identification of
some patterns of variation of airflow obstruction over time, both on a circadian and a longer term basis. 1.2 In particular, the recurrence of a morning dip of peak expiratory How rate (PEFR) in some cases has confirmed the well-known clinical finding of a possible worsening of asthma during the nighttime sleep; the phenomenon has been extensively investigated in hospitalized patients,3-7 and its role as a risk factor for sudden deaths due to asthma has been underlined. 8.9 Although attention has been drawn to the fact that sudden respiratory arrest from asthma may occur in patients with previously "well-controlled" asthma, 10.11 experience regarding the behavior of morning PEFR in such patients is rather scanty, ~.13 and no prospective evaluation has yet been reported. Therefore, we reviewed our experience regarding an asthma clinic, in order to investigate the following aspects of the phenomenon: (1) the prevalence ofmorning dip among the population of outpatients supposed to be under stable conditions; (2) the main clinical and functional characteristics of those with morning dip; (3) the reversibility ofthe phenomenon in relation to the current therapeutic approaches; and (4) the relevant prognostic significance. MATERIAL AND METHODS
The whole investigation was carried out upon the records relevant *From the Cattedra di Fisiopatologia Respiratoria, University of Palermo and Istituto di Fisiopatologia Respiratoria CNR, Palermo, Italy. Supported by Consiglio Nazionale delle Ricerche grant 82.02159.04 and by Ministero della Pubblica Istruzione. tProfessor of Respiratory Pathophysiology. Manuscript received May 11; revision accepted December 17. Re,Jrint requests: Dr. BeUia, Istituto Medicina Generale e Pneu-
mologia, Via Trabucco lBO, 90146 Palermo, Italy
significant difference between mean PEFR measured throughout two weeks was found. At 6 to 12 weeks, morning dip was not found in 19 of 38 subjects in group A and appeared in seven of38 subjects in group B, with no clearcut relationship to treatment being evident. At 25 to 104 weeks, no significant difference between therapeutic requirements and the forced expiratory volume in one second was detected; therefore, unlike the short-term, morning dip is not a risk factor for worse long-term prognosis.
to outpatients collected from September 1981 through June 1983 by physicians in charge of the asthma clinic of a teaching hospital. All data had been collected before-and independently of-the planning of the present study; and, therefore, no inBuence, whatsoever, was exerted upon all decisions concerning diagnosis and treatment of patients. Protocol Phase 1. The investigation (Fig 1) was initially carried out upon the records relevant to 246 consecutive adolescent or adult asthmatic patients under stable clinical conditions, as defined by the absence of exacerbation of symptoms and of changes in therapeutic regimen during the past three months. All satisfied the criteria for definition ofasthma proposed by the A. C. C. E -A.'[ S. Joint Committee on Pulmonary Nomenclature. 14 After screening by questionnaire, the subjects were submitted to physical examination and spirometric testing (Spirotrac II System; Vitalograph). Then everyone was issued a mini-Wright's peak Bowmeter and instructed to record PEFR at home four times daily (on waking, at lunchtime, in the late afternoon, and at bedtime) for two weeks; on each occasion, three measurements were performed, and the highest one was recorded on a diary chart. During this phase of scrutiny, therapeutic regimens in use before the study were kept unmodified; only the occasional use ofadditional ~-adrenergic stimulants by the aerosol route as needed was allowed, provided it was accurate recorded on the diary chart; however, patients were advised that, independently of the regimen, bronchodilator therapy always should have been preceded by PEFR measurement. At the end of this first monitoring period, a new clinical and functional assessment was performed, including the computerized storage ofPEFR values. Phase 2. On the basis of data collected during the previous phase, suitable therapeutic adjustments were made by physicians in charge. Then monitoring was continued for at least four additional weeks and, in any case, as long as judged necessary on the basis of individual situations. A further evaluation of clinical and functional status was performed at 6 to 12 weeks (median, nine weeks) from the enrollment of patients, along with the collection of PEFR values recorded thus far. Phase 3. Long-term evolution was evaluated at 25 to 104 weeks CHEST / 88 / 1 / JULY, 1985
89
II
Phase
Week
o
2
III
... .......... ......................... .............. ..... ...... 6-12
25-104
Evaluation of morning dip Clin. and Funct. 0 Assessment
Treatment
Unmodified
Modified as Needed
Modified as Needed
(median, 69 weeks) from the beginning of the study, when a final overall assessment was performed.
Methods Prevalence of Morning Dip. This was evaluated on PEFR data coming from phase 1 by applying the analysis of variance to seek for least significant difference between means relevant to the four daily measurements at a probability level of p
As cited previously, a significant morning fall of PEFR was found in 38 out of246 patients, resulting in a prevalence ofIS percent in the overall series. The main characteristics of the two samples, along with the result of statistical analysis, are listed in Table 1; no significant difference was found as far as age, sex, and 80
FIGURE 1. Diagram of design of study.
duration of the syndrome were concerned. Conversely, the differences concerning the fullowing characteristics ofgroup A were significant: a higher proportion of perennial cases; more frequent intrinsic pathogenesis; and rarer occurrence of sensitization to mites. An equal proportion of patients in both groups was reported to experience nighttime or early-morning asthma. As far as functional characteristics are concerned, the behavior of forced expiration is presented in Figure 2; on the average, FEVl was significantly lower in group A at the beginning of the experience, whereas the differences recorded at further controls were found as nonsignificant. If all of the data of daily monitoring Table I-Main Characteristics of the Samples Data
Group A
Group B
No. of subjects Sex Male Female Mean (± SO) age, yr Smoker Yes No Mean (± SO) duration of asthma, yr Course of asthma Perennial Seasonal Pathogenesis of asthma Extrinsic Intrinsic Sensitization Mites Other None Sleep-associated worsening of asthma Yes No
38
38
15 23 35±13
17 21 3O±15
6 32
7 31
9.0±8.4
7.6±7.8
33* 5
29* 9
22
16*
31* 7
lIt 11 16
18 t 13 6
19 19
19 19
*p
100
•
'tJ
characteristic of morning dip included 12 out of the 22 patients who during the previous two weeks had been submitted to administration of a slow-release preparation oftheophylline, as well as one subject who had not received any treatment; the remaining six who shared the loss of morning dip had been put on inhaled 13-adrenergic stimulants alone (one) or in association with beclomethasone dipropionate (five). Finally, no significant difference between median therapeutic needs relevant to phase 3 was recorded, whereas higher requirements characterized group A during the previous two phases (Fig 4).
*
80
U
'ij
• 60
..
a:
;; 40 W
LL
20
o
6-12
25-104 Week
DISCUSSION
2. Behavior of FEV, (expressed as percent of mean predicted value) recorded at beginning of trial (week 0) and at end of three phases in group A (shaded columns) and group B (open columns). Bars represent 1SD. Significant difference is indicated by asterisk (p<0.05). FIGURE
are considered (Fig 3), mean PEFRs recorded during phase 1in the two groups are not significantly different, whereas a slight but significant increase of the index in phase 2, with respect to phase 1, is recorded in each group. Along with this improvement, a significant decrease of the degree of variability within each subject was pointed out, as expressed by mean coefficients of variation (± 1 SO) changing from 14.8 ± 10.4 percent to 8.7 ± 5.2 percent in group A and from 11.4 ±5.9percent to 7.5±5.1percent in group B; these differences were all statistically significant. Concerning reversibility, from Figure 3, it can be seen that in phase 2 the character of morning dip was no longer evident in 50 percent (19) of group A, whereas the opposite (ie, the appearance of a morning dip in phase 2) occurred in seven patients ofthe control group (18 percent); neither event was related to the starting level of functional impairment or to basic clinical characteristics of subjects. It is noteworthy that the subgroup who lost the A
• •
600 ':"c:
'e
~
a:
500 400
LL
w 300
Q.
200 100
Phase
.8.
....
~o
••• I
1-0.-4
.-0
T
••r• •• ~
• L
• .0
•1.
~.
0
0 •• 0 00
0
B 0 0
0
•
0 000 0
~
0
J•
8 8
080
~I-
""1f-
df
00 00 0
or
Y
0
00 0
.**
NS II
The phenomenon of diurnal variation of asthmatic symptoms has long been known and has been functionally demonstrated since the early 1960s;16 however, only recently has it been underlined that deterioration of respiratory function occurring during sleep may represent a potential risk factor. Sudden death from asthma has been shown retrospectively to occur more frequently from midnight to 8 AM,17 whereas the incidence of unexpected ventilatory arrest correlated with the presence of excessive diurnal variation of PEFR with an early morning fall. S As most deaths due to asthma occur outside a hospital1s. 19 and not rarely as a consequence of sudden attacks bursting out of an apparently stable picture, we designed our study in order to perform as wide a screening of morning dip as possible in a population featuring most of the clinical situations occurring in the current outpatient practice. In order to rule out oscillations due to random variability, as well as regular patterns other than morning dip, we decided to take into account only those cases in whom morning reading differed significantly from each of the other measurements, regardless of the amount of this difference. On the basis of such a conservative approach, the prevalence of the
NS
**II
FIGURE 3. Mean value of PEFR recorded throughout phase 1 and 2 in each subject of group A (left) and B (right). Solid symbols refer to those with morning dip, open symbols refer to those without dip. Horizontal bars represent mean value for group. Significant differences are indicated by asterisks (p<0.0l). NS. not significant.
CHEST I 88 I 1 I JULY. 1985
91
3
-
o-
=
........
0
...
0 0000
................ ....
•
••
00 0000
....
00 0000 0000 0000
....
0000 0000 0000 0000
..••••.........• .... .... .... .... ....
A
B
A
B
A
....
0000 0000 0000
000 0000 0000
•••
**
Phase I
eM
000 0000 0000
••
*
Phase II
000 0000 0000
00 0000
00 0000
8888
NS
0000
B
Phase III
phenomenon in our series is lower than those reported in the literature;8,12,13,20 although the stringency of the criterion for quantitative definition ofmorning dipping may partially account for such a finding, differences in the characteristics of investigated samples may give an additional explanation. In fact, previous reports either deal with hospital series8,20 or are concerned with selected outpatient samples, such as subjects just discharged from the hospital13 or, in any case, all showing airflow obstruction during the course of the investigation. 12 On the average, these samples featured situations more severe than in patients of our series who shared only the characteristic of clinical stability, even though within the context of different situations ranging from latent asthma to chronic (although well tolerated) aitway obstruction. This difference in prevalence may be explained by the view that morning dipping is a reHection of the severity ofasthma, rather than a distinguishing feature of any specific syndrome. 21 In fact, no unique interpretation ofthe phenomenon is allowed on the basis of the few differences found between the characteristics ofthe two groups; the finding ofa lower prevalence of extrinsic pathogenesis and, in particular, of hypersensitivity to house dust mites among those with morning dip, only confirms that the latter21 or even atopy does not seem to play an important role in the genesis of the phenomenon. On the other hand, support for the previously cited view seems to be lent by the worse functional picture showed by those with morning dip at the beginning ofthe experience (Fig 2); however, if all of the PEFR values of the first monitoring phase are taken into account, comparable levels of functional impairment are found. In other terms the most prominent difference between groups is likely to be relevant not to the severity of the picture, but to an enhanced variability ofbronchomotor tone throughout 82
000
FIGURE 4. Therapeutic scores of three phases (see text) relevant to each subject in group A (solid symbols) and group B (open symbols). Single asterisk indicates significant difference (p
the day. Therefore, at least in stable asthma, the occurrence of a nighttime deterioration in a single patient cannot always be correlated with the overall level ofairway obstruction and consequently cannot be reliably anticipated on the basis of any episodic assessment of impairment of pulmonary function performed during the day. The need of monitoring at home that stems out of these considerations is even more evident if one considers the variable reliability of case histories; in fact, the unawareness of a morning dip, shown by half of group A confirms the reduced sensitivity toward minor oscillations in their obstruction seen in some asthmatic subjects. 22,23 On the other hand, the evidence of an equal proportion of those without morning dip reporting a nocturnal worsening, points out that the phenomenon may be temporary and reversible, so as to be cited in the history, although not being demonstrable in that very phase of the disease. Support for this view is lent by the results of phase 220. Remission of the morning fall in PEFR occurred in half of the cases in connection with heterogeneous treatments, mainly based on associations always including sympathomimetic drugs; although in a general sense, this result may be interpreted in the light of the role played by an early morning reduction of plasma epinephrine as a causative factor of morning dip, 5 evidence coming from the overall series is somewhat more intriguing. First, no distinguishing basic characteristic was found in subjects showing reverSibility; secondly, therapeutic adjustments with respect to phase 1 were performed only in a minority of subjects (four, who were put on associated therapy). Thirdly, remission occurred without apparent cause in one subject. Finally, among the 22 subjects whose treatment included the preparation presumably most effective in preventing nocturnal asthma (ie, sustainedPeak Expiratory Flow and Stable Asthma (Bel1I8 et III)
action aminophylline24), a failure was recorded in ten; even though no information was available in the notes as to plasma levels of the drug, previous unpublished experiences relevant to the specific drug used in this study indicate that therapeutic concentrations are usually attainable for as long as 12 hours in most adult patients by the standard dosage suggested by the manufacturer and used throughout this study. In addition, no evidence of factors possibly affecting clearance of theophylline was recorded in our patients, who in the vast majority were nonsmokers. The response to therapy in our series may be compared with a previously reported one25 in which, in spite of apparent therapeutic levels of bronchodilator drugs, an objective improvement of PEFR was shown in half of the patients only, and diurnal pattern was not abolished. A thorough assessment of the relevant effectiveness of different treatment was beyond the aims ofthe present study; nevertheless, the bulk of evidence coming from this investigation, including the unexpected appearance of morning dip in group B, suggests that, like pathogenesis is unclear, the evolution ofthe phenomenon over time, either spontaneously or in response to "adequate" treatment, is also hardly predictable. In the light of this variable behavioJ; it is not surprising that no correlation could be found between the finding of a recurrent morning dip in a certain phase of the disease and long-term evolution of the process (phase 3); in fact, the phenomenon may be regarded as the hallmark of a transient increase in airway susceptibility to endogenous or exogenous precipitating factors acting during nighttime sleep and, as such, more likely related to variations of the clinical picture occurring within a short time. Unfortunately, our observations about short-term outcome (phase 2) cannot be applied to test this hypothesis, since they were affected by therapeutic decisions which, in turn, may have been influenced by the phenomenon under investigation. Nevertheless, the results of previously cited experiences,8.9 although relevant to different contexts, as well as the consideration of the relatively low cost of the procedure, warrant the application of home monitoring to the evaluation of all asthmatic subjects, even in their allegedly asymptomatic phase, where the unfavorable prognostic meaning of an increased variability of PEFR has already been demonstrated. 23 Should a morning dip be found, every effort should be made not only to abolish this fastidious phenomenon itsel( but, more importantly, to correct the underlying condition of exaggerated airway reactivity, since the latter may lead to the exacerbation of the syndrome.
REFERENCES 1 Turner-Warwick M. On observing patterns ofairflow obstruction in chronic asthma. Br J Dis Chest 1977; 71:73-86 2 Bellia ~ Cibella F, Migliara G, Oddo S, Peralta G, Mangiacavalloa A. II monitoraggio funzionale dell'asma bronchiale. Lotta Tuberc Mal Polm Soc 1984; 53:683-92 3 Soutar CA, Castell J, Ijanduola 0, Turner-Warwick M. Nocturnal and morning asthma: relationship to plasma corticosteroids and response to cortisol infusion. Thorax 1975; 30:436-40 4 Hetzel MR, Clark TJH. Does sleep cause nocturnal asthma? Thorax 1979; 34:749-54 5 Barnes ~ Fitzgerald G, Brown M, Dollery C: Nocturnal asthma and changes in circulating epinephrine, histamine and cortisol. N Engl J Med 1980; 303:263-71 6 Montplaisir J, Walsh J, Malo JL. Nocturnal asthma: features of attacks, sleep and breathing pattern. Am Rev Respir Dis 1982; 125:18-22 7 Damluji SAL, Thompson PJ, Citron KM, Turner-Warwick M. Effect of naloxone on circadian rhythms in lung function. Thorax 1983; 38:914-18 8 Hetzel MR, Clark TJH, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977; 1:808-11 9 Bateman JRM, Clarke SW Sudden death in asthma. Thorax 1979; 34:40-4 10 William MH, Levin M. Sudden death from bronchial asthma. Am Rev Respir Dis 1966; 94:608-11 11 Galay EL. Sudden respiratory arrest from asthma. Chest 1982; 82:387 12 Bagg LR, Hughes DTD. Diurnal variation in peak expiratory flow in asthmatics. Eur J Respir Dis 1980; 61:298-302 13 Hetzel MR, Clark TJH. Comparison of normal and asthmatic circadian rhythms in peak expiratory 80w rate. Thorax 1980; 35:732-38 14 ACCP-ATS joint Committee on Pulmonary Nomenclature. Pulmonary terms and symbols. Chest 1975; 67:583-93 15 Snedecor G~ Cochran WG. Statistical methods. 7th edt Ames, Ia: Iowa State University Press, 1980:233 16 Lewinsohn HC, Capel L, Smart G. Changes in FEV throughout the day. Br Med J 1960; 1:462-64 17 Cochrane GM, Clark TJH. A survey of asthma mortality in patients between ages 35 and 64 in the greater London hospitals in 1971. Thorax 1975; 30:300-05 18 McDonald JB, Seaton A, Williams DA. Asthma deaths in Cardif( 1963-74: 90 deaths outside hospital. Br Moo J 1976; 1:1493-95 19 Ormerad L~ Stableforth DE. Asthma mortality in Birmingham, 1975-7. Br Med J 1980; 1:687-90 20 Connolly CK. Diurnal rhythms in airway obstruction. Br J Dis Chest 1979; 73:357-66 21 Connolly CK. House dust mite hypersensitivity: morning dipping and severity of wheeze. Respiration 1981; 42:258-62 22 Rubinfeld AR, Pain MCR How mild is mild asthma? Thorax 1977; 32:177-81 23 Bellia ~ Cibella F: Coppola ~ Greco ~ Insalaco G, Milone F: et ale Variability ofpeak expiratory flow rate as a prognostic index in asymptomatic asthma. Respiration 1984; 46:328-33 24 Barnes Pj, Greening A~ Neville L, Rimmers J, Poole GW. Single-dose slow-release aminophylline at night prevents nocturnal asthma. Lancet 1982; 1:299-301 25 Fairfax Aj, Nabb WR, Davies HJ, Spiro SG. Slow-release oral salbutamol and aminophylline in nocturnal asthma: relation of overnight changes in lung function and plasma drug levels. Thorax 1980; 35:526-30
CHEST I 88 I 1 I JULY, 1985
93
Characteristics and prognostic relevance of morning dip of peak expiratory.Row rate (PEFR) were evaluated in stable asthmatic subjects. Among 246 outpatients monitored four times daily for two weeks, 38 (group A) showed a significant difference between morning reading of PEFR and each of the others; they were compared to 38 randomly selected patients (group B) not showing morning dip in PEFR. Less frequent seasonal course, extrinsic pathogenesis, and sensitization to mites characterized group A; starting airftow limitation was more severe in those with morning dip, but no
H orne monitoring ofbronchial asthma with portable peak Howmeters has allowed the identification of
some patterns of variation of airflow obstruction over time, both on a circadian and a longer term basis. 1.2 In particular, the recurrence of a morning dip of peak expiratory How rate (PEFR) in some cases has confirmed the well-known clinical finding of a possible worsening of asthma during the nighttime sleep; the phenomenon has been extensively investigated in hospitalized patients,3-7 and its role as a risk factor for sudden deaths due to asthma has been underlined. 8.9 Although attention has been drawn to the fact that sudden respiratory arrest from asthma may occur in patients with previously "well-controlled" asthma, 10.11 experience regarding the behavior of morning PEFR in such patients is rather scanty, ~.13 and no prospective evaluation has yet been reported. Therefore, we reviewed our experience regarding an asthma clinic, in order to investigate the following aspects of the phenomenon: (1) the prevalence ofmorning dip among the population of outpatients supposed to be under stable conditions; (2) the main clinical and functional characteristics of those with morning dip; (3) the reversibility ofthe phenomenon in relation to the current therapeutic approaches; and (4) the relevant prognostic significance. MATERIAL AND METHODS
The whole investigation was carried out upon the records relevant *From the Cattedra di Fisiopatologia Respiratoria, University of Palermo and Istituto di Fisiopatologia Respiratoria CNR, Palermo, Italy. Supported by Consiglio Nazionale delle Ricerche grant 82.02159.04 and by Ministero della Pubblica Istruzione. tProfessor of Respiratory Pathophysiology. Manuscript received May 11; revision accepted December 17. Re,Jrint requests: Dr. BeUia, Istituto Medicina Generale e Pneu-
mologia, Via Trabucco lBO, 90146 Palermo, Italy
significant difference between mean PEFR measured throughout two weeks was found. At 6 to 12 weeks, morning dip was not found in 19 of 38 subjects in group A and appeared in seven of38 subjects in group B, with no clearcut relationship to treatment being evident. At 25 to 104 weeks, no significant difference between therapeutic requirements and the forced expiratory volume in one second was detected; therefore, unlike the short-term, morning dip is not a risk factor for worse long-term prognosis.
to outpatients collected from September 1981 through June 1983 by physicians in charge of the asthma clinic of a teaching hospital. All data had been collected before-and independently of-the planning of the present study; and, therefore, no inBuence, whatsoever, was exerted upon all decisions concerning diagnosis and treatment of patients. Protocol Phase 1. The investigation (Fig 1) was initially carried out upon the records relevant to 246 consecutive adolescent or adult asthmatic patients under stable clinical conditions, as defined by the absence of exacerbation of symptoms and of changes in therapeutic regimen during the past three months. All satisfied the criteria for definition ofasthma proposed by the A. C. C. E -A.'[ S. Joint Committee on Pulmonary Nomenclature. 14 After screening by questionnaire, the subjects were submitted to physical examination and spirometric testing (Spirotrac II System; Vitalograph). Then everyone was issued a mini-Wright's peak Bowmeter and instructed to record PEFR at home four times daily (on waking, at lunchtime, in the late afternoon, and at bedtime) for two weeks; on each occasion, three measurements were performed, and the highest one was recorded on a diary chart. During this phase of scrutiny, therapeutic regimens in use before the study were kept unmodified; only the occasional use ofadditional ~-adrenergic stimulants by the aerosol route as needed was allowed, provided it was accurate recorded on the diary chart; however, patients were advised that, independently of the regimen, bronchodilator therapy always should have been preceded by PEFR measurement. At the end of this first monitoring period, a new clinical and functional assessment was performed, including the computerized storage ofPEFR values. Phase 2. On the basis of data collected during the previous phase, suitable therapeutic adjustments were made by physicians in charge. Then monitoring was continued for at least four additional weeks and, in any case, as long as judged necessary on the basis of individual situations. A further evaluation of clinical and functional status was performed at 6 to 12 weeks (median, nine weeks) from the enrollment of patients, along with the collection of PEFR values recorded thus far. Phase 3. Long-term evolution was evaluated at 25 to 104 weeks CHEST / 88 / 1 / JULY, 1985
89
II
Phase
Week
o
2
III
... .......... ......................... .............. ..... ...... 6-12
25-104
Evaluation of morning dip Clin. and Funct. 0 Assessment
Treatment
Unmodified
Modified as Needed
Modified as Needed
(median, 69 weeks) from the beginning of the study, when a final overall assessment was performed.
Methods Prevalence of Morning Dip. This was evaluated on PEFR data coming from phase 1 by applying the analysis of variance to seek for least significant difference between means relevant to the four daily measurements at a probability level of p
As cited previously, a significant morning fall of PEFR was found in 38 out of246 patients, resulting in a prevalence ofIS percent in the overall series. The main characteristics of the two samples, along with the result of statistical analysis, are listed in Table 1; no significant difference was found as far as age, sex, and 80
FIGURE 1. Diagram of design of study.
duration of the syndrome were concerned. Conversely, the differences concerning the fullowing characteristics ofgroup A were significant: a higher proportion of perennial cases; more frequent intrinsic pathogenesis; and rarer occurrence of sensitization to mites. An equal proportion of patients in both groups was reported to experience nighttime or early-morning asthma. As far as functional characteristics are concerned, the behavior of forced expiration is presented in Figure 2; on the average, FEVl was significantly lower in group A at the beginning of the experience, whereas the differences recorded at further controls were found as nonsignificant. If all of the data of daily monitoring Table I-Main Characteristics of the Samples Data
Group A
Group B
No. of subjects Sex Male Female Mean (± SO) age, yr Smoker Yes No Mean (± SO) duration of asthma, yr Course of asthma Perennial Seasonal Pathogenesis of asthma Extrinsic Intrinsic Sensitization Mites Other None Sleep-associated worsening of asthma Yes No
38
38
15 23 35±13
17 21 3O±15
6 32
7 31
9.0±8.4
7.6±7.8
33* 5
29* 9
22
16*
31* 7
lIt 11 16
18 t 13 6
19 19
19 19
*p
100
•
'tJ
characteristic of morning dip included 12 out of the 22 patients who during the previous two weeks had been submitted to administration of a slow-release preparation oftheophylline, as well as one subject who had not received any treatment; the remaining six who shared the loss of morning dip had been put on inhaled 13-adrenergic stimulants alone (one) or in association with beclomethasone dipropionate (five). Finally, no significant difference between median therapeutic needs relevant to phase 3 was recorded, whereas higher requirements characterized group A during the previous two phases (Fig 4).
*
80
U
'ij
• 60
..
a:
;; 40 W
LL
20
o
6-12
25-104 Week
DISCUSSION
2. Behavior of FEV, (expressed as percent of mean predicted value) recorded at beginning of trial (week 0) and at end of three phases in group A (shaded columns) and group B (open columns). Bars represent 1SD. Significant difference is indicated by asterisk (p<0.05). FIGURE
are considered (Fig 3), mean PEFRs recorded during phase 1in the two groups are not significantly different, whereas a slight but significant increase of the index in phase 2, with respect to phase 1, is recorded in each group. Along with this improvement, a significant decrease of the degree of variability within each subject was pointed out, as expressed by mean coefficients of variation (± 1 SO) changing from 14.8 ± 10.4 percent to 8.7 ± 5.2 percent in group A and from 11.4 ±5.9percent to 7.5±5.1percent in group B; these differences were all statistically significant. Concerning reversibility, from Figure 3, it can be seen that in phase 2 the character of morning dip was no longer evident in 50 percent (19) of group A, whereas the opposite (ie, the appearance of a morning dip in phase 2) occurred in seven patients ofthe control group (18 percent); neither event was related to the starting level of functional impairment or to basic clinical characteristics of subjects. It is noteworthy that the subgroup who lost the A
• •
600 ':"c:
'e
~
a:
500 400
LL
w 300
Q.
200 100
Phase
.8.
....
~o
••• I
1-0.-4
.-0
T
••r• •• ~
• L
• .0
•1.
~.
0
0 •• 0 00
0
B 0 0
0
•
0 000 0
~
0
J•
8 8
080
~I-
""1f-
df
00 00 0
or
Y
0
00 0
.**
NS II
The phenomenon of diurnal variation of asthmatic symptoms has long been known and has been functionally demonstrated since the early 1960s;16 however, only recently has it been underlined that deterioration of respiratory function occurring during sleep may represent a potential risk factor. Sudden death from asthma has been shown retrospectively to occur more frequently from midnight to 8 AM,17 whereas the incidence of unexpected ventilatory arrest correlated with the presence of excessive diurnal variation of PEFR with an early morning fall. S As most deaths due to asthma occur outside a hospital1s. 19 and not rarely as a consequence of sudden attacks bursting out of an apparently stable picture, we designed our study in order to perform as wide a screening of morning dip as possible in a population featuring most of the clinical situations occurring in the current outpatient practice. In order to rule out oscillations due to random variability, as well as regular patterns other than morning dip, we decided to take into account only those cases in whom morning reading differed significantly from each of the other measurements, regardless of the amount of this difference. On the basis of such a conservative approach, the prevalence of the
NS
**II
FIGURE 3. Mean value of PEFR recorded throughout phase 1 and 2 in each subject of group A (left) and B (right). Solid symbols refer to those with morning dip, open symbols refer to those without dip. Horizontal bars represent mean value for group. Significant differences are indicated by asterisks (p<0.0l). NS. not significant.
CHEST I 88 I 1 I JULY. 1985
91
3
-
o-
=
........
0
...
0 0000
................ ....
•
••
00 0000
....
00 0000 0000 0000
....
0000 0000 0000 0000
..••••.........• .... .... .... .... ....
A
B
A
B
A
....
0000 0000 0000
000 0000 0000
•••
**
Phase I
eM
000 0000 0000
••
*
Phase II
000 0000 0000
00 0000
00 0000
8888
NS
0000
B
Phase III
phenomenon in our series is lower than those reported in the literature;8,12,13,20 although the stringency of the criterion for quantitative definition ofmorning dipping may partially account for such a finding, differences in the characteristics of investigated samples may give an additional explanation. In fact, previous reports either deal with hospital series8,20 or are concerned with selected outpatient samples, such as subjects just discharged from the hospital13 or, in any case, all showing airflow obstruction during the course of the investigation. 12 On the average, these samples featured situations more severe than in patients of our series who shared only the characteristic of clinical stability, even though within the context of different situations ranging from latent asthma to chronic (although well tolerated) aitway obstruction. This difference in prevalence may be explained by the view that morning dipping is a reHection of the severity ofasthma, rather than a distinguishing feature of any specific syndrome. 21 In fact, no unique interpretation ofthe phenomenon is allowed on the basis of the few differences found between the characteristics ofthe two groups; the finding ofa lower prevalence of extrinsic pathogenesis and, in particular, of hypersensitivity to house dust mites among those with morning dip, only confirms that the latter21 or even atopy does not seem to play an important role in the genesis of the phenomenon. On the other hand, support for the previously cited view seems to be lent by the worse functional picture showed by those with morning dip at the beginning ofthe experience (Fig 2); however, if all of the PEFR values of the first monitoring phase are taken into account, comparable levels of functional impairment are found. In other terms the most prominent difference between groups is likely to be relevant not to the severity of the picture, but to an enhanced variability ofbronchomotor tone throughout 82
000
FIGURE 4. Therapeutic scores of three phases (see text) relevant to each subject in group A (solid symbols) and group B (open symbols). Single asterisk indicates significant difference (p
the day. Therefore, at least in stable asthma, the occurrence of a nighttime deterioration in a single patient cannot always be correlated with the overall level ofairway obstruction and consequently cannot be reliably anticipated on the basis of any episodic assessment of impairment of pulmonary function performed during the day. The need of monitoring at home that stems out of these considerations is even more evident if one considers the variable reliability of case histories; in fact, the unawareness of a morning dip, shown by half of group A confirms the reduced sensitivity toward minor oscillations in their obstruction seen in some asthmatic subjects. 22,23 On the other hand, the evidence of an equal proportion of those without morning dip reporting a nocturnal worsening, points out that the phenomenon may be temporary and reversible, so as to be cited in the history, although not being demonstrable in that very phase of the disease. Support for this view is lent by the results of phase 220. Remission of the morning fall in PEFR occurred in half of the cases in connection with heterogeneous treatments, mainly based on associations always including sympathomimetic drugs; although in a general sense, this result may be interpreted in the light of the role played by an early morning reduction of plasma epinephrine as a causative factor of morning dip, 5 evidence coming from the overall series is somewhat more intriguing. First, no distinguishing basic characteristic was found in subjects showing reverSibility; secondly, therapeutic adjustments with respect to phase 1 were performed only in a minority of subjects (four, who were put on associated therapy). Thirdly, remission occurred without apparent cause in one subject. Finally, among the 22 subjects whose treatment included the preparation presumably most effective in preventing nocturnal asthma (ie, sustainedPeak Expiratory Flow and Stable Asthma (Bel1I8 et III)
action aminophylline24), a failure was recorded in ten; even though no information was available in the notes as to plasma levels of the drug, previous unpublished experiences relevant to the specific drug used in this study indicate that therapeutic concentrations are usually attainable for as long as 12 hours in most adult patients by the standard dosage suggested by the manufacturer and used throughout this study. In addition, no evidence of factors possibly affecting clearance of theophylline was recorded in our patients, who in the vast majority were nonsmokers. The response to therapy in our series may be compared with a previously reported one25 in which, in spite of apparent therapeutic levels of bronchodilator drugs, an objective improvement of PEFR was shown in half of the patients only, and diurnal pattern was not abolished. A thorough assessment of the relevant effectiveness of different treatment was beyond the aims ofthe present study; nevertheless, the bulk of evidence coming from this investigation, including the unexpected appearance of morning dip in group B, suggests that, like pathogenesis is unclear, the evolution ofthe phenomenon over time, either spontaneously or in response to "adequate" treatment, is also hardly predictable. In the light of this variable behavioJ; it is not surprising that no correlation could be found between the finding of a recurrent morning dip in a certain phase of the disease and long-term evolution of the process (phase 3); in fact, the phenomenon may be regarded as the hallmark of a transient increase in airway susceptibility to endogenous or exogenous precipitating factors acting during nighttime sleep and, as such, more likely related to variations of the clinical picture occurring within a short time. Unfortunately, our observations about short-term outcome (phase 2) cannot be applied to test this hypothesis, since they were affected by therapeutic decisions which, in turn, may have been influenced by the phenomenon under investigation. Nevertheless, the results of previously cited experiences,8.9 although relevant to different contexts, as well as the consideration of the relatively low cost of the procedure, warrant the application of home monitoring to the evaluation of all asthmatic subjects, even in their allegedly asymptomatic phase, where the unfavorable prognostic meaning of an increased variability of PEFR has already been demonstrated. 23 Should a morning dip be found, every effort should be made not only to abolish this fastidious phenomenon itsel( but, more importantly, to correct the underlying condition of exaggerated airway reactivity, since the latter may lead to the exacerbation of the syndrome.
REFERENCES 1 Turner-Warwick M. On observing patterns ofairflow obstruction in chronic asthma. Br J Dis Chest 1977; 71:73-86 2 Bellia ~ Cibella F, Migliara G, Oddo S, Peralta G, Mangiacavalloa A. II monitoraggio funzionale dell'asma bronchiale. Lotta Tuberc Mal Polm Soc 1984; 53:683-92 3 Soutar CA, Castell J, Ijanduola 0, Turner-Warwick M. Nocturnal and morning asthma: relationship to plasma corticosteroids and response to cortisol infusion. Thorax 1975; 30:436-40 4 Hetzel MR, Clark TJH. Does sleep cause nocturnal asthma? Thorax 1979; 34:749-54 5 Barnes ~ Fitzgerald G, Brown M, Dollery C: Nocturnal asthma and changes in circulating epinephrine, histamine and cortisol. N Engl J Med 1980; 303:263-71 6 Montplaisir J, Walsh J, Malo JL. Nocturnal asthma: features of attacks, sleep and breathing pattern. Am Rev Respir Dis 1982; 125:18-22 7 Damluji SAL, Thompson PJ, Citron KM, Turner-Warwick M. Effect of naloxone on circadian rhythms in lung function. Thorax 1983; 38:914-18 8 Hetzel MR, Clark TJH, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977; 1:808-11 9 Bateman JRM, Clarke SW Sudden death in asthma. Thorax 1979; 34:40-4 10 William MH, Levin M. Sudden death from bronchial asthma. Am Rev Respir Dis 1966; 94:608-11 11 Galay EL. Sudden respiratory arrest from asthma. Chest 1982; 82:387 12 Bagg LR, Hughes DTD. Diurnal variation in peak expiratory flow in asthmatics. Eur J Respir Dis 1980; 61:298-302 13 Hetzel MR, Clark TJH. Comparison of normal and asthmatic circadian rhythms in peak expiratory 80w rate. Thorax 1980; 35:732-38 14 ACCP-ATS joint Committee on Pulmonary Nomenclature. Pulmonary terms and symbols. Chest 1975; 67:583-93 15 Snedecor G~ Cochran WG. Statistical methods. 7th edt Ames, Ia: Iowa State University Press, 1980:233 16 Lewinsohn HC, Capel L, Smart G. Changes in FEV throughout the day. Br Med J 1960; 1:462-64 17 Cochrane GM, Clark TJH. A survey of asthma mortality in patients between ages 35 and 64 in the greater London hospitals in 1971. Thorax 1975; 30:300-05 18 McDonald JB, Seaton A, Williams DA. Asthma deaths in Cardif( 1963-74: 90 deaths outside hospital. Br Moo J 1976; 1:1493-95 19 Ormerad L~ Stableforth DE. Asthma mortality in Birmingham, 1975-7. Br Med J 1980; 1:687-90 20 Connolly CK. Diurnal rhythms in airway obstruction. Br J Dis Chest 1979; 73:357-66 21 Connolly CK. House dust mite hypersensitivity: morning dipping and severity of wheeze. Respiration 1981; 42:258-62 22 Rubinfeld AR, Pain MCR How mild is mild asthma? Thorax 1977; 32:177-81 23 Bellia ~ Cibella F: Coppola ~ Greco ~ Insalaco G, Milone F: et ale Variability ofpeak expiratory flow rate as a prognostic index in asymptomatic asthma. Respiration 1984; 46:328-33 24 Barnes Pj, Greening A~ Neville L, Rimmers J, Poole GW. Single-dose slow-release aminophylline at night prevents nocturnal asthma. Lancet 1982; 1:299-301 25 Fairfax Aj, Nabb WR, Davies HJ, Spiro SG. Slow-release oral salbutamol and aminophylline in nocturnal asthma: relation of overnight changes in lung function and plasma drug levels. Thorax 1980; 35:526-30
CHEST I 88 I 1 I JULY, 1985
93