Effects of inhaled salmeterol and salbutamol (albuterol) on morning dips compared in intensive care patients recovering from an acute severe asthma attack

(1)

M. Ritz J. B. Thorens M. Arnold-Ketterer J. C. Chevrolet

Effects of inhaled salmeterol and

salbutamol (albuterol) on morning dips

compared in intensive care patients

recovering from an acute severe asthma

attack

Received: 27 March 1997 Accepted: 24 September 1997

This work was supported in part by a grant from Glaxo (Sch6nbtihl, Berne) Switzer- land

M. Ritz • J. B. Thorens - J. C. Chevrolet ( ~ ) Medical Intensive Care,

University Hospital, Geneva, 24,

rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland

FAX: +41 (22) 372 9105 J. B. Thorens

Respiratory Division,

H6pital Cantonal Universitaire de Gen~ve, Geneva, Switzerland

M. Arnold-Ketterer Medical Clinic I,

H6pital Cantonal Universitaire de Gen6ve, Geneva, Switzerland

Abstract Objective: To assess t h e effect of a long-acting i n h a l e d fl2- agonist, salmeterol (SM), c o m p a r e d to a short-acting i n h a l e d fl2-agonist, salbutamol (or a l b u t e r o l , SB), o n the o c c u r r e n c e of m o r n i n g dip ( M D ) in patients r e c o v e r i n g f r o m a n a c u t e s e v e r e asthma attack ( A S A ) . Design: P r o s p e c t i v e s t u d y Setting: 18-bed, m e d i c a l i n t e n s i v e care unit (ICU) in a u n i v e r s i t y hospital.

Patients: 19 patients suffering f r o m an A S A .

Interventions: Serial m e a s u r e m e n t s o f the p e a k e x p i r a t o r y flow r a t e ( P E F R ) , arterial b l o o d gases, vital capacity and f o r c e d e x p i r a t o r y vol- u m e in o n e second ( F E V I ) w e r e p e r f o r m e d from admission. All patients were first t r e a t e d with i.v. m e - thyl p r e d n i s o l o n e and i.v. SB. O n c e the P E F R was stable a n d > 35 % o f p r e d i c t e d value, i.v. SB was s t o p p e d while i.v. steroids w e r e m a i n t a i n e d ,

a n d p a t i e n t s w e r e r a n d o m i s e d to ei- t h e r i n h a l e d SB (9 patients, 400 ~tg e v e r y 4 h) o r i n h a l e d SM (10 p a - tients, 100 ~tg e v e r y 12 h). Results: T h e m e a n a d m i s s i o n P E F R was 26.1 + 11.7 % o f the p r e d i c t e d v a l u e a n d was n o t d i f f e r e n t b e t w e e n t h e two groups. M D was m o r e fre- q u e n t with SB (6/9 p a t i e n t s ) t h a n with SM (4/10). T h e s e v e r i t y o f M D , e x p r e s s e d in 1/min fall in P E F R , was h i g h e r in SB t h a n in S M (106 + 25 vs 55 + 37; p < 0.05). Discussion: M D is f r e q u e n t in A S A . In A S A , SM a p p e a r s to r e d u c e t h e f r e q u e n c y a n d t h e s e v e r i t y o f M D m o r e t h a n SB. T h e clinical implica- tions o f this o b s e r v a t i o n , p a r t i c u l a r - ly a l o w e r i n g of m o r t a l i t y a n d a s h o r t e n i n g o f t h e I C U stay, r e m a i n to b e i n v e s t i g a t e d . Key words A s t h m a - A c u t e s e v e r e a s t h m a • M o r n i n g dip • S a l b u t a m o l • A l b u t e r o l • S a l m e t e r o l

Introduction

N o c t u r n a l s y m p t o m s a n d w o r s e n i n g of asthma at the e n d o f the night are c o m m o n f e a t u r e s in asthma patients [1-3]. T h e n a d i r o f the p e a k e x p i r a t o r y flow rate ( P E F R ) at this t i m e is called m o r n i n g dip ( M D ) [4]. A t t h e p r e s e n t time, the cause(s) of this n o c t u r n a l worsen- ing is u n k n o w n . A l t h o u g h a c i r c a d i a n r h y t h m o f changes in airway calibre is o b s e r v e d in n o r m a l persons, t h e r a n g e of t h e s e c h a n g e s is m u c h g r e a t e r in patients with a s t h m a [5, 6]. T h e r e a r e p r o b a b l y several coexisting fac- tors, including vagal t o n e [7], b o d y t e m p e r a t u r e [8], al-

lergens [9] a n d a v a r i a t i o n o f h o r m o n e s [10] f a v o u r i n g a n d / o r c a u s i n g this a i r w a y instability. F u r t h e r m o r e , in t h e hospital, r e s p i r a t o r y arrests d u e to a s t h m a , s o m e - t i m e s l e a d i n g to d e a t h , a r e m o r e c o m m o n at t h e e n d o f t h e night [11-13] a n d p r o b a b l y c o r r e s p o n d t o t h e M D o b s e r v e d at this time. U n t i l r e c e n t l y , the available i n h a l e d b r o n c h o d i l a t o r s , d u e to t h e i r s h o r t half-life, c o u l d n o t c o v e r t h e full 8 h o f a n o r m a l night's sleep, so t h a t m a n y studies o n n o c t u r - nal a s t h m a w e r e c o n d u c t e d with o r a l t h e o p h y l l i n e o r oral s u s t a i n e d s l o w - r e l e a s e fl2-agonists. T h o u g h t h e s e t r e a t m e n t s a r e s o m e t i m e s e f f e c t i v e in r e d u c i n g n o c t u r -

(2)

n a l s y m p t o m s , m a n y p a t i e n t s c a n n o t t o l e r a t e t h e r a p e u - t i c a l l y e f f e c t i v e d o s e s [ 1 4 - 1 7 ] . S a l m e t e r o l ( S M ) , a n e w i n h a l e d fl2-agonist, d i f f e r s f r o m c o n v e n t i o n a l fl2-mimetic d r u g s in t h a t it p r o d u c e s b r o n c h o d i l a t a t i o n f o r up to 12 h a f t e r a single i n h a l e d d o s e [18, 19]. This m a y be d u e t o t h e l o n g l i p o p h i l i c side c h a i n t h a t p e r m i t s persis- t e n t b i n d i n g a n d r e p e a t e d s t i m u l a t i o n at t h e f l - a d r e n o - c e p t o r site. S a l m e t e r o l is e f f e c t i v e in i n c r e a s i n g t h e m o r n i n g P E F R v a l u e a n d in r e d u c i n g t h e n o c t u r n a l s y m p t o m s in p a t i e n t s w i t h c h r o n i c s t a b l e a s t h m a [ 2 0 - 23], b u t , as f a r as w e k n o w , h a s n e v e r b e e n t e s t e d in p a - t i e n t s r e c o v e r i n g f r o m a n e p i s o d e o f a c u t e s e v e r e asth- m a in a n i n t e n s i v e c a r e unit. T h e a i m o f o u r s t u d y w a s t o c o m p a r e t h e e f f e c t of in- h a l e d S M , a l o n g - a c t i n g / 3 2 - a g o n i s t , w i t h t h a t o f i n h a l e d s a l b u t a m o l ( S B ) ( o r a l b u t e r o l ) , a s h o r t - a c t i n g fl2-agonist, o n t h e p r e v a l e n c e a n d i n t e n s i t y o f M D in p a t i e n t s r e c o v e r i n g f r o m a n a c u t e a s t h m a a t t a c k , s i n c e a d e - c r e a s e in o r a b o l i t i o n o f t h e M D m i g h t r e d u c e m o r t a l i t y f o r s u c h p a t i e n t s .

Patients and methods

Patients were admitted into the medical intensive care unit (ICU) for an acute severe asthma attack, defined as a PEFR of less than 35 % of the predicted value and blood gases showing hypoxaemia with either normocapnia or hypercapnia. The present prospective study was approved by the Ethical Committee of the University Hospital of Geneva and all patients gave informed consent, except the patient who was intubated, for whom consent was obtained from next of kin.

According to a standard treatment policy in our institution, all patients were treated with supplemental oxygen by face mask, i.v. prednisolone (Ultracorten H; 3-5 mg/kg per day given in six daily doses) and i.v. SB (= albuterol, Ventolin; 5-30 Ixg/min). Once the blood gas values were normalized and the P E F R was > 35 % of the predicted value and stable (i. e., showing less than 10 % variability, defined as the difference between the highest and the lowest values of PEFR, divided by the lowest value times 100) during the day and during the night, the i.v. SB was withdrawn and nebulization of SB with decreasing doses over 8 h were instituted (2.5 mg at 8 a.m., 1.25 mg at 12 a.m., 1.25 mg at 4 p.m.). The patients were then randomly assigned either to inhaled SM (Sere- vent), 4 inhalations of 25 ~tg twice daily, or inhaled SB 2 inhalations of 200 ~xg six times a day, given by a metered-dose inhaler connec- ted to a spacer (Volumatic). The i.v. prednisolone was held con- stant throughout the study at the same dose as at admission (3- 5 mg/kg), and the use of theophylline or ipratropium bromide was not allowed. Antibiotic therapy was prescribed by the attending staff if necessary.

P E F R was measured every 2 h during 24 h from the end of the i.v. SB administration, by using a Wright peak flow gauge. The forced expired volume in 1 s (FEV1) and the forced vital capacity (FVC) were measured every 4 h with a portable spirometer (Micro Medical, Rochester, England). The highest value among three at- tempts for each measurement was recorded. Samples for arterial blood gases were drawn from the arterial line at the same time as the P E F R measurement was made. MD was defined as a difference of more than 15 % in P E F R between the highest diurnal reading and the 4 a.m. reading from the first night after randomization

was conducted [2, 4]. No supplementary treatment was instituted during the study.

Statistical comparison of the prevalence of MD between the two treatment groups was performed using a chi-square test, or Fisher's exact test, when appropriate. The fall in PEFR, age, duration of asthma, height and weight of both groups were compared using an unpaired Student's t-test. The heart rate, respiratory rate, blood pressure and blood gas results were compared using a paired Student's t-test. All p values were based on two-sided tests, and a p value of 0.05 or less was considered to indicate statistical signifi- cance. The StatView II Abacus Concept statistical package for the Apple Macintosh was used.

Results N i n e t e e n a s t h m a t i c p a t i e n t s t o o k p a r t in t h e study, 9 in t h e SB g r o u p a n d 10 in t h e S M g r o u p . O n l y 1 p a t i e n t w a s i n t u b a t e d a n d r e q u i r e d m e c h a n i c a l v e n t i l a t i o n f o r 12 h ( S B g r o u p ) . T h e r e w e r e n o d r o p o u t s . T h e c h a r a c - teristics o f all t h e p a t i e n t s a r e g i v e n in T a b l e 1. B o t h t r e a t m e n t g r o u p s w e r e s i m i l a r w i t h r e s p e c t t o all vari- ables. T a b l e 2 g i v e s t h e p a t i e n t s ' c h a r a c t e r i s t i c s just b e - f o r e r a n d o m i s a t i o n t o t h e SB o r S M g r o u p . A s o n a d m i s - sion, n o d i f f e r e n c e b e t w e e n t h e t w o g r o u p s c o u l d b e f o u n d at this t i m e . T a b l e 3 s h o w s t h e r e s u l t s o f t h e pul- m o n a r y f u n c t i o n tests. P a t i e n t s in t h e SB g r o u p s u f f e r e d a h i g h e r p r e v a l e n c e o f M D (6/9 vs 4/10). M D s w e r e also w o r s e , i.e., d e e p e r in t h e SB g r o u p s as e x p r e s s e d e i t h e r in 1/min fall in P E F R o r in p e r c e n t a g e d e c r e a s e in P E F R (106_+25 vs 55 +_ 3 7 1 / m i n a n d 37.5+_9.4 vs 23.4 + 6 . 4 % , cf. T a b l e 3). F i g u r e 1 s h o w s t h e P E F R v a l u e s d u r i n g t h e n i g h t in t h e p a t i e n t s p r e s e n t i n g a M D . A t m i d n i g h t a n d 2 a . m . , b o t h g r o u p s s h o w e d a slight fall in P E F R , w h i l e at 4 a . m . t h e SB g r o u p e x h i b - ited a l a r g e r dip. A f t e r t h e M D s , P E F R s i m p r o v e d in b o t h g r o u p s , t h e 8 a . m . r e c o r d i n g b e i n g c l o s e t o t h e h i g h e s t d i u r n a l v a l u e o f t h e p r e c e d i n g day. T h e F E V 1 a n d F V C r e s u l t s w e r e n o t i n t e r p r e t a b l e : i n d e e d , m o s t p a t i e n t s c o u l d n o t p r o d u c e s u f f i c i e n t l y l o n g e x p i r a t i o n t h r o u g h t h e s p i r o m e t e r w i t h o u t e x p e r i e n c i n g b o u t s o f i n t e n s e c o u g h i n g , a c o m m o n f i n d i n g a f t e r a s e v e r e asth- m a a t t a c k . N e v e r t h e l e s s , P E F R m e a s u r e m e n t s w e r e re- liable b e c a u s e o f t h e s h o r t e x h a l a t i o n t i m e n e e d e d f o r t h e m e a s u r e m e n t r e c o r d e d v e r y e a r l y in t h e e x p i r a t i o n p h a s e . T a b l e 4 s h o w s s o m e o f t h e h a e m o d y n a m i c a n d b l o o d gas m e a s u r e m e n t s at t h e t i m e o f t h e b e s t d i u r n a l P E F R a n d at t h e t i m e o f t h e M D . T h e r e w a s a s i g n i f i c a n t in- c r e a s e in t h e p a r t i a l p r e s s u r e o f c a r b o n d i o x i d e in arterial b l o o d ( P a C O 2 ) a n d a d e c r e a s e in p H d u r i n g t h e M D , t h o u g h t h e m a g n i t u d e o f t h e c h a n g e w a s small. N e i t h e r o x y g e n a t i o n , a s s e s s e d b y t h e P a O ] F I O 2 in r a t i o b e t w e e n t h e p a r t i a l p r e s s u r e o f o x y g e n in a r t e r i a l b l o o d a n d f r a c t i o n a l i n s p i r e d o x y g e n , n o r h e a r t r a t e n o r b l o o d p r e s s u r e w a s d i f f e r e n t d u r i n g t h e M D . T h e r e w a s n o cor- r e l a t i o n b e t w e e n t h e i n c r e a s e in P a C O 2 a n d t h e fall in

(3)

Table 1 Patients' general characteristics at admission. Values are mean + SD or numbers

(PEFR peak expiratory flow

rate, pHa arterial pH, PaCOe,

PaO e partial pressure of carbon

dioxide and of oxygen in arte- rial blood, FIO 2 fractional in- spired oxygen, B E a arterial base excess) Salbutamol Salmeterol pa Number of patients Sex (F/M) Age (years) Height (cm) Weight (kg)

Duration of asthma (years)

History of nocturnal asthma symptoms Atopic status

Previous history of acute severe asthma Regular use of inhaled flz-mimetics Regular use of inhaled steroids

P E F R at admission (% predicted value) pHa at admission

PaCO 2 at admission (kPa) PaOJFIO2 at admission (kPa) BEa at admission (mEq/1)

9 10 7/2 6/4 44.3 _+ 22.8 36.7 + 16.3 NS 164 + 10 169 + 15 NS 64.6 + 12.6 71.3 ± 34.8 NS 18.2 ± 18.0 14.3 _+ 11.4 NS 3 4 3 4 2 3 7 7 4 5 28.6 + 11.6 25.4 _+ 12.1 NS 7.29 + 0.13 7.36 ± 0.06 NS 7.06 + 2.9 6.63 _+ 0.85 NS 37.5 _+ 8.5 36.5 _+ 5.5 NS -2.6 ± 4.3 -2.1 ± 3.4 NS Student's t-test Salbutamol Salmeterol pa Table 2 Patients" characteris-

tics at the time of random±sa-

t±on. Values are mean + SD Time from admission into ICU

to random±sat±on (h) 21.1 + 25.0 19.9 _+ 12.0 NS a Need for mechanical ventilation

before random±sat±on (n) 1 0 NS b

P E F R (% predicted value) 55 + 12 46 + 21 NS a P E F R variability under i.v. SB (%) 6 + 2 5 + 3 NS a

pHa 7.40 + 0.06 7.40 + 0.04 NS a PaCO 2 (kPa) 4.3 + 0.3 4.5 _+ 0.6 NS a PaO2/FIO2 ( k P a / F I O J 40 + 8 34 + 7 NS a BEa (mEq/1) -2.6 + 4.3 -2.1 + 3.4 NS a a Student's t-test b Chi-square test Salbutamol Salmeterol p Number of MDs/number of patients 6/9 4/10 NS a Maximal P E F R fall (1/min) 106 + 25 55 + 37 < 0.05 b Maximal P E F R fall (%) 37.5 + 9.4 23.4 + 6.4 < 0.05 b

Table 3 Characteristics of morning dips (MDs)

Fall in P E F R indicates the difference in P E F R between the highest diurnal value and the 4 a.m. re- cording a Fisher's exact-test b Student's t-test P E F R d u r i n g t h e M D n o r b e t w e e n t h e fall i n p H a n d i n P E F R . T h e r e w e r e n o d i f f e r e n c e in h a e m o d y n a m i c s o r b l o o d g a s e s b e t w e e n t h e S B a n d S M g r o u p s . Discussion I n t h i s study, w e d e m o n s t r a t e d t h a t i n h a l e d S M , 100 Ixg t w i c e daily, c o m p a r e d w i t h i n h a l e d S B 400 ~tg six t i m e s a day, p r o d u c e d a b e t t e r c o n t r o l l e d , i . e . a m o r e s t a b l e , P E F R d u r i n g t h e n i g h t in p a t i e n t s r e c o v e r i n g f r o m a n a c u t e s e v e r e a s t h m a a t t a c k . S M h a s a l r e a d y b e e n c o m p a r e d t o S B , a s h o r t - a c t i n g f l 2 - a g o n i s t , i n p a t i e n t s w i t h s t a b l e c h r o n i c a s t h m a [ 2 0 - 23]. S M p r o d u c e d a n i n c r e a s e i n t h e F E V 1 o v e r 12 h a n d in t h e m o r n i n g P E F R , as w e l l as a d e c r e a s e i n t h e n u m b e r o f n i g h t s o f d i s t u r b e d s l e e p a n d a n i m p r o v e - m e n t in t h e q u a l i t y o f s l e e p , a s s e s s e d b y e l e c t r o e n c e p h a -

(4)

P E F R

(%)

110

+ SALBUTAMOL

---o- SALMETEROL

1~ ~

9O

80

7O

Mean +- SD 5C • 2 4 2 4 6 8 Time (hours)

Fig.1 Nocturnal peak expiratory flow rate

PEFR,

expressed as a percentage of the highest diurnal value ( 0 ) recorded during the day preceding the night shown on the graph. * p < 0.05

lography. In o u r study, w e i n v e s t i g a t e d t h e e f f e c t s of in- h a l e d S M or SB in I C U p a t i e n t s r e c o v e r i n g f r o m an a c u t e s e v e r e a s t h m a a t t a c k , a clinical s i t u a t i o n in which, as far as we know, n o p r e v i o u s i n f o r m a t i o n exists on the c o m p a r a t i v e e f f i c a c y o f b o t h agents.

S e v e r a l m e t h o d o l o g i c a l p o i n t s o f o u r s t u d y s h o u l d b e clarified.

First, t h e d o s e o f S M t h a t we used, 100 btg t w i c e a day, w a s h i g h e r t h a n t h e 50 Ixg t w i c e a d a y u s u a l l y r e c o m - m e n d e d . This is d u e to t h e fact t h a t m o s t s t u d i e s h a v e b e e n c o n d u c t e d o n c h r o n i c s t a b l e a s t h m a t i c patients. T h e p a t i e n t s w e h a v e i n v e s t i g a t e d w e r e just r e c o v e r i n g f r o m a n a c u t e s e v e r e a s t h m a crisis. M o r e o v e r , t h e switch f r o m i.v. SB to t h e i n h a l e d fl2-mimetic was d o n e in a s h o r t p e r i o d o f t i m e , so t h a t we d e c i d e d to c o n d u c t o u r s t u d y with t h e m a x i m a l r e c o m m e n d e d doses. This was d o n e - as r e q u e s t e d b y o u r E t h i c a l C o m m i t t e e - in or- d e r to a v o i d a n a b r u p t d e t e r i o r a t i o n o f t h e a s t h m a con- trol. D e s p i t e t h e f a c t t h a t B e n n e t t et al. [24] h a v e re- c e n t l y d e m o n s t r a t e d t h a t t h e s y s t e m i c effects o f i n h a l e d S M o n h e a r t r a t e a n d b l o o d p r e s s u r e w e r e ' m o r e i m p o r - t a n t t h a n t h e e f f e c t s o f i n h a l e d SB, we did n o t notice a n y d i f f e r e n c e in t h e h e a r t r a t e , r e s p i r a t o r y r a t e or b l o o d p r e s s u r e b e t w e e n t h e S M or SB g r o u p s during t h e night, s u g g e s t i n g t h a t b o t h t r e a t m e n t r e g i m e n s w e r e p r o b a b l y e q u i p o t e n t .

Second, b e c a u s e e v e r y p a t i e n t did not inhale the

fl2-

m i m e t i c at e x a c t l y the s a m e t i m e of the day, we c a n n o t e x c l u d e that t h e e f f e c t s o f S M or SB could h a v e b e e n different due to d i f f e r e n t t i m e s o f administration. H o w - ever, the d i u r n a l a n d n o c t u r n a l P E F R profiles w e r e quite similar w i t h i n g r o u p s o f " m o r n i n g d i p p e r s " , on ei- t h e r SB or SM, w h e r e a s t h e m a g n i t u d e of the M D s w e r e different, as s h o w n in Fig. 1, b e t w e e n the t w o g r o u p s o f p a t i e n t s w h e n c o n s i d e r e d b y t h e t r e a t m e n t option. Fur- t h e r m o r e , M D , as d e f i n e d , o c c u r r e d effectively at a r o u n d 4 a . m . (4.2 _ 0.8 h a . m . , m e a n + SD). In addi- tion, a l t h o u g h we did n o t assess t h e subjective t o l e r a n c e to SM or SB, n o p a t i e n t in e i t h e r g r o u p n e e d e d a rescue t r e a t m e n t during t h e s t u d y b e c a u s e of w o r s e n i n g asth- m a . All this suggests t h a t t h e t i m e of a d m i n i s t r a t i o n o f the drugs, p r o v i d e d t h a t t h e d u r a t i o n of action o f t h e m e d i c a t i o n is a c c o u n t e d for, is n o t essential for stabiliz- ing t h e a i r w a y t o n e in p a t i e n t s r e c o v e r i n g f r o m an at- t a c k o f acute s e v e r e a s t h m a .

O t h e r a u t h o r s h a v e a l r e a d y p u b l i s h e d d a t a on asth- m a a n d l o n g - a c t i n g fl2-mimetics. R a b e et al. [25] investi- g a t e d the effects o f f o r m o t e r o l a n d SM on a i r w a y re- s p o n s i v e n e s s o v e r 24 h in m i l d l y a s t h m a t i c patients, b y m e a s u r i n g the F E V 1 e v e r y 4 h. B o t h drugs w e r e supe- rior to p l a c e b o in c o n t r o l l i n g t h e airway tone, b u t a cir- c a d i a n r h y t h m o f a i r w a y t o n e a n d responsiveness, with a w o r s e n i n g of t h e F E V 1 at 4.30 a.m., was still d e t e c t - able. In o u r study, 6/9 p a t i e n t s in the SB a n d 4/10 p a - tients in the SM g r o u p d e v e l o p e d an M D , d e s p i t e ag- gressive a n t i - a s t h m a t i c m e d i c a t i o n , a l t h o u g h the m a g n i - t u d e of the fall in P E F R was less i m p o r t a n t in the SM group. This m a y i n d i c a t e t h a t t h e b e t t e r a i r w a y stability of SM c o m p a r e d to SB is p r e d o m i n a n t l y due to the long- er s t i m u l a t i o n of t h e f l z - a d r e n o c e p t o r of a i r w a y s m o o t h m u s c l e , b u t t h a t t h e r e still exists a circadian r h y t h m o f a i r w a y i n f l a m m a t i o n . This a i r w a y t o n e instability is n o t c o n t r o l l e d b y fl2-mimetics, d e s p i t e the fact t h a t SM has s o m e a n t i - i n f l a m m a t o r y p r o p e r t i e s [26]. To s u p p o r t t h e role of i n f l a m m a t i o n in n o c t u r n a l a s t h m a , r e c e n t studies h a v e s h o w n a d e c l i n e o f e n d o t h e l i n - 1 a n d an i n c r e a s e in eosinophilic c a t i o n i c p r o t e i n a n d l y m p h o c y t e c o u n t in b r o n c h o a l v e o l a r l a v a g e fluid t a k e n at 4 p . m . a n d 4 a. m. [27, 28]. T h e s e findings d o n o t p r o v e that t h e s e inflam- m a t o r y c h a n g e s i n d e e d c a u s e n o c t u r n a l a s t h m a , b u t

Table 4 Haemodynamic and blood gas values in patients presenting a morning dip (comparison between the parame- ters recorded with the highest diurnal P E F R vs during M D )

Highest diurnal PEFR Morning dip p

Respiratory rate (breaths/min) 23 _+ 5 22 + 5

Heart rate (beats/min) 87 _+ 13 78 + 13

Systolic blood pressure (mmHg) 117 + 17 117 _+ 18

Diastolic blood pressure (mm Hg) 62 + 9 62 + 9

pHa 7.42 _+ 0.03 7.39 _+ 0.03 PaCO 2 (kPa) 4.5 + 0.7 4.7 _+ 0.5 BEa (mEq/1) -1.9 + 2.9 -2.2 __ 3.3 PaO2/FIO2 (kPa/FIO2) 38 + 8 35 + 8 a Student's t-test NS NS NS NS < 0.05 a 0.05 a NS NS

(5)

t h e y suggest a role f o r i n f l a m m a t o r y m e d i a t o r s in p o t e n - tiating airway i n f l a m m a t i o n . O n t h e o t h e r hand, we can- n o t b e sure t h a t such an i n f l a m m a t o r y c o m p o n e n t m a y h a v e p a r t i c i p a t e d in t h e M D t h a t we o b s e r v e d in o u r patients, b e c a u s e we did n o t p e r f o r m b r o n c h o a l v e o l a r l a v a g e while o u r p a t i e n t s r e c e i v e d high d o s e s of i. v. cor- ticosteroids. F u r t h e r m o r e , a u t o n o m i c n e r v o u s s y s t e m activity affecting the a i r w a y n a r r o w i n g in o u r patients c a n n o t b e excluded, as o u r p a t i e n t s did n o t receive ipra- t r o p i u m b r o m i d e , which h a s b e e n s h o w n to r e d u c e noc- t u r n a l a s t h m a [29].

W e could n o t assess t h e e f f e c t o f S M on m o r b i d i t y (i. e. the length o f stay in t h e I C U a n d / o r o t h e r p a r a m e - ters) a n d m o r t a l i t y in o u r s t u d y d u e to the small n u m b e r of patients. It is well k n o w n t h a t a m a r k e d diurnal varia- t i o n in P E F R entails a h e i g h t e n e d risk o f a s t h m a recur- r e n c e , and, s o m e t i m e s , o f d e a t h , in the days following I C U discharge [13]. It is t h u s p o s s i b l e t h a t the b e t t e r stability of the P E F R with S M m a y r e d u c e m o r t a l i t y in patients r e c o v e r i n g f r o m an a c u t e s e v e r e a s t h m a attack a n d d i s c h a r g e d to t h e w a r d , b u t this r e m a i n s to b e stud- ied with larger n u m b e r s of patients. T h e high p r e v a l e n c e (52 % ) o f p a t i e n t s p r e s e n t i n g a n M D in o u r study indi- c a t e s t h a t a high p r o p o r t i o n o f p a t i e n t s r e m a i n s at risk a f t e r an acute s e v e r e a s t h m a a t t a c k , d e s p i t e subjective i m p r o v e m e n t a n d n o r m a l i z a t i o n of b l o o d gases, and t h a t serial a s s e s s m e n t o f t h e P E F R is still m a n d a t o r y w h e n m a n a g i n g such p a t i e n t s . Finally, a n o t h e r p o t e n t i a l b e n e f i t o f u s i n g S M i n s t e a d o f i.v. SB in t h e s e p a t i e n t s c o u l d b e t o r e d u c e t h e c o s t s o f h o s p i t a l i z a t i o n . In o u r I C U , t h e m e a n l e n g t h o f s t a y f o r a c u t e s e v e r e a s t h m a p a t i e n t s is less t h a n 4 d a y s [1993-1996, 89 a c u t e a s t h m a p a t i e n t s ; l e n g t h o f s t a y ( m e a n + SD): 3.37 + 2.25 days]. T h e c o s t f o r 2 4 - h t r e a t - m e n t w i t h i.v. SB (5 ixg/min) is a b o u t U. S. $ 40, w h e r e a s it a m o u n t s to o n l y a r o u n d U. S. $ 3 f o r 200 ~tg o f i n h a l e d SM. Thus, t h e switch f r o m SB to S M w o u l d o n l y r e s u l t in a s m a l l c o s t savings, unless t r e a t m e n t using S M c o u l d r e d u c e t h e l e n g t h o f s t a y b y a l l o w i n g t h e t r a n s f e r o f a p a t i e n t , o n c e w e a n e d f r o m a c o n t i n u o u s i. v. i n f u s i o n , t o an i n t e r m e d i a t e c a r e unit, w h e r e a e r o s o l t h e r a p y c o u l d b e m o r e easily u n d e r t a k e n . W e c o n c l u d e t h a t in p a t i e n t s r e c o v e r i n g f r o m a n a c u t e s e v e r e a s t h m a a t t a c k i n h a l e d S M 100 ~tg t w i c e a d a y is m o r e e f f e c t i v e t h a n i n h a l e d SB 400 ~tg six t i m e s a d a y in r e d u c i n g t h e p r e v a l e n c e a n d i n t e n s i t y o f M D as a s s e s s e d b y serial P E F R m e a s u r e m e n t s . T h i s c o u l d r e d u c e t h e m o r t a l i t y f o r such p a t i e n t s a n d s h o r t e n t h e i r I C U stay, b u t t h e s e p o i n t s r e m a i n to b e i n v e s t i g a - t e d in a l a r g e r p o p u l a t i o n . In a d d i t i o n , M D s e e m s to b e f r e q u e n t , w h e n s y s t e m a t i c a l l y l o o k e d for, in p a - tients r e c o v e r i n g f r o m an a c u t e a s t h m a a t t a c k in t h e I C U setting.

Acknowledgements We are indebted to Dr. Philippe Jolliet for helpful criticisms and invaluable linguistic assistance.

References

1. Turner-Warwick M (1988) Epidemiolo- gy of nocturnal asthma. Am J Med 85 [Suppl 1B]: 6-8

2. Douglas N (1985) Asthma at night. Clin Chest Med 6:663-674

3. Douglas N (1989) Nocturnal asthma. QJM 264:279-289

4. Turner-Warwick M (1977) On observ- ing patterns of airflow obstruction in chronic asthma. Respir Med 71:73-86 5. Hetzel M, Clark T (1980) Comparison

of normal and asthmatic circadian rythms in peak expiratory flow rate. Thorax 35:732-738

6. Connolly C (1979) Diurnal rhythms in airway obstruction. Respir Med 73: 357-366

7. Morrison J, Pearson S, Dean H (1988) Parasympathetic nervous system in nocturnal asthma. BMJ 296:1427-1429 8. Chen W, Chai H (1982) Airway cooling

and nocturnal asthma. Chest 81:675-680 9. Davies R, Green M, Schofield N (1976) Recurrent nocturnal asthma after expo- sure to grain dust. Am J Respir Crit Care Med 114:1011-1019

10. Barnes R Fitzgerald G, Brown M, Dol- lery C (1980) Nocturnal asthma and changes in circulating epinephrine, his- tamine and cortisol. N Engl J Med 303: 263-367

11. Cochrane G, Clark T (1975) A survey of asthma mortality in patients between ages 35 and 64 in the Greater London hospitals in 1971. Thorax 30:300-305 12. Bateman J, Clarke S (1979) Sudden

death in asthma. Thorax 34:40--44 13. Hetzel M, Clark T, Branthwaite M

(1977) Asthma: analysis of sudden deaths and ventilatory arrests in hospital. BMJ 1:808--811

14. Barnes E Neville L, Greening A, Tim- mers J, Poole G (1982) Single-dose slow release aminophylline at night pre- vents nocturnal asthma. Lancet I: 299- 301

15. Fairfax A, McNabb W, Davies H, Spiro S (1980) Slow-release salbutamol and aminophylline in nocturnal asthma: re- lation of overnight changes in lung func- tion and plasma drug levels. Thorax 35: 526--530

16. Stewart I, Rhind G, Power J, Flenley D, Douglas N (1987) Effects of sustained release terbutaline on symptoms and sleep quality in patients with nocturnal asthma. Thorax 42:797-800

17. Rhind G, Connaughton J, McPie H, Douglas N, Flenley D (1985) Sustained release choline theophyllinate in nocturnal asthma. BMJ 291:1605-1607 18. Ullman A, Svedmyr N (1988) Salmeter-

ol, a new long acting inhaled B z adreno- ceptor agonist: comparison with salbu- tarnol in adult asthmatic patients. Tho- rax 43:674-678

19. Anderson S, Rodwell L, Du Toit J, Young I (1991) Duration of protection by inhaled salmeterol in exercise-in- duced asthma. Chest 100:1254-1260 20. Fitzpatrick M, Mackay T, Driver H,

Douglas N (1990) Salmeterol in nocturnal asthma: a double blind, placebo con- trolled trial of long acting inhaled

f12

(6)

21. Ullman A, Hedner J, Svedmyr N (1990) Inhaled salmeterol and salbutamol in asthmatic patients. A n evaluation of asthma symptoms and the possible de- velopment of tachyphylaxis. Am J Re- spir Crit Care Med 142:571-575 22. Pearlman D, Chervinsky P, LaForce C,

Seltzer J, Southern L, Kemp J, Dock- horn R, Grossman J, Liddle R, Yancey W, Cocchetto D, Alexander J, Van As A (1992) A comparison of salmeterol with albuterol in the treatment of mild- to-moderate asthma. N Engl J Med 327:1420-1425

23. D'Alonzo G, Nathan R, Henochowicz S, Morris R, Ratner P, Rennard S (1994) Salmeterol xynafoate as maintenance therapy compared with albuterol in patients with asthma. JAMA 271: 1412- 1416

24. Bennett J, Smyth E, Wilding E Tatters- field A (1994) Systemic effects of salbutamol and salmeterol in patients with asthma. Thorax 49:771-774

25. Rabe K, J(Srres R, Nowak D, Behr N, Magnussen H (1993) Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 hours in bronchial asthma. A m J Re- spir Crit Care Med 147:1436-1441 26. L6dfahl C, Chung K (1991) Long-acting

fl2-adreneceptor agonists: a new per- spective in the treatment of of asthma. Eur Resp J 4:218-226

27. Kraft M, Beam W, Wenzel S, Zamora M, O'Brien R, Martin J (1993) Blood and bronchoalveolar lavage endothe- lin-1 levels in nocturnal asthma. Am J Respir Crit Care Med 149:947-952 28. Mackay T, Wallace W, Howie S, Brown

P, Greening A, Church M, Douglas N (1994) Role of inflammation in nocturnal asthma. Thorax 49:257-262 29. Coe C, Barnes P (1986) Reduction of

nocturnal asthma by an inhaled anti- cholinergic drug. Chest 90:485-488