Elsevier

Journal of Critical Care

Volume 33, June 2016, Pages 145-150
Journal of Critical Care

Effect of theophylline on ventilator-induced diaphragmatic dysfunction

https://doi.org/10.1016/j.jcrc.2016.01.007Get rights and content

Abstract

Purpose

To evaluate the effect of theophylline in patients with ventilator-induced diaphragmatic dysfunction (VIDD).

Materials and Methods

Patients who required mechanical ventilation at least 72 hours, met the criteria for a spontaneous breathing trial, and had evidence of VIDD by ultrasonography were included in the study.

Results

Of the 40 patients, 21 received theophylline and 19 did not. Clinical characteristics were similar in the 2 groups. Assessment of VIDD showed no between-group differences in baseline diaphragmatic excursion (DE) of both hemidiaphragms. Changes in DE from baseline to 72 hours (ΔDE) were significantly higher in the theophylline group than in the nontheophylline group in the right (3.5 ± 4.5 mm vs 0.4 ± 2.1 mm; P = .004) and left (3.2 ± 5.1 mm vs 0.1 ± 4.0 mm; P = .03) hemidiaphragms and in the total DE of both diaphragms (6.9 ± 9.1 mm vs 0.5 ± 5.7 mm; P = .02). In the theophylline group, theophylline was effective for the diaphragms with VIDD, whereas it was not effective for the diaphragms without VIDD. ΔDE in the right (rs = − 0.49, P = .006) hemidiaphragm and total Δ DE in both diaphragms (rs = − 0.46, P = .01) correlated negatively with weaning time.

Conclusions

Theophylline significantly improved diaphragmatic movements in patients with VIDD. Our results warrant a larger study to determine whether theophylline use has benefits during weaning from mechanical ventilation.

Introduction

Pulmonary gas exchange in patients unable to maintain sufficient alveolar ventilation can be sustained by mechanical ventilation (MV). However, 20% to 30% of ventilated patients experience difficulties in weaning from ventilator support [1], which are known to be associated with significant morbidity and mortality [2]. Even for a short period, MV was found to induce diaphragmatic weakness due to atrophy and contractile dysfunction, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD) [3]. Ventilator-induced diaphragmatic dysfunction is believed to be one of the major contributors to weaning difficulties in many patients [4], [5].

Among the diagnostic tools available to evaluate the diaphragm are fluoroscopy and determination of phrenic nerve conduction [6], [7]. These modalities, however, may be technically challenging and even unsafe, making them less than ideal for critically ill patients. Ultrasonography (US) is increasingly used in the intensive care unit (ICU) for diagnostic and therapeutic purposes [8]. M-mode US has been shown to be safe and easy to perform at the bedside, as well as being able to directly evaluate diaphragmatic motion with high interobserver agreement [9], [10]. M-mode US is useful in detecting VIDD, with diaphragmatic excursion (DE) less than 10 mm or negative (paradoxical diaphragmatic movement) during spontaneous breathing trials (SBTs) distinguishing between patients with and without VIDD [11].

Methylxanthines, especially aminophylline and theophylline, have been shown to have various pharmacologic actions such as bronchodilation [12], anti-inflammation [13], [14], and stimulation of respiration [15] and respiratory neuronal network [16], [17]. Theophylline is also a general muscle agonist. It increases heart muscle contractility and efficiency, improves endurance and grip strength in patients with neuromuscular diseases [18], and increases respiratory muscle activity such as intercostal muscle, transversus abdominis muscle, and diaphragm [19], [20], [21]. These findings suggested that methylxanthines may be therapeutic in patients with weaning difficulties associated with VIDD. To our knowledge, however, the efficacy of methylxanthines in patients with VIDD has not been determined. This study, therefore, evaluated the effects of theophylline on outcomes of patients with VIDD.

Section snippets

Study design and data collection

This retrospective cohort analysis included MV patients admitted to the ICU who had US-diagnosed VIDD and were deemed ready to wean. The patients were divided into groups who were (theophylline group) and were not treated with theophylline (nontheophylline group). Patients' clinical characteristics, including demographic factors, comorbidities, causes of ICU admission, vital signs, and laboratory data and ultrasonographic findings of diaphragms before the weaning process, were collected, as

Results

Of the 40 patients who fulfilled the inclusion criteria, 21 were in theophylline group and 19 were in nontheophylline group. Table 1 shows the clinical characteristics of these patients. The percentage of men was lower in the theophylline group than in the nontheophylline group (38% vs 79%; P = .01). There were no between-group differences in age and comorbidities. In both groups, most admissions to the ICU were for severe sepsis or septic shock, with pneumonia being the most common cause of

Discussion

This study showed that low-dose theophylline treatment significantly improved diaphragmatic movements in patients with VIDD. These effects were especially prominent for the diaphragms having VIDD. Theophylline was well tolerated by study patients, with no significant adverse drug reactions as to mandate discontinuation. To our knowledge, this is the first study to evaluate the efficacy and safety of theophylline in weaning patients diagnosed as having VIDD.

Mechanical ventilation is known to

Conclusions

In conclusion, low-dose theophylline improved diaphragmatic movements in patients with VIDD undergoing ventilator weaning. Further large prospective clinical studies are needed to confirm these results.

Conflicts of interest

None.

Acknowledgments

We thank Richard Alexander and Christopher Wells for providing language editing services (Bioedit Ltd).

References (39)

  • T. Vassilakopoulos et al.

    Ventilator-induced diaphragmatic dysfunction

    Am J Respir Crit Care Med

    (2004)
  • J.C. Goldstone et al.

    Maximum relaxation rate of the diaphragm during weaning from mechanical ventilation

    Thorax

    (1994)
  • A. Purro et al.

    Physiologic determinants of ventilator dependence in long-term mechanically ventilated patients

    Am J Respir Crit Care Med

    (2000)
  • G.B. Chavhan et al.

    Multimodality imaging of the pediatric diaphragm: anatomy and pathologic conditions

    Radiographics

    (2010)
  • Y.M. Luo et al.

    Assessment of diaphragm paralysis with oesophageal electromyography and unilateral magnetic phrenic nerve stimulation

    Eur Respir J

    (2000)
  • B. Bouhemad et al.

    Clinical review: bedside lung ultrasound in critical care practice

    Crit Care

    (2007)
  • T. Lloyd et al.

    Diaphragmatic paralysis: the use of M mode ultrasound for diagnosis in adults

    Spinal Cord

    (2006)
  • W.Y. Kim et al.

    Diaphragm dysfunction assessed by ultrasonography: influence on weaning from mechanical ventilation

    Crit Care Med

    (2011)
  • B.G. Cosio et al.

    Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages

    J Exp Med

    (2004)
  • Cited by (19)

    • Phrenic nerve paralysis and phrenic nerve reconstruction surgery

      2022, Handbook of Clinical Neurology
      Citation Excerpt :

      One notable exception is the drug theophylline. Although this pharmacologic agent has been traditionally categorized as a bronchodilator with smooth muscle relaxant properties, there is evidence that it also enhances diaphragmatic contractility (Landsberg et al., 1990; Kim et al., 2016). This medication has primarily been used in an inpatient population to promote weaning in patients with ventilator-induced diaphragm dysfunction, likely due to the potential toxicity and need for serum theophylline level monitoring.

    • Ultrasound Protocols to Assess Skeletal and Diaphragmatic Muscle in People Who Are Critically Ill: A Systematic Review

      2021, Ultrasound in Medicine and Biology
      Citation Excerpt :

      Four studies were evaluated by the PEDro scale (Table 5): two scored 6 points (Moukas et al. 2002; Gerovasili et al. 2009); one scored 8 points (Fischer et al. 2016); and one scored 10 points (Gruther et al. 2008). Regarding the diaphragmatic-muscle studies evaluated by the Newcastle–Ottawa Quality Assessment Scale for Cohort Studies (Table 6), 10 studies (Ferrari et al. 2014; Lerolle et al. 2009; Goligher et al. 2017; Schepens et al. 2015; Blumhof et al. 2016; Carrie et al. 2017; Banerjee et al. al. 2018; Dres et al. 2016; Pirompanich et al. 2018; Zhihua et al. 2019) scored 6 points; 8 studies (Kim et al. 2016; Haji et al. 2015; Umbrello et al. 2015; Zambon et al. 2016; Samantha et al. 2017; Johnson et al. 2018; Theerawit et al. 2018; Twose et al. 2018) 5 points; 8 studies (Toledo et al. 2010; Antenora et al. 2016; Dubé et al. 2017; Dhungana et al. 2017; Huang et al. 2017; Palkar et al. 2018a; Palkar et al. 2018b; Nakanishi et al. 2019) 7 points; 5 scored 8 points (Baldwin 2014; Jung et al. 2016; Kim et al. 2016; Zhou et al. 2017); 4 scored 2 points (Balaji et al. 1990; Urvoas et al., 1994; Dorffner et al. 1998; Valette et al., 2015); 4 studies scored 9 points (Goligher et al 2015a, 2017; Mariani et al. 2015; Dionisio et al. 2019); 2 scored 4 points (Dinino et al. 2014; Francis et al. 2016); and 1 scored 3 points (Grosu et al. 2012). Two diaphragmatic-muscle studies were evaluated by the Newcastle–Ottawa Quality Assessment Scale adapted for cross-sectional studies (Table 7), both obtaining five points (Sarwal and Vivier et al., 2012).

    • Novel dual-template molecular imprinted electrochemical sensor for simultaneous detection of CA and TPH based on peanut twin-like NiFe<inf>2</inf>O<inf>4</inf>/CoFe<inf>2</inf>O<inf>4</inf>/NCDs nanospheres: Fabrication, application and DFT theoretical study

      2021, Biosensors and Bioelectronics
      Citation Excerpt :

      At the same time, it also has a certain stimulating effect on the respiratory system. Theophylline (TPH, Fig. S1B) is a methylxanthine drug, which possesses the functions of cardiotonic, diuretic, dilating coronary artery, and relaxing bronchial smooth muscle (Kim et al., 2016). It's often used as a bronchodilator to treat asthma and chronic obstructive pulmonary disease (Zhao et al., 2020).

    • Ultrasound Imaging for Diaphragm Dysfunction: A Narrative Literature Review

      2019, Journal of Cardiothoracic and Vascular Anesthesia
      Citation Excerpt :

      Although theophylline rarely is prescribed because of its overemphasized adverse effects, this drug shows the propensity to increase diaphragm activity and that of the accessory respiratory muscles. Recently, Kim et al. demonstrated that 200 mg/d of theophylline significantly improved diaphragmatic performance in patients, shown using US evidence of VIDD.77 Regarding VIDD, potentials of the diaphragmatic muscle action are reduced quickly by CMV during proteolysis.9

    View all citing articles on Scopus
    1

    Equal contributors.

    View full text