Dear Editor

In the April 2004 issue, Atzori and coworkers reported therapeutic effects of depleting HO activity on bleomycin-induced pulmonary fibrosis in mice.[1]

Administration of an HO inhibitor (Zn-deuteroporphyrin IX-2,4-bisethylene glycol, Zndt) 7 days following bleomycin treatment was associated with pathological improvement, reduced accumulation of collagen, and TGF-beta1 level in the lung in a dose dependent manner. The paper clearly demonstrates that at the latter phase of the pathological processes elicited by bleomycin, the presence of HO activity supports alveolar cell apoptosis and the development of pulmonary fibrosis by the oxidative activity of ferrous iron, a byproduct of HO-1 enzymatic activity. These observations, however, are in contrast to previous data suggesting that overexpression of HO in the lung provides therapeutic benefits in animals treated with hyperoxia, lipopolysaccharide, influenza virus, Pseudomonas aeruginosa, and bleomycin.[2-4]

It is important that most of these studies have used a gene transfer technique that provides transient excessive HO gene expression in a limited number of macrophages and alveolar cells. Since carbon monoxide (CO) and bilirubin both protect bleomycin-treated lung from massive pulmonary fibrosis, the therapeutic effect of using HO-1 cDNA could be attributed to the subsequent production of these molecules in the lung. The transient gene transfer strategy allows the production of sufficient CO and bilirubin from the transfected cells in the local milieu while minimizing harmful side effects of accumulating ferrous iron in the lung. It is critical to eliminate the deleterious effect of iron in order to maximize the potential benefit of using HO-1 as a novel therapeutic target in clinical situations. The dilemma of manipulating HO for inflammatory lung diseases could be resolved when the HO enzyme activity in the lung can be tightly controlled at an appropriate level at each stage of the disease.

References

1. Atzori, L., F. Chua, S. E. Dunsmore, et al. 2004. Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol. Thorax 59(3):217-23.

2. Morse, D., and A. M. Choi. 2002. Heme oxygenase-1: the "emerging molecule" has arrived. Am J Respir Cell Mol Biol 27(1):8-16.

3. Tsuburai, T., T. Kaneko, Y. Nagashima, A. et al. 2004. Pseudomonas aeruginosa-induced neutrophilic lung inflammation is attenuated by adenovirus-mediated transfer of the heme oxygenase 1 cDNA in mice. Hum Gene Ther 15(3):273-85.

4. Tsuburai, T., M. Suzuki, Y. Nagashima, S. et al. 2002. Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway. Hum Gene Ther 13(16):1945-60.

Dear Editor

I have read with interest the BTS guidelines for the insertion of a chest drain. In the last paragraph (15) you have recommended that during the insertion of a chest tube in a patient on a high pressure ventilation (especially with positive end expiratory pressure-PEEP), it is essential to disconnect from the ventilator at time of insertion. I have some concerns about this recommendation. I think it was based on the hypothetical risk that the lung may come closer to the wound site or even forced out through the wound as the pleura is breached given the high airways pressure. I think this risk is over exaggerated and its significance is at best disputable. When high mean airway pressure is required to expand a lung with poor compliance, this pressure may not significantly affect the intrapeural or intrathoracic pressure and therefore sudden decompression when the pleura is breached is unlikely. The risk of disconnection from the ventilator is well known. Especially in patients requiring high inflation pressures and high PEEP, sudden disconnection from the ventilator can be associated with severe alveolar de-recruitment and consequently profound hypoxia which my not simply and quickly respond to re-connection. Blunt discetion is reasonably safe for pneumothorax and large effusions. For small effusions, ultrasound guided grains are probably safer keeping in mind that small effusions are very common in critically ill patients due to various reasons and their drainage is not normally indicated unless proven to be infected.

Dear Editor

We thank Dr Lee for his interest in our reports.[1,2] However, he appears to confuse the terms “treatment failure” and “non-responder”. “Treatment failure,” as defined in the original report for our study,[1] referred to a clinical outcome (a composite endpoint of hospitalization, need for excluded medication, or need for prolonged acute asthma treatment in the emergency setting). In contrast, “non-responders” generally refers to a subset of patients who fail to surpass a defined threshold of response. As we have commented previously using chronic asthma as an example, simplistic “responder/non-responder” analyses often fail to account for clinically important aspects of disease variability and the impact of treatment intervention.[3] Moreover, in our initial report of intravenous montelukast in acute asthma,[1] a systematic analysis of baseline variables did not identify any factor which predicted response to intravenous montelukast, in terms of either FEV1 or treatment failures, with the exception of baseline FEV1.

The present report [2] addressed the relationship between FEV1 and cysteinyl leukotriene production, as measured by LTE4 excretion. A similar analysis of treatment failures and LTE4 levels is complicated by the fact that unlike baseline FEV1 which was measured before administration of study drug, treatment failures tended to be reduced by intravenous montelukast.[1] Nevertheless, 27/201 patients (15 (11.1%) in the montelukast group and 12 (18.2%) in the placebo group) met one or more of the criteria for treatment failure during the study. Of these, 20 patients had LTE4 data for analyses. Compared to patients who did not meet the criteria for treatment failures and who had LTE4 data available (n=161), LTE4 levels were numerically higher at baseline in the treatment failure group, although this did not reach statistical significance (see Table 1). Were Dr Lee’s hypothesis correct, LTE4 levels should have been lower amongst treatment failures. Accordingly, the data suggest that rather than serving as a useful predictor of clinical outcome, elevated LTE4 levels are more likely a marker of worsened acute asthma severity, consist with our analyses of LTE4 levels and FEV1.[2] Taken together, the data provide a strong biological rationale for the observed benefit of antileukotriene therapy in acute asthma.[1]

Table 1 LTE4 levels (pg/mg creatinine) during Acute Period By Clinical Outcome

1 Geometric Mean

References

1. Camargo CA, Smithline HA, Malice M-P, et al. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 2003;167:528-37.

2. Green SA, Malice M-P, Tanaka W, Tozzi CA, et al.Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax 2004;59:100-4.

3. Zhang J, Yu C, Holgate ST, Reiss TF. Variability and lack of predictive ability of asthma and endpoints in clinical trials. Eur Resp J 2002; 20:1102-1109.

Dear Editor

The British asthma guidelines recommended salbutamol loading dose (LD) 15mcg/kg and maintenance dose (MD) 1-2mcg/kg/min (5mcg/kg/min in intensive care) for children’s acute severe asthma.[1] Terbutaline is similarly used in some paediatric units.
My concerns are:

(A) this MD can be several-fold the adult dose (e.g. 30-150 mcg/min in 30kg-child versus 3- 20mcg/min in adult!);
(B) it is not based on reliable clinical evidence or pharmacokinetics;
(C) blood level progressively increases to a very high steady state concentration (Css); and
(D) there are no safety studies for the higher range of doses! Similarly, the pharmacokinetics of terbutaline does not rationalize a higher dose/weight in children than in adults. [2]

Salbutamol is a racemic mixture of an active, rapidly metabolised, R-enantiomer and the inactive S-enantiomer, which might be antagonistic, pro-inflammatory or exacerbate airway reactivity. [3,4] Prolonged high-dose infusion results in S-enantiomer preferential accumulation that may enhance competitive antagonism. Unlike salbutamol, the active terbutaline enantiomer (+T) preferentially accumulates (Table 1). Therefore, there is a strong case for the use of terbutaline or R-salbutamol (levalbuterol) whenever prolonged high-dose intravenous therapy is indicated.

Table 1 Pharmacokinetics of Terbutaline and Salbutamol