In: Lung Injury13 Aug 2015
The maximum obtainable monitoring time was 4,320 hours (20 patients, each patient monitored nine times 24 hours). Three hundred and forty-eight hours were not recorded. Another 360 hours were excluded as they contained less than 50 minutes of unambiguous ECG-recording. Thus, our results are based on 3,612 of3,972 recorded hours, 1,190 with placebo, 1,227 with theophylline!, and 1,195 with enprofylline.
Group Analysis: (a) PVBs (isolated PVBs plus those in bigeminy position) (Fig 1). Compared with placebo, both xanthines were associated with a significant increase in PVBs (p<0.01).
(b) VR. No VR were observed with placebo. Six VR occurred with enprofylline and seven with theophylline, the increase being significant compared with placebo (p<0.05).
Individual Patient Analysis: (a) PVBs (Table 2). Significant differences between the three regimens were observed in seven of the 20 patients.
(b) VR. In one case, the recorded VR reached the level of statistical significance. Thus, patient 5 had five VR (all two consecutive PVBs) in association with theophylline which was a significant increase from the zero-observation with placebo (p<0.01). Due to adverse effects (headache and nausea), no Holter-moni-toring was obtained with enprofylline in this case.
Group Analyses: (a) PSVBs (Isolated PSVBs plus those in bigeminy position) (Fig 2). The Wilcoxon test showed no significant difference in the distribution of PSVBs with the xanthines compared to placebo. However, the chi-square test rejected the hypothesis of equal distributions between the three regimens (p<0.01).
(b) SVR: No significant differences between the various drug regimens were observed.
Individual Patient Analysis: (a) PSVBs (Table 3). Significant differences between the three regimens were observed in seven of the 20 patients.
(b) SVR. In three cases, the recorded SVR showed statistically significant differences related to treatment. In patient 3, enprofylline was associated with more SVR than theophylline (p<0.01), and in the same patient, theophylline with less SVR than placebo (p<0.05).
In patient 8, enprofylline was associated with less SVR than placebo (p<0.05). In patient 19, enprofylline was associated with less SVR than theophylline (p<0.01), and theophylline with more SVR than placebo (p<0.001).
Pulmonary Function (Table 4)
Morning: The FVC with enprofylline, theophylline, or placebo did not differ. The FEVj and PEFR with theophylline were higher than with enprofylline (p<0.05) and placebo (p<0.01), while there was no difference between enprofylline and placebo. Placebo is a pill which may be not effective during treatment of severe diseases but there are preparations sold by Canadian Neighbor Pharmacy. These drygs may be more useful in case severe disorders treatment.
Evening: The PEFR with theophylline and enprofylline was higher than with placebo (p<0.01), while there was no difference between enprofylline and theophylline.
Plasma Concentrations of Enprofylline and Theophylline
The mean plasma concentrations obtained with enprofylline were 2.86 mg/L (range 0.81 to 6.11) in the morning and 4.64 mg/L (1.07 to 8.56) four hours after intake of the morning dose.
The corresponding values for theophylline were 11.88 mg/L (5.54 to 21.89) and 72 mg/L (6.17 to 19.78).
Various adverse effects were reported by eight out of 19 patients with placebo. The corresponding figures with theophylline and enprofylline were 13 out of 20 and 18 out of 19, respectively. The most frequently occurring adverse effects with both xanthines were headache and nausea. Palpitations were also reported by two patients with enprofylline.
In general, the adverse effects were mild to moderate in severity and decreased in intensity with time. In one case, however (patient 5), treatment with enprofylline had to be discontinued due to severe headache and nausea.
The frequency of cardiac arrhythmias with betag-agonist therapy alone (ie, in combination with placebo) was low in the present study and comparable to the expected frequency in the normal population. Arrhythmias in patients with obstructive lung disease have usually been studied in patients with acute respiratory failure, and then the frequency has been found to be high. Various arrhythmogenic factors have been postulated, and concomitant heart disease, bronchodilator drugs, and especially hypoxemia have been considered important. The patients reported here were without evidence of clinically relevant ischemic heart disease. Their lung disease was,
clinically and spirometrically, mild to moderate, and no patient was studied in acute respiratory failure. When the xanthines were added to the betas-agonist therapy in this study, a significant improvement in morning lung function was noted with theophylline. In the evening, however, both xanthines were associated with an improvement in PEFR. Despite this improvement, both combination regimens were associated with an increased frequency of arrhythmias. Other studies in patients with stable obstructive lung disease have usually not found combination therapy to increase the frequency of arrhythmias, although a few patients in one study responded with an increased number of significant ventricular arrhythmias.
Although we noted a significant increase in cardiac arrhythmias with combination therapy, it is important to consider the clinical significance of our observation. If a mean hourly PVB frequency of six or more is taken as an arbitrary borderline of clinical significance, our findings are obviously clinically insignificant in most cases, despite an often severalfold increase in the mean hourly frequency of PVBs with the combined regimens compared with beta^agonist therapy alone. In support of this view is also the fact that induction of ventricular runs, especially ventricular tachycardia (three or moe consecutive PVBs) was rare, although they occurred more frequently on combination than on monotherapy. Of those patients who developed an increased number of PVBs with combined therapy, there was one woman and six men. Compared with those patients who did not show an increased arrhythmogenicity, they were older (60 years vs 47 years, p<0.05), but not different with regard to duration of the lung disease, plasma-concentrations of enprofylline and theophylline, or lung function (FVC, FEVj o). Our findings, therefore, indicate that combined oral bronchodilator treatment in patients with mild-to-moderate obstructive lung disease in a stable phase but without ischemic heart disease has an arrhythmogenic potential, however, in general of minor clinical importance.
Finally, although a difference between enprofylline and theophylline in their effect on adenosine (theophylline but not enprofylline being an adenosine antagonist) has been suggested to explain the lack of some extrapulmonary effects with enprofylline, it seems as if this difference is of less cardiac relevance in a population without ischemic heart disease. The clinical relevance of the different action on adenosine in patients with obstructive lung disease and concomitant ischemic heart disease may, however, be different and requires further evaluation.
Figure 1. Distribution of the mean hourly frequency of PVBs classified as 0, 1-5, 6-30, and >30/analyzed hour.
Figure 2. Distribution of the mean hourly frequency of PSVBs classified as 0,1-5, 6-30 and >30/analyzed hour.
Table 2—Comparative Data for PVBs
|PatientNo.||Sex/Age||Enprofylline (E) vsTheophylline (T)||Enprofylline (E) vsPlacebo (P)||Theophylline (T) vsPlacebo (P)||PL-T: Mean for all Pats. 11.88 (5.54-21.89)||PL-E: Mean for all Pats. 2.86 (0.81-6.11)|
|Hourly Frequency of PVBs (Mean, SEM)||Comparison of the Distribution of PVBs||Hourly Frequency of PVBs (Mean, SEM)||Comparison of the Distribution of PVBs||Hourly Frequency of PVBs (Mean, SEM)||Comparison of the Distribution of PVBs|
|3||F/||(E) 8.3, 1.9||E>T||(E) 8.3, 1.9||E>P||(T) 0.7, 0.2||T>P||11.46||2.66|
|58||СГ) 0.7, 0.2||<0.001||(P) 0.4, 0.2||<0.001||(P) 0.4, 0.2||<0.01|
|5||М/||No Holter||—||No Holter||—||(T) 33.2, 5.2||T>P||8.86||—|
|64||with E||with E||(P) 7.7, 1.8||<0.001|
|6||М/||(E) 1.1, 0.3||E<T||(E) 1.1, 0.3||E<P||(T) 10.5, 1.5||T>P||6.83||1.15|
|54||СГ) 10.5, 1.5||<0.001||(P) 2.5, 0.4||<0.001||(P) 2.5, 0.4||<0.001|
|7||М/||(E) 6.0, 0.5||E>T||(E) 6.0, 0.5||E>P||СГ) 0.7, 0.1||T>P||10.09||4.57|
|61||(T) 0.7, 0.1||<0.001||(P) 0.3, 0.1||<0.001||(P) 0.3, 0.1||<0.001|
|8||М/||(E) 0.2, 0.1||NS||(E) 0.2, 0.1||E>P||(T) 0.3, 0.1||T>P||12.47||4.63|
|59||(T) 0.3, 0.1||(P) 0.01, 0.02||<0.01||(P) 0.01, 0.02||<0.001|
|13||М/||(E) 11.7, 1.5||E>T||(E) 11.7, 1.5||E>P||(T) 4.8, 0.9||T>P||9.93||6.11|
|46||(T) 4.8, 0.9||<0.05||(P) 1.2, 0.3||<0.001||(P) 1.2, 0.3||<0.001|
|17||М/||(E) 2.9, 1.0||NS||(E) 2.9, 1.0||E>P||(T) 2.6, 0.6||T>P||11.36||2.05|
|76||(T) 2.6, 0.6||(P) 0.2, 0.1||<0.001||(P) 0.2, 0.1||<0.001|
Table 3—Comparative Data for PSVBs
Hourly Frequency of PSVBs (Mean, SEM)
(E) 1.8, 0.2
ine (E)line (T)Comparison of the Distribution of PSVBs
Hourly Frequency of PSVBs (Mean, SEM)
(E) 1.8, 0.2
ine (E)B(P)Comparison of the Distribution of PSVBs
Hourly Frequency of PSVBs (Mean, SEM)
СГ) 0.6, 0.1
line (T)°(P)Comparison of the Distribution of PSVBs
|PL-T: Mean for all Pats. 11.88 (5.54-21.89)11.46||PL-E: Mean for all P&ts. 2.86 (0.81-6.11)2.66|
|58||fT) 0.6, 0.1||<0.001||(P) 1.0, 0.2||<0.001||(P) 1.0, 0.2||<0.05|
|7||М/||(E) 0.4, 0.1||NS||(E) 0.4, 0.1||E<P||(T) 0.8, 0.3||NS||10.09||4.57|
|61||(T) 0.8, 0.3||(P) 0.7, 0.1||<0.05||(P) 0.7, 0.1|
|8||М/||(E) 0.5, 0.1||E>T||(E) 0.5, 0.1||NS||00 о.з, o.i||NS||12.47||4.63|
|59||00 о.з, o.i||<0.05||(P) 0.4, 0.1||(P) 0.4, 0.1|
|11||М/||(E) 0.1, 0.04||NS||(E) 0.1, 0.04||E<P||СП 0.2, 0.1||NS||13.57||0.81|
|62||(T) 0.2, 0.1||(P) 0.3, 0.1||<0.05||(P) 0.3, 0.1|
|17||М/||(E) 2.8, 0.4||E<T||(E) 2.8, 0.4||E<P||(T) 4.6, 0.4||NS||11.36||2.05|
|76||(T) 4.6, 0.4||<0.01||(P) 3.8, 0.4||<0.01||(P) 3.8, 0.4|
|18||F/||(E) 0.5, 0.1||NS||(E) 0.5, 0.1||E>P||СГ) 0.3, 0.1||NS||10.99||0.92|
|47||(T) 0.3, 0.1||(P) 0.2, 0.1||<0.05||(P) 0.2, 0.1|
|19||F/||(E) 0.4, 0.1||E<T||(E) 0.4, 0.1||NS||00 2.4, 0.7||T>P||9.99||2.40|
|44||(T) 2.4, 0.7||<0.01||(P) 0.6, 0.1||(P) 0.6, 0.1||<0.01|
Table 4—Pulmonary Function Study Results
|FVC||T||3.72± 1.04||TvsE NS||—|
|(L)||P||3.62 ±1.01||TvsP NS||—|
|E||2.66 ±0.93||EvsP NS||—|
|(L/s)||P||2.59 ±0.87||T>P p<0.01||—|
|FEV10||E||73.5 ±10.1||EvsP NS||—|
|-x 100||T||76.7±10.5||T>E p<0.05||—|
|E||424 ±125||EvsP NS||458 ±115||E>P p<0.01|
|PEFR||T||440±130||T>E p<0.05||464 ±118||TvsE NS|
|(L/min)||P||412 ±124||T>P p<0.01||440 ±120||T>P p<0.01|
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