Recent studies have suggested that the prevalence of ventilator-induced diaphragmatic weakness is very high and that this harm can even occur on the first day of mechanical ventilation in an ICU. That said, the degree of diaphragmatic weakness, injury, and atrophy is significantly correlated with the duration of ventilator support. According to previous studies, prolonged mechanical ventilation patients who experience difficulty in being weaned from the mechanical ventilation should have a high prevalence of diaphragmatic weakness and function loss.
Mechanical ventilation-induced diaphragmatic unloading is associated with oxidative stress in the diaphragm due to the production of reactive oxygen species, with this problem potentially occurring even within 3 to 6 h after the initiation of mechanical ventilation. Animal studies have revealed that the activities of the enzymes nicotinamide adenine dinucleotide phosphate oxidase and xanthine oxidase, being potential sources of reactive oxygen species, are significantly elevated in the diaphragm after prolonged mechanical ventilation.[25,26] Theophylline inhibits xanthine oxidase activity and therefore may protect the diaphragm against mechanical ventilation-induced oxidative stress and contractile dysfunction. Furthermore, in studies of patients with chronic obstructive pulmonary disease, theophylline has been found to have a potent and long-lasting effect in terms of increasing the strength of and suppressing fatigue in the diaphragm. Several other studies have also suggested that theophylline increases diaphragmatic contractility and reduces diaphragmatic fatigue.[28,29] Our results are consistent with these previous studies and suggest that theophylline may benefit prolonged mechanical ventilation patients by improving their diaphragmatic function.
In a recent study of ICU patients that used ultrasonographic examinations for the assessment of diaphragmatic motion, theophylline was found to significantly improve the diaphragmatic movements of patients with VIDD, whereas it did not affect the diaphragmatic movements of patients without VIDD. In that study, all the patients included had been treated with mechanical ventilation for at least 72 hours, while cases involving prolonged weaning were excluded. Besides, they examined diaphragmatic motion by ultrasound. They did not study weaning profile such as PImax and RSBI to assess whole respiratory muscle strength, as they are global measures of it.[19,20] In our study, the patients all experienced weaning difficulty and had used mechanical ventilation for at least 21 days. According to previous studies, patients with prolonged mechanical ventilation should have a high prevalence of VIDD.[9,23] However, theophylline has been shown to have inotropic effects on diaphragms, and the results of this study demonstrated the beneficial effects of theophylline on PImax and RSBI when attempting to wean patients from prolonged mechanical ventilation. According to our results, the weaning success rate was higher for the theophylline group than for the non-theophylline group, although not significantly so. One possible explanation for this finding is that the weaning of prolonged mechanical ventilation patients from mechanical ventilation is a difficult and multi-factorial process, one that does not rely solely on respiratory muscle strength.
Most patients in the respiratory care center receiving mechanical ventilation are fed via a nasogastric tube. In our hospital, the theophylline preparation typically used is a sustained-release preparation that cannot be ground up for nasogastric tube administration. So, we treated the patients in this study with aminophylline, which contains 85.7% anhydrous theophylline. The calculated dose of theophylline was 343 mg/d, with the mean checked serum concentration being 9.3 μg/ml, which is near the lower limit of a therapeutic dose (mean serum concentration ≥10 μg/ml) as assessed by previous studies.[27,30] That said, it is interesting to note that in the previously mentioned study, even low doses of theophylline resulting in a mean serum concentration of 4.6 μg/ml improved diaphragmatic movements. Relatedly, it has been reported that even low concentrations of theophylline (<5 μg/ml) can restore and increase histone deacetylase-2 activity, thus reducing oxidative stress in the diaphragm. That said, given that the current study involved patients with different characteristics than the patients in those earlier studies, lower doses and the dose-response relationships of theophylline require further study, especially with regard to possible adverse effects.
The present study had many limitations. First, the study was retrospective and the design might be not rigorous enough. So, there might latent bias existed, although we’ve tried our best to avoid it. Second, we measured PImax and RSBI to assess respiratory muscle strength, as they are global measures of it. However, these 2 measures may lack specificity. As such, further studies are warranted and should, if possible, seek to avoid the limitations of the present study.
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