TY - JOUR
AU - FACS, David G. Greenhalgh, MD,
AB - Steroids have been used for decades to treat many chronic lung diseases. The key hypothesis for the use of steroids is to reduce a prolonged and destructive inflammatory response. In addition, glucocorticoids may enhance the responsiveness to beta-agonists (which themselves reduce airway reactivity and mucosal edema).1 The anti-inflammatory effects not only reduce the destructive effects of persistent inflammation, but they may also reduce mast cells and thus inhibit the response to allergens. In smoke inhalation injury the response to the insult may be as damaging as the original injury—so it makes sense that steroids may improve the outcome of inhalation injury. Glucocorticoids may have theoretic advantages but their use is not without risk. A major concern is increased potential for infections in patients already at risk for sepsis. The well-known side effects of systemic treatment have led to the common use of inhaled steroids. The concept is that the drugs are delivered to the site of activity while minimizing the ill effects. There are both local and systemic side effects of inhaled steroids.2,3 Local effects include pharyngitis, dysphonia, reflex cough, bronchospasm, and oropharyngeal candidiasis. Because the lungs are a highly efficient avenue for drug delivery (such as delivery of nicotine in cigarettes) it is not surprising that there are systemic side effects of inhaled corticosteroids (ICS). Inhaled ICS can suppress the hypothalamic-pituitary-adrenal (HPA) axis function even to the point of causingadrenal crisis. In children, suppressed growth velocity (as measured by lower leg length) has been well documented. The delayed growth velocity is reversed with the cessation of the ICS. Patients of all ages may have reduced bone mineral density that increases the risk for fractures and osteoporosis. There are potentialchanges to the skin (thinning and increased bruising) and eyes (increased risks for cataracts and glaucoma) that result from inhaled steroids. Despite these known side effects ICS have become quite common in treating chronic pulmonary diseases. The most studied disease is asthma. The current feeling is that long-term ill effects of asthma are the result of an excessive inflammatory response. Therefore, the use of ICS has become quite common. The studies that support the use of ICS are well designed and have led to “level-one evidence.” The National Heart, Lung, and Blood Institute of the National Institute of Health has supported excellent studies. There are two well-organized groups for these studies: the Asthma Clinical Research Network (ACRN) for adults and Childhood Asthma Research and Education Network for pediatrics. An excellent review of the current studies has recently been published.4 A brief summary of the asthma studies will be provided. An early ACRN study examined the question of whether regular use of a beta-agonist (albuterol) was any better than “as-needed” use. The ACRN Beta Agonist study revealed no difference and suggested that beta-agonists should only be used on an “as-needed” basis.5 The Salmeterol or Corticosteroids study asked if the long-acting beta-agonist salmeterol could replace inhaled triamcinolone.6 They found that salmeterol could not replace the use of the ICS. The next ACRN study, the “Salmeterol ± Inhaled Corticosteroids” (SLIC) trial, asked if adding salmeterol to a low-dose ICS prevented the need to increase the ICS dose.7 During periods of ICS reductionthere was no difference in treatment failures whether salmeterol was used or not. After elimination of ICS, the salmeterol group had fewer treatment failures. The conclusion was that salmeterol allowed for a 50% reduction in the ICS dose but would not allow for the elimination of ICS altogether. Another important finding was that there are variations in the response to beta-agonists dependent upon genotypic changes in the β2-adrenergic receptor. The Beta-Adrenergic Response by Genotype trial determined whether there were different responses to beta-agonists based on variations in the 16th amino acid of the β2-adrenergic receptor.8 They found that patients with the Gly/Gly 16th amino acid genotype had functional improvements in response to albuterol, whereas the Arg/Arg genotype failed to respond to the beta-agonist. A retrospective review of the Salmeterol or Corticosteroids study and SLIC trials supported the finding that the Arg/Arg β2-adrenergic receptor genotype failed to respond to salmeterol as the other genotype.9 These studies give an example of why there are marked variations in response to specific agents in clinical trials. Another trial was performed to assess the relative dosing and efficacy of various ICS products. The DOSE of Inhaled Corticosteroids with Equisystemic Effects study examined the dose required to induce HPA-axis suppression.10 HPA-axis suppression was determined by several assays including serial urine and plasma cortisol concentrations, and serum osteocalcin measurements. A ranking of relative efficacy was determined based on the dose causing 10% HPA-axis suppression. The rank order of side-effect potency was according to labeled doses: flunisolide-CFC (1), triamcinolone acetonide-CFC (1.19:1), BDP-CFC (1.69:1), FP-DPI (2.08:1), budesonide-DPI (3.45:1), and FP-CFC (8.33:1). [CFC = chlorofluorocarbon, BDP = beclomethasone dipropionate, FP = fluticasone propionate, DPI = dry powder inhaler]. Another useful trial, the Measuring Inhaled Corticosteroid Efficacy study made benefit/risk assessments for controller therapies.11 Thirty patients with mild-to-moderate asthma were randomized to 18 weeks of escalating doses of either BDP-CFC or FP-CFC metered-dose inhalers, followed by a 3-week administration of high-dose FP-DPI to assess maximum effects. They found that low-dose FP-CFC was associated with the maximum improvement in FEV1 values, whereas a medium dose of BDP-CFC was required to achieve a similar effect. For both agents, the dose required for HPA-axis suppression was higher than the dose for maximal FEV1 improvement. Another important note for future inhalation injury trials was that approximately one third had poor responses to any ICS treatment. Finally, the Improving Asthma Control trial was performed to answer the question: Do mild asthma patients need daily anti-inflammatory “controller” therapy?12 They randomized patients with mild asthma to budesonide, zafirlukast (a leukotriene receptor antagonist) or placebo and found that all groups had similar rates of asthma exacerbation. Recent studies from different groups provide similar findings of benefit of ICS. In the Leukotriene or Corticosteroid or Corticosteroid-Salmeterol trial by the American Lung Association Asthma Clinical Research Center, patients were randomized to inhaled fluticasone (100 µg twice daily), montelukast 5 to 10 mg (each night), or fluticasone (100 µg) plus salmeterol (50 µg) each night.13 There was a 20% failure rate for the either of the steroid groups, whereas there was a 30% failure rate for montelukast (hazard ratio for both comparisons was 1.6 (95% confidence interval, 1.1–2.6, P = 0.03). In the Beclomethasone plus Salmeterol Treatment study, patients with mild asthma were randomized to receive placebo twice daily plus beclomethasone (250 µg) and albuterol (100 µg) in a single inhaler as needed; placebo plus albuterol (100 µg) as needed; beclomethasone (250 µg) twice daily and albuterol (100 µg) as needed; or beclomethasone (250 µg) plus albuterol (100 µg) in a single inhaler twice daily plus albuterol (100 µg) as needed.14 They found that the symptom-driven use of the combination drugs “as needed” did as well as the regular dosing of inhaled steroids. Both of these studies led to potential methods for reducing the cumulative dosing of ICS. The Childhood Asthma Research and Education Network performed similar studies for children. The first trial, the Prevention of Early Asthma in Kids trial, addressed the question: can early recognition and treatment of children at increased risk of asthma prevent its clinical expression or affect any pulmonary function changes?15 Children, ages 2 to 3 years with a “positive modified asthma predictive index” were treated for 2 years with either two puffs of fluticasone 44 µg per puff administered through an metered-dose inhaler or placebo. During treatment there was a 4.8% greater proportion of “episode-free” days (P = .006), a 32% lower rate in exacerbations (P < .001) and a 53% reduction in supplementary ICS use (P < .001). There were some side effects with a reduction in growth velocity and height. This trial suggested that ICS treatment can reduce symptom burden. Unfortunately, symptoms returned 2 to 3 months after treatment and the natural course was not altered. The next study, Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid trial was an 8-week cross-over comparison of FP-DPI (100 mg twice a day) vs montelukast (5–10 mg).16 A response was indicated by a 7.5% reduction in FEV1 or greater. The results indicated that 17% of the 126 participants responded to both medications, 23% responded to FP-DPI alone, 5% responded to montelukast alone, and 55% responded to neither. Subsequent analyses suggested that the ICS was better than the leukotriene receptor antagonist. Finally, the Pediatric Asthma Controller trial was designed to compare three contemporary asthma controller regimens.17 Three groups were compared FP-DPI 100 µg twice daily (FP monotherapy), FP-DPI 100 µg once daily/salmeterol 50 µg twice daily (combined), and montelukast 5 mg at night. The primary outcome was “asthma control days.” All groups improved compared to baseline, but FP monotherapy gained a mean of 42 “asthma control days” over montelukast. FP monotherapy and combined treatments were comparable for most outcomes, but FP monotherapy still had improvements in some parameters. The conclusion was that FP monotherapy was the best option for children. All of these asthma studies were well controlled and led to some excellent concepts. The other area where well-controlled trials were performed was for the use of steroids for the treatment of acute respiratory distress syndrome (ARDS). Early studies provided the steroids relatively late in the course of treatment. A large multicenter trial randomized ARDS patients to treatment with either methylprednisolone 30 mg/kg every 6 hours times four doses or placebo. They found similar mortality rates of 60% vs 63% for treatment or placebo, respectively.18 These earlier suggested that the treatment of ARDS with steroids was not justified. Agarwal et al19 has recently performed a meta-analysis of the use of steroids for ARDS. He reviewed six studies (three with early treatment and three with late treatment) and concluded that there was no role for steroids in ARDS. For the early treatment the odds ratio was 0.57 (95% CI 0.25–1.32) and for late treatment the odds ratio was 0.58 (95% CI 0.22–1.53). Meduri and Yates20 suggest that resistance or insensitivity may develop with time in those patients treated with low doses of corticosteroids. His animal studies suggested that the insensitivity may be reversed or prevented by quantitatively adequate and prolonged doses of corticosteroids.20 This concept was the basis for a study which he led. He gave prolonged treatment of methylprednisolone (loading dose of 1 mg/kg, 1 mg/kg/day for 14 days, with taper until day 28) with a reasonable number of patients with ARDS (N = 68) vs placebo (N = 28).21 He found a divergence of outcomes in the group treated with steroids. He found a one point decrease in the “Lung Injury Score” in more patients treated with methylprednisolone (69.8% vs 35.7%, P = .002). There were more treated patients breathing without assistance (53.9% vs 25.0%, P = .01), lower Lung Injury Score, C-reactive protein, multiple organ dysfunction syndrome scores, duration of mechanical ventilation (P = .002), ICU stay (0.007), reduced ICU mortality (20.6% vs 42.9%, P = .03), and a lower rate of infections (P = .0002). This relatively small study suggests that when properly dosed, treating ARDS patients with steroids might have some benefit. The studies that have examined the effects of steroids on smoke inhalation injury are inadequate and disappointing. In the late 1970s and early 1980s at least two studies were performed which did not demonstrate any improvement.22,23 In contrast, there were suggestions of increased infections in those patients treated with steroids. In addition, there have been two retrospective reviews of the treatment of smoke inhalation injury were the result of major disasters. A review from Seattle examined the outcomes of victims of the Las Vegas Hotel fire.24 People with isolated smoke exposure were treated in four hospitals with two using steroids and two avoiding their use. The results of their multivariate analysis revealed no difference. More recently, Koreans involved in a major subway fire (Daegu, Korea) were treated with methylprednisolone19 or not.22,25 There were no differences in pulmonary function tests at 3 and 6 months in these patients with isolated smoke inhalation injury. The lack of efficacy of steroids for smoke inhalation injury has also been supported by animal studies, but there are some reports of improvement in cytokine production.26,27 In summary, investigations into the role of using steroids for inhalation injury in burns have been inadequate and disappointing. CONCLUSION The use of steroids for the treatment of inhalation injury could potentially be a useful adjunct for patients with severe inhalation injury and burns. Controlling the excessive inflammation that leads to an ARDS-like picture may benefit some patients. The results of the asthma and recent ARDS studies do suggest that there might be an effective treatment for minimizing prolonged problems. However, further study of the risk/benefit ratio of steroid administration postinhalation injury are needed before adopting steroids into the treatment of inhalation injury. This study was supported by Shriners Hospital for Children Grant #8431. REFERENCES 1. 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TI - Steroids in the Treatment of Smoke Inhalation Injury
JF - Journal of Burn Care & Research
DO - 10.1097/BCR.0b013e3181923c08
DA - 2009-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/steroids-in-the-treatment-of-smoke-inhalation-injury-H6ynw2kS8v
SP - 165
EP - 169
VL - 30
IS - 1
DP - DeepDyve
ER -