Respiratory Medicine (1992) 86, 419-423
Nebulized fenoterol causes greater cardiovascular and hypokalaemic effects than equivalent bronchodilator doses of salbutamol in asthmatics P. BREMNER, C. BURGESS*, R. BEASLEY,K. WOODMAN, S. MARSHALL, J. CRANE AND N. PEARCE
Department of Medicine, Wellington School of Medicine, P.O. Box 7343 Wellington South, Wellington, New Zealand
The pulmonary and extrapulmonary effects of two doses of nebulized fenoterol (5 mg) salbutamol (5 mg) and ipratropium bromide (0'5 mg) at 60 min intervals were compared in nine patients with asthma in a double-blind, randomized study. Measurements of heart rate, blood pressure, electromechanical systole (QS2I), QTc interval, FEV~ and plasma potassium were made at baseline and at 15, 30 and 60 min after each nebulization. Both fl-agonists caused significantly greater inotropic (QS2I), chronotropic (HR), electrocardiographic (QTc) and hypokalaemic effects than ipratropium bromide (IB), with fenoterol being more potent than salbutamol. Fenoterol had no greater effect on FEV~ than salbutamol although both were superior to lB. Only the first four subjects had two doses as originally intended, because the second administration of fenoterol resulted in marked cardiovascular effects and hypokalaemia. The observed differences in extrapulmonary effects between fenoterol and salbutamol provide a plausible group of mechanisms which may explain the increased risk of death associated with fenoterol in severe asthmatics. Introduction
Epidemiological studies in New Zealand (1-3) and Canada (4) have established that the use of fenoterol is associated with an increased risk of death from asthma compared with salbutamol. The mechanisms by which fenoterol has this effect have not been addressed in these studies, but may relate to either its use in the acute attack, or its long term use (5). One approach to investigate the potential mechanisms by which the use of fenoterol in the acute attack increases the risk of death, would be to compare its extrapulmonary effects with those of salbutamol when administered by nebulization. This form of delivery may be particularly relevant, for the pattern of a greater relative risk of death associated with fenoterol when administered by nebulizer compared with metered dose inhaler (MDI), has generally been observed in the case-control studies (1,3) a finding which may relate to the greater dose of drug delivered by nebulization. We have shown in normal individuals that fenoterol has greater cardiovascular and metabolic effects than salbutamol when administered by nebulizer (6,7). However, one cannot necessarily extrapolate these Received 25 March 1991 and accepted in revised form 18 December 1991. *To whom correspondence should be addressed. 0954-61 I 1/92/050419 + 05 $08.00/0
findings to an asthmatic population, as this would ignore the potential influence of//-receptor tachyphylaxis (8), and the intrinsic differences in//-receptor function in patients with asthma (9). In addition, comparative studies in asthmatics allow the relative bronchodilator efficacy of the different fl-agonists to be determined. In this present study we have examined the cardiovascular, respiratory and metabolic effects of equivalent bronchodilator doses of nebulized feaoterol and salbutamol in patients with asthma. Ipratropium bromide (IB) was included as a haemodynamic and metabolic placebo, providing bronchodilation necessary for patients instructed to withold their regular fl2-agonist therapy for at least 6 h prior to the study. Patients and Methods
Nine stable asthmatics (six female), mean age 30 years (range 22--40 years), and mean forced expiratory volume in 1 s (FEVI) of 71% (range 50-108%) of predicted, were studied. All subjects used an inhaled fl2-agonist and an inhaled steroid, and two were taking oral theophylline. All patients were asked to abstain from caffeine-containing beverages, and their inhaled fl2-agonist drug for 6 h, and their oral theophylline for 24 h prior to each study. Subjects attended the laboratory on three occasions at least 48 h apart in the fasting state. After resting © 1992 Baillirre Tindall
P. Bremner et al.
supine for 10min, baseline recordings of electromechanical systole (QS2), the high speed surface ECG, blood pressure and FEVj were made. Blood was taken for measurement of plasma potassium (K). The subjects then inhaled two doses of either 5 mg of fenoterol, 5 mg of salbutamol, or 0.5 mg of IB via a Pari-inhalierboy nebulizer at 60-min intervals. Recordings were made at 15, 30 and 60 min after each nebulization. The treatments were randomized and administered double-blind. Only the first four subjects had two doses as originally intended, because the second administration of fenoterol resulted in profound cardiovascular effects and marked hypokalaemia (see Results). Electromechanical systole (QS.,) was measured from simultaneous photographic recordings of the ECG and phonocardiogram as previously described (10). It was corrected for heart rate using a formula developed in our laboratory (11). The QT interval was measured from the ECG and corrected for heart rate using the Bazett formula (12). Plasma K was measured using an Ionetics 310 electrolyte analyser. The FEV~ was recorded as the highest of two consecutive recordings, 30 s apart (dry wedge spirometer, Vitalograph, U.K.). Blood pressure was measured automatically using a Hewlett Packard 78352A monitor. STATISTICAL ANALYSIS
Analysis was undertaken by means of the SAS statistical package. A three-way analysis of variance, using subject, drug and time effects, were employed. Each drug was compared against the others at the various time points. The significance level was adjusted for the risk of erroneously detecting a significant difference when making multiple comparisons, by using Bonferroni's inequality (P/number of comparisons) (13). Thus, drug comparisons were considered to be significantly different if P ~<0-0056. Results
All nine subjects tolerated a single dose of each bronchodilator. Only the first four subjects had two doses as originally intended, because a second administration of fenoterol resulted in a marked fall in K and other adverse effects, including marked tremor, nausea and tachycardia. There were no significant differences between subjects' control measurements on any of the three study days. I. 0-60 MINUTES(NINESUBJECTS)
Heart rate (HR) (Fig. 1) Fenoterol caused a significantly greater increase in heart rate than IB at all time points, whereas salbutamol
was only significantly different at 15 min. Fenoterol caused a significantly greater increase than salbutamol at both 30 and 60 min.
QSel (Fig. 1) Fenoterol caused a significantly greater reduction in QS2I (indicating a greater positive inotropic effect) than salbutamol at both 15 and 30 min. Both fenoterol and salbutamol reduced QS,I more than IB at all time points.
QTc &terval When compared to IB, fenoterol prolonged QTc at all time points whereas salbutamol was significantly different at 15 and 30min. Fenoterol significantly prolonged QTc at 60 min when compared to salbutamol (mean+sEM 38.3+7.2 versus 15-9_5.3ms, respectively).
Blood pressure (data not shown) There were no significant differences between any of the agents.
FEVI ( Fig. I ) There were no significant differences between salbutamol and fenoterol in their ability to increase the FEV r Although IB increased the FEV~, it was always significantly less than the fl_,-agonists.
Plasma K (Fig. 1) At 60 min, fenoterol reduced plasma K by a mean of -0"79 mmol 1-l (range - 0 - 5 to - 1.1) compared to - 0 " 2 6 m m o l l -~ (range - 0 . 1 to - 0 . 5 ) and - 0 - 0 5 m m o l l -~ (range 0.1 to - 0 . 3 ) for salbutamol and IB, respectively. 2. 60-120 MINUTES(FOURSUBJECTS) The extra dose of fl-agonist resulted in marked increases in H R and QTc interval, and decreases in QS_,I and plasma K for both salbutamol and fenoterol (Fig. 2). The changes were significantly greater for fenoteroI compared with salbutamol for H R and QS2I at all time points. By 120min plasma K fell to a mean of 2.65 m m o l l - t (baseline of 4.0) following fenoterol compared to 3-75 mmol 1-t (baseline of 3.97) for IB and 3-0 mmol I-~ (baseline of 3.95) for salbutamol. The extra dose offl-agonist resulted in only a further small increase in FEVp As with the p-agonists, a second dose of IB resulted in a small increase in FEVj; however, there were no
Effects of nebulized bronchodilators
I0 -25 o -35
0-0 L, _/ o
0-2 -0"8 l
Fig. 1 The effect oftreatment (mean + SEM)on heart rate (H R), total electromechanical systole (QS2I),plasma potassium (K *) and forced expiratory volume in 1 s (FEVI) for nine subjects. ( © ) Ipratropium bromide: ( • ) fenoterol; () salbutamol.
associated changes in either the cardiovascular or plasma K measurements. Discussion
In the New Zealand Asthma Mortality Survey of 1981-83 (14), over 25% of all deaths occurred in patients who were using home nebulizers. Of these, a disproportionately greater number were prescribed fenoterol than would have been expected from national sales. More recently, a series of case-control studies have shown that the self-administration of fenoterol by nebulizer is associated with an increased risk of death from asthma compared with salbutamol (1-3). This present study complements the epidemiological studies, in that it has highlighted one group of potential mechanisms whereby the self-administration of fenoterol by nebulizer may increase the risk of death. Fenoterol caused greater cardiovascular and metabolic effects than equal doses of salbutamol without any significantly greater improvement in FEVt. The greater inotropic response following fenoterol is due to a greater degree of stimulation of both fla- and
fl2-receptors in the myocardium (t5). The effects on heart rate are also likely to be due to both cardiac fl~and fl.,-receptor stimulation, in addition to a reflex response secondary to peripheral vasodilation. This combination of a marked increase in myocardial contractility and heart rate results in a greater myocardial oxygen demand, which may be deleterious in the situation of hypoxaemia. In addition to these greater inotropic and chronotropic effects, fenoterol also prolonged the QTc interval more than salbutamol. Prolongation ofthis interval has been associated with an increased risk of ventricular arrhythmias, particularly in the situation of an increase in heart rate (16). Indeed, Tandon demonstrated that equal doses of fenoterol are associated with a greater frequency ofventricular ectopic beats than salbutamol (17). The decrease in plasma K following fl2-agonists is due to stimulation o f N a - K ATPase causing K to move from the extra-cellular to the intracellular compartment (18). The greater degree of hypokalaemia observed with fenoterol supports previous studies which have shown that fenoterol is a more potent fl_,-agonist than
P. Bremner et al. 60
I I I I I I
I I I
-o -0-4 -0-2 -2
I I I
t I I I
I I I I
~ ~ iI 90
I i I 120
Fig.2 Thee•ect•ftreatment(mean-•-sEM)•nheartrate(HR)•t•ta•e•ectr•mechanica•syst••e(QS2•)•p•asmap•tassium(K ÷) and forced expiratory volume in I s (FEV,) in the four subjects who received a second dose of drug. ( <>) Ipratropium bromide; ( • ) fenoterol; () salbutamol. salbutamol (5). However, it is important to recognise that this greater potency did not provide any greater improvement in the FEV,. This suggests that the effects ofp-agonists on the airways may be more easily 'saturated' than that on plasma K, the latter reflecting systemic #2-receptor effects. It could be argued that the administration of a second dose of p-agonist 60 min after the first is excessive and greater than that recommended by either the manufacturers or physicians. However, asthmatic patients with home nebulizers self administer large doses of p-agonists during severe asthma. For example, we have recently observed that over a third of patients with home nebulizers self administered flagonist by this method more than six times in the 24 h prior to hospital admission, in addition to over 20 actuations of their MDI (19). While we do not recommend the use of such high doses of#-agonist by nebulizer, in this study we have used a dosage regime similar to that used in clinical practice.
Although the effects of the second dose offl-agonist should be interpreted with caution, due to the very small number of subjects studied, they are worthy of comment. The subjects felt nauseous~ weak and experienced a marked tremor, while severe hypokalaemia and marked cardiac effects were noted. These extrapulmonary effects were of considerably greater magnitude with fenoterol than salbutamol, and were not associated with a further significant increase in FEV,. Compared to either of the p2-agonists, IB had no discernible cardiovascular or hypokalaemic effects, confirming its role as an adequate control for the extrapulmonary effects caused by fl2-agonists. As previously reported, IB was less effective as a bronchodilator agent than the beta agonist drugs (20). We conclude that nebulized fenoterol causes considerably greater cardiovascular and hypokalaemic effects than equivalent bronchodilator doses of salbutamol. Although this study is limited by the small number of subjects studied, the observed differences in
Effects o f nebulized bronchodilators
extrapulmonary effects were of sufficient magnitude to provide one plausible group o f mechanisms which explain the increased risk o f death associated with fenoterol.
Acknowledgements We thank Mrs H. Bark and Mrs M. Stretch for secretarial assistance. This study was supported by grants from the Medical Research Council of New Zealand, Riker 3M, and G l a x o New Zealand Limited.
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