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The diuretic effect of adding aminophylline or theophylline to furosemide in pediatric populations: a systematic review

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Abstract

The diuretic effect of the combined furosemide and aminophylline/theophylline among pediatric patients remains unclear. The primary aim of this systematic review was to examine the clinical diuretic effects (urine output and fluid balance) of co-administration of furosemide and aminophylline/theophylline as compared to furosemide alone in pediatric population. Ovid MEDLINE, CENTRAL, and EMBASE were searched from its inception until March 2022 for observational studies and randomized controlled trials (RCTs) comparing the administration of furosemide versus furosemide and aminophylline/theophylline in pediatric population. Case reports, case series, commentaries, letters to editors, systematic reviews, and meta-analyses were excluded. Five articles with a total sample population of 187 patients were included in this systematic review. As compared to the furosemide alone, our pooled data demonstrated that co-administration of furosemide and aminophylline/theophylline was associated with higher urine output (mean difference: 2.91 [90% CI 1.54 to 4.27], p < 0.0001, I2 = 90%) and a more negative fluid balance (mean difference − 28.27 [95% CI: − 46.21 to − 10.33], p = 0.002, I2 = 56%) than those who received furosemide alone.

Conclusion: This is the first paper summarizing the evidence of combined use of furosemide with aminophylline/theophylline in pediatric population. Our systematic review demonstrated that the co-administration of furosemide and aminophylline/theophylline could potentially yield better diuretic effects of urine output and negative fluid balance than furosemide alone in pediatric patients with fluid overload. Given the substantial degree of heterogeneity and low level of evidence, future adequately powered trials are warranted to provide evidence regarding the combined use of aminophylline/theophylline and furosemide as diuretic in the pediatric population.

What is Known:

• Fluid overload is associated with poor prognosis for children in the intensive care unit.

• The ineffective result of furosemide alone, even at high dose, as diuretic agent for children with diuretic resistant fluid overload in the intensive care unit.

What is New:

• This is the first systematic review that compares furosemide alone and co-administration of furosemide and aminophylline/theophylline.

• This paper showed potential benefit of co-administration of furosemide and aminophylline/theophylline promoting urine output and negative fluid balance compared to furosemide alone.

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Abbreviations

A1 receptor:

Adenosine 1 receptor

A2 receptor:

Adenosine 2 receptor

A3 receptor:

Adenosine 3 receptor

cAMP:

Cyclic adenosine monophosphate

CI:

Confidence Interval

CYP 450:

Cytochrome: 450

ECMO:

Extracorporeal membrane oxygenation

eGFR:

Estimated Glomerular Filtration Rate

ICU:

Intensive care unit

PICO:

Population, Intervention, Comparison, Outcome

PKA:

Protein Kinase A

PRISMA:

Preferred Reporting Items for Systematic Reviews

RCT:

Randomized controlled trial

TNF-alpha:

Tissue necrosis factor-alpha

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Acknowledgements

The authors would like to express our gratitude to Dr. E. Scott Halstead for his help in providing us with the raw data of the paper we included in our study.

Author information

Authors and Affiliations

  1. Queen Elizabeth University Hospital, Glasgow, UK

    Paul Van Siang Lian Mang & Jun Chuen Hui

  2. School of Medicine, University of Leeds, Leeds, UK

    Rachel Si Jing Tan

  3. Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    M. Shahnaz Hasan & Ka Ting Ng

  4. Department of Paediatrics, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    Yao Mun Choo

  5. Department of Anaesthesia and Intensive Care Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt

    Mohammed F. Abosamak

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  1. Paul Van Siang Lian Mang
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Contributions

Both authors Paul Van Siang Lian Mang and Jun Chuen Hui contributed equally to the work: literature search, data extraction, data analysis, writing first and final draft of the manuscript, critically reviewed, and edited the manuscript. Rachel Si Jing Tan supervised data analysis and extraction and edited the first draft of the manuscript. Ka Ting Ng contributed substantially to the conception of the study, supervised data extraction and analysis, critically reviewed the manuscript for intellectual content and edited the manuscript. M. Shahnaz Hasan, Yao Mun Choo, and Mohammed F. Abosamak critically reviewed the manuscript for intellectual content and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ka Ting Ng.

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The authors declare no competing interests.

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Van Siang Lian Mang, P., Hui, J.C., Tan, R.S.J. et al. The diuretic effect of adding aminophylline or theophylline to furosemide in pediatric populations: a systematic review. Eur J Pediatr 182, 1–8 (2023). https://doi.org/10.1007/s00431-022-04655-w

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