Intramuscular triamcinolone acetonide in chronic

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Thorax 1985;40: 840-845

Intramuscular triamcinolone acetonide in chronic
severe asthma
DT McLEOD, SJ CAPEWELL, JENNIFER LAW, W MAcLAREN, A SEATON
From the Chest Unit, City Hospital, and Institute of Occupational Medicine, Edinburgh

ABSTRACT, Seventeen subjects with chronic severe asthma completed a 48 week prospective,
double blind study with crossover of treatment at 24 weeks, in which triamcinolone acetonide
80 mg intramuscularly every four weeks was compared with oral prednisolone 10 mg daily.
Spirometry, twice daily measurements of peak expiratory flow rate, and self assessment of asthma
symptom scores showed significant improvement during triamcinolone treatment; less extra pred-
nisolone was required and there was significant weight loss. Two patients withdrew, one because
of dissatisfaction with prednisolone and one because of side effects while taking triamcinolone.
Three were withdrawn, one with proximal muscle weakness and two because of intercurrent
illness. Adrenal suppression, bruising, and hirsuitism were worse with triamcinolone, other side
effects being comparable. On completion of the study 16 of the 17 patients opted to continue
taking triamcinolone acetonide. This treatment is an important addition to the therapeutic
options available for chronic severe asthma.

The introduction of corticosteroids revolutionised               Methods
the treatment of asthma in the 1950s' and inhaled
corticosteroids subsequently produced further sub-                 Twenty two patients agreed to take part in the study.
stantial benefits for many asthmatics by reducing or               All had longstanding asthma and had previously
abolishing the need for regular oral corticosteroid                shown considerable variability in ventilatory func-
treatment.2 Some asthmatic patients continue to                    tion spontaneously and at least 20% improvement
have symptoms with persistently poor ventilatory                   in FEV, with corticosteroid treatment. All had
function despite continuous oral corticosteroid                    required a minimum of 10 mg oral prednisolone
treatment. These patients are frequently much dis-                 daily for several years as well as inhaled bec-
abled by their disease and improve appreciably                     lomethasone 400 ,ug daily; with this combination all
only with unacceptably high doses of corticosteroids.              had peak flow rates less than 70% of predicted.
They therefore pose both a therapeutic dilemma and                 None had suffered an exacerbation of symptoms or
an important challenge in asthma research.                         had needed to increase the dose of prednisolone in
   We have treated such patients with intramuscular                the four weeks before entering the study.
triamcinolone acetonide for some years and have                       All patients gave written consent and the study
formed the impression that this often has consider-                protocol was approved by the local ethical commit-
able advantages for the patient, a suggestion sup-                 tee. Patients were instructed in the completion of a
ported by two previous studies.34 To confirm this,                 diary card, recording twice daily peak flow rate (best
we selected patients with chronic severe asthma who                of three blows), day and night symptom scores (from
required at least 10 mg of prednisolone as daily                   0 = "no symptoms" to 4 = "symptoms requiring
maintenance treatment in addition to inhaled                       emergency treatment"'), extra treatment required,
corticosteroids, and compared monthly intramuscu-                  and any other comments. They were examined
lar triamcinolone acetonide with daily oral pred-                  every four weeks with measurement of FEV, FVC,
nisolone in a study using objective measurements                   weight, and blood pressure; urine analysis; and fun-
and diary card assessment.                                         doscopy. Proximal muscle weakness was tested by
Address for reprint requests: Dr A Seaton,   Institute of Occupa-
                                                                   asking the patient to stand upright from the squat-
tional Medicine, Edinburgh EH8 9SU.                                 ting position five times in quick succession. Cushin-
                                                                   goid appearance, bruising, and peripheral oedema
Accepted 29 April 198S                                             were scored in terms of severity on a five point scale.
                                                                 840
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Intramuscular triamcinolone acetonide in chronic severe asthma                                        841
In addition, on entry and at 12, 24, 36, and 48 weeks both the " triar' and the " active" bottles were
a full blood count was done and concentrations of counted.
electrolytes, urea, calcium, phoshate, and alkaline       The data were entered into a Prime 750 compu-
phosphatase were checked. A short tetracosactrin ter. Statistical methods were primarily descriptive,
test (250 ,g given by intramuscular injection with paired t tests being used to test the significance of
plasma cortisol recorded at 0 and 30 minutes) was any differences observed.
performed on entry and at the end of each 24 week
period of treatment.                                    Results
   We used a 48 week double blind, placebo control-
led study design, with crossover of treatment after Twenty two subjects, 15 men and seven women
24 weeks. Active treatment-triamcinolone (mean age 56 years, range 23-71) started the study.
acetonide 80 mg intramuscularly every four weeks Two smoked 10 cigarettes daily and three were
or prednisolone 10 mg orally each day-was given ex-smokers. Three were withdrawn from the study:
to all patients along with the corresponding placebo one suffered a myocardial infarct 20 weeks after
tablets or placebo injections. Patients were ran- starting the study; one died of bronchial carcinoma,
domly allocated in equal numbers to the initial which was diagnosed at 28 weeks; and one noted
active treatment and instructed to take their trial increasing proximal muscle weakness at 40 weeks
tablets early each morning. After the 48 weeks all (16 weeks after starting triamcinolone). Two others
subjects were asked to state whether they preferred withdrew, one because of no improvement after
the first or second 24 week treatment period, after eight weeks of prednisolone and one because of
which the code was broken.                              weight loss and muscle weakness after 12 weeks of
   Subjects were instructed to treat an exacerbation triamcinolone. Thus 17 subjects completed the
during the trial by taking extra prednisolone, 20 study but sufficient data were collected on the
mg/day for at least five days, and then reduce it in patient who completed 40 weeks to permit his inclu-
their usual way. All were supplied with labelled sion in the analysis.
active prednisolone for this purpose. Other treat-
ment, such as inhaled or oral sympathomimetics, PEAK FLOW RATES: DIFFERENCES BETWEEN
was continued unchanged throughout the study. All TREATMENTS
changes in treatment were recorded on the diary The mean results of the peak flow recordings are
cards and at each clinic visit the remaining tablets in shown in the figure. The patients who started with

                                                                       _.- PM          TRIAMCINOLONE FIRST
                                                                        - - --   -AM TRIAMCINOLONE FIRST
                                                                         -  PREDNISOLONE FIRST
                                                                             -    PM
                   350   r-                                            -APM PREDNISOLONE FIRST

                   330 I
                                                                                             /     0000,
            PEAK
                   310   _-
            FLOW
            RATE 290
            (I.min )
                   270

                   250 1-

                   230 _-

                         L    1   2      3       4    5     6     7     8               9     10       11    12
                                                MONTHS FROM START OF TRIAL
             Mean peak flow rates recorded morning and evening through the trial. Continuous lines
             represent subjects who received triamcinolone for the first six months and interrupted lines those
             who received prednisolone first.
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842                                                                 McCleod, Capewell, Law, MacLaren, Seaton
triamcinolone had higher average peak flows at the         Table 2 Peak flow rates with triamcinolone for months I
start of the study (mean values 288 versus 250 1           and 2 compared with months 4 and 5 for 18 patients (mean
min-'). This was a chance difference and did not affect    values with standard deviations in parentheses)
the analysis as each patient was compared with him-                      Peak flow rate (I min - ')
self or herself on the second treatment. Those sub-
jects receiving triamcinolone had consistently higher                    Months I and 2          Months 4 and 5      p value
readings than those receiving prednisolone through-         Morning      280 (69.7)              297 (75.9)
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Intramuscular triamcinolone acetonide in chronic severe asthma                                                                    843
Table 3 Peak flow rate values (1 min-') for 18 patents: second versus fourth week duing each four week cycle (mean
values with standard deviations in parentheses)
                 Triamcinolone                                                    Prednisolone
                 Week 2               Week 4                p                     Week 2                Week 4                p
Morning          277 (81.9)           266 (7X.3)
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844                                                                     McCleod, Capewell, Law, MacLaren, Seaton
Table 6 Numbers ofpatients developing side effects                not a new idea. Methyl prednisolone acetate given
                                                                  every two weeks has been shown to lessen the over-
Side effect                   Triamcinolone        Prednisolone   all severity of asthma symptoms.9 This intermittent
Bruising                                                          high dose "pulse" corticosteroid treatment has been
  Armsandhands              10                      10            shown in other diseases to alter alveolar mac-
  Shins                      4*                      1
Muscle weakness              2                       0            rophage function in a dose dependent fashion,
Muscle pain                  6                       4            decrease the level of immune complexes, alter alveo-
Ankle oedema (intermittent) 3                        2
Facial hirsuitism            3                       1            lar macrophage function, and reduce the number of
Increased Cushingoid                                              neutrophils in the lung,'0 yet even in high dosage is
  appearance                 3                       7            remarkably safe. After the injection of triam-
*There was more pretibial bruising with triamcinolone.            cinolone acetonide the peak plasma concentration is
                                                                  achieved within three to 48 hours, after which there
acetonide every 28 days, equivalent to 2.86 mg/day,               is a steady decline until the drug is virtually unde-
is more effective than 10 mg of prednisolone daily.34             tectable in plasma after 21 days." Thus clinical
This suggests that triamcinolone acetonide is more                activity, while being reduced somewhat in the fourth
potent in terms of its effect on the airways, though              week, lasts much longer than the period during
not necessarily so in respect of systemic side effects            which the drug is detectable. Monthly injection of
and adrenal suppression. Such a view is supported                 triamcinolone acetonide is, in essence, a form of
by a study in which significantly less adrenal sup-               such "pulse" treatment with high plasma concentra-
pression was noted with triamcinolone acetonide4                  tions, particularly in the first week. This may be one
and by another in which no greater suppression was                of its antiasthma mechanisms.
found after two years' treatment with triamcinolone                  The relative potency of different corticosteroids is
acetonide.3 Our finding of greater adrenal suppres-               clearly important in interpretation of our results.
sion with triamcinolone acetonide may be due to our               Cautious interpretation is required, as estimation of
studying an older age group with more severely                    potency depends not only on the animal model but
impaired adrenals before entry, as a result of previ-             also on the target organ or tissue tested and the
ous prolonged prednisolone treatment. Others,                     route of administration. Experiments on rats or
using 60 mg intramuscularly every four to six weeks,              mice, species sensitive to corticosteroids, may bear
have found that adrenal recovery occurs before the                no relationship to what occurs in man, with his rela-
next injection in half of the patients.56 To judge by             tive resistance to corticosteroids. More than 20
experience from the disciplines of dermatology and                years ago modified corticosteroids with unusually
rheumatology, where triamcinolone acetonide                        high topical potency on human skin were developed
40-60 mg every four to six weeks has been used                    by forming 16,17-acetonides or by esterification at
widely, major side effects have been remarkably                    the 17 or 21 position (or both). By this means the
few.7 Menstrual irregularities in half of the pre-                 topical anti-inflammatory activity 'was much
 menopausal women have been reported, resulting                    increased while the systemic glucocorticoid effects
from altered levels of gonadotrophins and ovarian                  were little changed. A vasoconstriction assay on
 hormones.8 Patients tend to lose weight, not always               human skin using alcohol solutions of cortico-
 a bad thing in chronic asthmatics, perhaps because                steroids under occlusive dressings showed that the
 of loss of fat or less salt and water retention; the              relative topical potency of dexamethasone to triam-
 possibility of subclinical myopathy remains specula-              cinolone acetonide to beclomethasone dipropionate
 tive. Blood glucose and electrolyte concentrations                was 0.8:100:500.12 Given intravenously, however,
 are unaffected. In our wider experience outside this              beclomethasone dipropionate was equivalent to
 study, proximal myopathy occurs in about 5% but                   dexamethasone in lowering cortisol (implying a simi-
 this complication should not be exaggerated, being                lar systemic glucocorticoid effect). While triam-
 easily detected and reversible. Bruising is more not-             cinolone acetonide is about 100 times more potent
 able, particularly in those over 60 years of age.7 The            than dexamethasone on human skin, its relative
 risk of osteoporosis has not been assessed and merits             potency with respect to reduction of plasma cortisol
 further study. Long term side effects may be further              does not appear to have been investigated.
 reduced by using triamcinolone acetonide judici-                     One of the actions of corticosteroids leads to the
 ously. It may be possible in individual patients to               synthesis of a factor that blocks phospholipase A2,
 reduce the injection dose as well as to extend the                thus preventing the biosynthesis of a whole cascade
 interval between injections from four to six or even              of lipid mediators.'3 The potency of this inhibition
 eight weeks.                                                      closely parallels anti-inflammatory activity. If there-
    Transferring asthmatic patients from oral to                   fore a local anti-inflammatory effect within the air-
 parenteral long acting corticosteroid treatment is                way were a critical factor in the unique efficacy of
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Intramuscular triamcinolone acetonide in chronic severe asthma                                             845
corticosteroids in asthma, and if this effect within     corticosteroid-resistant asthma. Br J Dis Chest 1979;
the bronchial mucosa were relatively greater than         73:39-44.
the systemic glucocorticoid effect, the benefits 4 Willey RF, Fergusson RJ, Godden DJ, Crompton GK,
would outweigh potential side effects.                    Grant IWB. Comparison of oral prednisolone and
                                                         intramuscular deport triamcinolone in patients with
   Most patients with asthma respond to pred-            severe chronic asthma. Thorax 1984;39:340-4.
 nisolone and we see no reason for changing the 5 Mikhail GR, Sweet LC, Mellinger RC. Parenteral
general use of this well tried drug. Growing aware-      long-acting corticosteroids: effect on hypothalamic-
ness of the problem of steroid resistant patients,'4     pituitary-adrenal function. Ann Allergy 1973;
however, raises the possibility that individual varia- 6 31: 337-43. Lech
tion in steroid cell membrane receptors may also          Droszcz W,       B, Malunowicz E, Piotrowska B. Fac-
                                                         tors influencing adrenocortical suppression during
alter the clinical response. Triamcinolone acetonide,    long-term triamcinolone acetonide therapy in asthma.
for reasons still poorly understood, appears to offer    Ann Allergy 1980;44: 174-6.
a valuable alternative to prednisolone in chronic 7 Arnold HL. Safer long-term steroid therapy with
severe asthma. It has the advantage of guaranteed        injected triamcinolone acetonide. Int J Dermatol
                                                          1978; 17:216-7.
compliance and it appears to be acceptable to most 8 Carson
of our patients.                                                  TE, Daane TA, Weinstein RL. Long-term
                                                         intramuscular administration of triamcinolone
                                                               acetonide. Arch Dermatol 1975; 111: 1585-7.
We are most grateful to Catherine McLennan,                  9 Nash J, Jacomb RG. Corticosteroid therapy in chronic
Morag McVittie, and ABH Hunter from the City                   asthma. Practitioner 1968;201: 358-61.
Hospital, Edinburgh; R Murdoch from the Institute           10 Keogh TA, Bernardo J, Hunninghake GW, Price DL,
of Occupational Medicine; Dr PH Lacey of Pfizer                Crystal RG. Effect of intermittent high dose parenteral
                                                               corticosteroids on the alveolitis of idiopathic pulmo-
Ltd; and P Woods of ER Squibb and Sons Ltd; and                nary fibrosis. Am Rev Respir Dis 1983; 127:18-22.
to Joyce Holywell and Elizabeth Crolla for typing           11 Kusama M, Sakauchi N, Kumaoka S. Studies of plasma
the manuscript. Dr Peter Howard gave us the origi-             levels and urinary excretion after intramuscular injec-
nal idea.                                                      tion of triamcinolone acetonide. Metabolism 1971;
                                                               20:590-6.
                                                            12 Harris DM. Some properties of beclomethasone di-
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Downloaded from http://thorax.bmj.com/ on January 22, 2015 - Published by group.bmj.com

                         Intramuscular triamcinolone
                         acetonide in chronic severe
                         asthma.
                         D T McLeod, S J Capewell, J Law, W MacLaren and A
                         Seaton

                         Thorax 1985 40: 840-845
                         doi: 10.1136/thx.40.11.840

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