Respiratory Medicine CME
Volume 1, Issue 2 , Pages 111-115, 2008

Efficacy/risk profile of triamcinolone acetonide in severe asthma: Lessons from one case study

Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, Villarroel 170, 08036 Barcelona, Spain

Received 26 November 2007; accepted 22 January 2008.

Article Outline

Summary 

Some prednisone-resistant asthma patients respond to intramuscular triamcinolone acetonide (TA). The use of TA has been questioned on the basis of its potential toxicity. TA's ratio of clinical efficacy to systemic effects compared with oral prednisone has not been clearly defined.

We report the case of a prednisone-insensitive severe asthma patient with insulin-dependent diabetes, hypertension and diabetic retinopathy treated with repeated sessions of laser therapy. By daily monitoring the needs of insulin doses we compared the systemic effects of prednisone and TA.

The analysis of the balance between systemic effects (insulin doses) and beneficial effects (PEF values) show that TA has a better benefit/risk profile than prednisone. The patient has been followed up for 3 years and has received injections of TA repeated at intervals ranging from 21 to 60 days according to patient response and the evolution of PEF and clinical symptoms. During this period the patient lost 3kg of weight, while presenting increased bone mineral density, normalized arterial tension, and improved proliferative diabetic retinopathy.

The present case report shows that TA has a better benefit/risk profile than prednisone. TA can be a valuable alternative in the control of some patients with severe prednisone-resistant asthma.

Keywords: Insulin, Refractory asthma, Severe asthma, Steroid-dependent asthma, Triamcinolone acetonide

 

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Introduction 

Response to glucocorticoids varies widely among asthma patients, with some improving with small doses of inhaled glucocorticoids, while others do not respond at all to high doses of systemic glucocorticoids.1

The so-called steroid-resistant asthma, constitutes a therapeutic challenge that at present has no efficacious alternative therapy.1

There is, however, an extended literature on the use of the intramuscular injection of triamcinolone acetonide (TA) in asthmatic patients who do not respond to prednisone. In most of these studies, asthma patients insensitive to prednisone show a very good response when treated with AT.2, 3, 4, 5, 6, 7, 8, 9

Two reasons are usually suggested to explain these differences in the response: (1) the improvement after the intramuscular injection of TA reflects nothing more than improvement in adherence to the treatment, and (2) triamcinolone is released from the acetonide or depot form of the drug by a slow enzymatic process of deacetonization. This results in a long pharmacological half-life with remarkable therapeutical efficacy but also with a high rate of corticosteroid-related toxicities. Thus, the injection of TA represents the use of a potent corticosteroid with pros and cons similar to those observed with very high doses of prednisone.10

Nevertheless, some observations do not appear to support these arguments. In fact, prednisone-resistant asthma patients who are good compliant subjects, respond to TA without apparently suffering from an evident increase in systemic side effects. On the contrary, these patients often lose weight, their cushingoid appearance of the face normalizes, and their blood pressure decreases, when they are switched from high doses of daily prednisone to shots of TA.7, 9

These observations support the notion that TA may be more effective than prednisone through a mechanism other than improved compliance, as well as suggesting that its therapeutic efficacy is not necessarily associated with the induction of more severe and unacceptable steroid-related systemic side effects.

Systemic side effects of glucocorticoids can be assessed by measuring cortisol levels at baseline and after corticotropin. However, these methods are not very useful in the daily monitoring of the systemic effects of glucocorticoids, particularly in severe asthma patients who are usually treated with fluctuating doses of systemic glucocorticoids.

In patients with diabetes mellitus treated with insulin, the use of glucocorticoids is usually associated with a proportional increase in the units of insulin needed to control serum glucose levels.11

We report the case of a corticosteroid-insensitive severe asthma patient who was also an insulin-dependent diabetic. By monitoring the needs of insulin doses on a daily basis, we compared the systemic effects of prednisone and TA. We also evaluated the response of asthma to prednisone and TA through daily monitoring of PEF, as well as through the assessment of clinical symptoms and the use of short-acting β2-agonist agents as rescue medication.

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Case report 

A 56-year-old man was referred to the Severe Asthma Clinic of our Institution for evaluation. Asthma has developed at the age of 39 with the characteristics of a severe process. Exacerbations occurred frequently, triggered by respiratory infections, physical activity, cold air, and exposure to irritants (paints, smoke). Attacks often occurred at night or in early morning. He had a chronic morning cough that produced scanty clear secretions. He had visited the emergency department on many occasions and had been admitted to hospital five times, but never to the intensive care unit. The patient has never smoked, had no history of allergy and the prick test to common allergens was negative. He was followed by a specialist in pulmonary medicine and treated with fluticasone (1000μg/day), salmeterol (100μg/day), montelukast (10mg/day), and oral prednisone (daily doses fluctuating between 10 and 70mg). He often used salbutamol as rescue medication and was also provided with a nebulizer to self-administer at home a combination of salbutamol and ipratropium bromide that he has used regularly (ranging from 2 to 6 nebulizations daily).

The patient had a history of diabetes mellitus that began at the age of 18 and treated with insulin (Unilong 375, Lilly, Spain; mean daily dose 40 units, ranging from 30 to 70 units). He presented various common complications associated with diabetes mellitus including: diabetic retinopathy, and erectile and urinary blander dysfunction. He had required laser therapy four times to treat the retinopathy. He also suffered from arterial hypertension treated with enalapril maleate.

The patient appeared to be compliant with respect to the medication and he used inhalers adequately. He had a normal weight for his height, gender and age, and he had a mild cushingoid face appearance.

The patient was followed up in the out-patient clinic and the presence of the comorbidities sometimes associated with refractory asthma (cardiac insufficiency, gastroesophageal reflux, and obstruction of the upper airway), was excluded. The patient remained symptomatic with daily symptoms, frequent night awakening and regular use of bronchodilator therapy. The daily dose of prednisone ranged from 10 to 60mg. With high doses of prednisone (60–70mg/day), the symptoms appeared to slightly improve but when the dose of prednisone was tapered below 25–20mg, they worsened again and the patients had to use nebulized bronchodilator therapy 5–6 times a day. Daily PEF measurements showed values from 150 to 230L/m changing in parallel to variations in the oral dose of prednisone.

A bone mineral densitometric (BMD) study showed a spine osteopenia (BMD=0.979g/cm2; T-score=−2.0; normal values T-score⩾−1.0).

To check the adequate use of medication and the response to glucocorticoids, the patient was admitted to hospital and treated with 70mg of prednisone (1mg/kg of weight) for 4 days, and the dose was progressively tapered by 10mg every 3 days. The patient was discharged on day ten and followed up in the out-patient clinic. The morning PEF slowly improved from a baseline value of 160L/m to a maximal of 230 with glucocorticoid therapy, but the improvement slowed down when the dose of oral prednisone was progressively tapered (Figure 1). The forced expiratory volume in the 1s (FEV1), rose from a baseline value of 54% of predicted to a maximal value of 63% predicted. Clinical symptoms followed a similar pattern to that of PEF, with an initial improvement followed by a progressive deterioration when the dose of prednisone was reduced. When the patient was on 10mg of prednisone, an intramuscular injection of 40mg of TA was administered and prednisone was discontinued. A dramatic and rapid increase in morning PEF was observed, rising from 150L/m up to 420L/m. The FEV1 went to up to 80% predicted from a baseline value of 57% predicted. There was a marked improvement in symptoms during the day and at night. The therapeutic effects of TA lasted for almost 4 weeks; after that period the PEF began to decline and the symptoms also restarted with nasal obstruction, productive cough, shortness of breath and night awakenings (Figure 1). After 4 weeks of occasional use of rescue medication, the patient had to take additional puffs of salbutamol almost daily.

  • View full-size image.
  • Figure 1. 

    Changes in morning PEF (L/m) with a burst of prednisone followed by an intramuscular injection of 40mg of triamcinolone acetonide (TA). PEF=peak expiratory flow.

A second injection of TA produced the same results and it was decided to maintain the patient on regular therapy with this drug. The patient has been followed up for 3 years. During this period he has received injections of TA repeated at intervals ranging from 21 to 60 days according to patient response and the evolution of PEF and clinical symptoms. All his other therapy (fluticasone, salmeterol, and montelukast) remained unchanged. He has not attended the emergency department and has not been hospitalized within this 3-year period.

In a routine control, the patient's ophthalmologist found a dramatic improvement in the proliferative diabetic retinopathy, with completed resolution of macular oedema and significant improvement in visual acuity. A BMD study after 1 year of TA therapy showed a 7.8% increase in BMD (1.063g/cm2; T-score=−1.5).

The monitoring of changes in daily insulin doses and PEF values was used to assess and compare the systemic effects and therapeutic efficacy of triamcinolone and prednisone. Figure 2 shows the mean change in insulin doses and morning PEF from four consecutive injections of TA repeated every 6 weeks. The insulin doses were increased immediately after the injection and progressively reduced until approximately the 18th day, and after that no more significant changes were observed. The PEF also steadily increased by reaching the maximal value around the third week. The PEF begun to decline around the fourth week and the decrease accelerated during the sixth week. Clinical symptoms usually reappeared within the fourth and fifth week. The sequence of clinical events almost always followed the same pattern: first, nasal obstruction, and rhinorrhea; second, cough, and bronchial secretions, and finally, shortness of breath and night awakenings.

  • View full-size image.
  • Figure 2. 

    Change in insulin doses (units) and morning PEF (L/m/10) from four consecutive injections of 40mg of triamcinolone acetonide (TA), repeated every 6 weeks. Values are expressed as mean±SD. PEF=peak expiratory flow.

Figure 3 shows the change in morning PEF and insulin doses during a burst of oral prednisone, started at 1mg/kg of weight (70mg/day) for 4 days and then progressively tapered 10mg every 3–4 days. There was an increase in the insulin doses in parallel to the increase in prednisone. The PEF also increased, but much less than with the injection of triamcinolone (Figure 2). If we take the doses of insulin as a marker of the systemic effect of the two glucocorticoids, and the changes in PEF as a measure of the efficacy of the therapies, the ratio of efficacy vs systemic side effects is clearly in favour of TA (Figure 2, Figure 3).

The effects of an injection of TA and a burst of prednisone on insulin doses are shown and compared in Figure 4. The maximal effect of TA appears to be equivalent to that exerted by 50–60mg of prednisone, while the effect of TA on insulin in the fifth and the sixth week, when its efficacy began to decline, seems to be close to that caused by 5mg of prednisone.

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Discussion 

The patient herein presented is representative of a small percentage in the whole asthma population, but he is not so rare in those specialized asthma clinics to which difficult-to-control asthma patients are usually referred. Despite the use of the most potent inhaled glucocorticoids associated with long-acting β2-agonist bronchodilators and antileukotriene drugs, these patients need regular treatment and/or frequent short courses of oral glucocorticoids. In some of these patients the response to systemic glucocorticoids is even poor or null (steroid-resistant asthma). Previous studies, and this case report, show that the injection of TA is very effective in asthma patients who do not respond to high doses of prednisone.2, 3, 4, 5, 6, 7, 8, 9

Whether the higher efficacy of TA is due to improved compliance, improved anti-inflammatory effects or both is a matter of debate. The use of TA is also questioned on the basis of the unacceptable toxicity that its use may cause.10

Intramuscular TA's ratio of clinical efficacy to systemic effects compared with oral prednisone has not been clearly defined. Various validated and standardized methods are available to easily and continuously monitor the pharmacological effects of antiasthma drugs, such as PEF measurement, scoring of symptoms and quantification of the needs of rescue medication. However, there are no similar tools available to closely and regularly assess the systemic effects of glucocorticoids in patients submitted to fluctuating doses of the drugs. Even more complicated is the comparative study of different glucocorticoids with disparate pharmacokinetic profiles such as prednisone and TA. The peak plasma concentration of TA occurs within 8–48h of injection, after which there is a steady decrease, with the drug being undetectable in plasma after 21 days12 In contrast, oral prednisone is rapidly absorbed across the gastrointestinal membrane. Peak effects can be observed after 1–2h. Prednisone is metabolized by the liver to the active metabolite prednisolone, which is then metabolized to inactive compounds. The plasma elimination half-life is 1h, whereas the biological half-life of prednisone is 18–36h.13

The diabetic condition of the glucocorticoid-resistant asthmatic presented in this case report, allowed us to daily monitor the systemic effect on a daily basis using the well-known effect of glucocorticoids on insulin doses. The use of PEF and its correlation with the changes in clinical symptoms also enabled us to compare the therapeutic efficacy of the two glucocorticoids. The analysis of the balance between systemic effects (insulin doses) and salutary effects (PEF values), presented in Figure 1, Figure 2, shows that TA has a better benefit/risk profile than prednisone.

The higher anti-inflammatory potency of TA compared to prednisone is also supported by the observed improvement in diabetic retinopathy when the patient started TA therapy. While the patient was on prednisone, he needed laser therapy several times; this treatment was no longer used in the 3-year follow-up period of observation during which he was on TA. This finding concurs with recent reports in the ophthalmology literature on the success of intravitreal administration of TA in the treatment of diabetic retinopathy apparently resistant to other glucocorticoids.14

Why could a single 4–6 weekly dose of TA improve control in a patient with a prednisone-resistant asthma? The change from oral to intramuscular administration was considered to account for the improvement in symptoms, lung function and sputum eosinophilia in a group of asthma patients not responding to oral prednisone who were treated with one single dose of 40mg of TA.8 Surprisingly, in the interpretation of the results, the authors did not take into account that they have changed not only the route, but also the glucocorticoid. The authors did not mention any of the previously reported studies on the use of TA in severe asthma, despite the fact that this option has been discussed by various researchers for over 20 years.2, 3, 4, 5, 6, 7, 9

Although the reason(s) why TA is more effective than prednisone in severe asthma are as yet unclear, most probably the pharmacological profile of TA could account, al least in part, for its greater anti-inflammatory potency. Perhaps continuous exposure of inflammatory cells to TA is more effective than the short contact to intermittent doses of prednisone.

The patient's 3-year follow-up also illustrates the good tolerability of TA. During this period the patient lost 3kg of weight, his BMD increased, his arterial tension normalized and treatment with enalapril maleate could be discontinued. These observations concur with previous reports showing significant fall in weight and improvement in hypertension control in patients on TA with respect to the period on prednisone therapy.7, 9 Previous studies have also shown that reduction of the glucocorticoid dose may result in a partial recovery of the lost BMD.15 Our findings suggest that treatment with TA caused less deleterious effects on bone mineralization than prednisone therapy.

However, not all patients tolerate TA so well, and muscular atrophy, menstrual irregularities and hirsutism have been reported in patients repeatedly treated with doses of TA higher than 40mg and/or for periods shorter than 4–5 weeks.6, 7 The patient reported herein developed bruising and skin fragility that resulted in frequent skin lacerations caused by minor trauma. Skin atrophy is one of the main side effects observed with TA therapy in comparison with prednisone treatment. There is no clear explanation accounting for the contrasting side effects exerted by TA on weight, hypertension, and bone mineralization compared to skin atrophy. Skin atrophy has been observed with fluorinated glucocorticoids administered by all routes (inhaled, systemic, and topical)16, 17 but the mechanisms involved in varying intensities of the systemic side effects of these drugs on different tissues and organs are as yet unclear.

In summary, intramuscular TA proved to be effective in a prednisone-resistant asthma patient. By assessing changes in insulin doses it was possible to closely monitor and compare the systemic side effects of TA and prednisone, two drugs with very different pharmacokinetic profiles. The analysis of the balance between systemic effects (insulin doses) and therapeutic effects (PEF values) shows that TA has a better benefit/risk profile than prednisone. In addition, some prednisone-associated side effects decreased during the 3-year follow-up treatment with TA. All in all, these findings suggest that TA can be a potentially valuable alternative in the control of some severe, prednisone-resistant asthma.

Elucidation of the mechanisms by which TA is more effective than prednisone in some severe asthmatics might help to better understand the origin of glucocorticoid resistance and could also contribute to the design of powerful new drugs to treat these patients, who are usually difficult to manage.

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Conflict of interest statement 

The author has no conflict of interest to declare in relation to this work.

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References 

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PII: S1755-0017(08)00010-9

doi:10.1016/j.rmedc.2008.01.005

Respiratory Medicine CME
Volume 1, Issue 2 , Pages 111-115, 2008

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