1 Bhatt GC, et al. Arch Dis Child 2019;0:1–10. doi:10.1136/archdischild-2018-315805 Original article Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: a systematic review Girish Chandra Bhatt, 1 Priya Gogia, 1 Martin Bitzan, 2 Rashmi Ranjan Das 3 To cite: Bhatt GC, Gogia P, Bitzan M, et al. Arch Dis Child Epub ahead of print: [please include Day Month Year]. doi:10.1136/ archdischild-2018-315805 1 Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Bhopal, Madhya Pradesh, India 2 Department of Pediatrics, Division of Nephrology, Montreal Children’s Hospital and McGill University, Montreal, Quebec, Canada 3 Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, Odisha, India Correspondence to Dr Girish Chandra Bhatt, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Bhopal, Madhya Pradesh, India; drgcbhatt@gmail.com Received 6 July 2018 Revised 26 November 2018 Accepted 22 January 2019 © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. ABSTRACT Objective To compare the effcacy and safety of theophylline or aminophylline for prevention of acute kidney injury (AKI) in neonates and children. Design Systematic review and meta-analysis with application of Grading of Recommendations, Assessment, Development and Evaluation system. Data sources PubMed/MEDLINE, Embase, Google Scholar and Cochrane renal group were searched from 1970 to May 2018. Eligibility criteria Randomised clinical trials and quasi-randomised trials comparing the effcacy and safety of prophylactic theophylline or aminophylline for prevention of AKI in neonates and children were included. The primary outcomes were: incidence of AKI, serum creatinine levels and all-cause mortality. Results A total of nine trials were included in the qualitative synthesis. Six trials including 436 term neonates with birth asphyxia who received a single dose of theophylline were fnally included in the meta-analysis. The pooled estimate showed 60% reduction in the incidence of AKI in neonates with severe birth asphyxia (RR: 0.40; 95% CI 0.3 to 0.54; heterogeneity: I 2 =0%) (moderate quality evidence), decrease in serum creatinine over days 2–5 (very low to low quality evidence) without signifcant difference in all-cause mortality (RR: 0.88; 95% CI 0.52 to 1.50; heterogeneity: I 2 =0%) (very low- quality evidence). A signifcant difference in the negative fuid balance, increase in GFR and decrease in urinary β2 microglobulin was seen in favour of theophylline. Conclusion and relevance A single dose of prophylactic theophylline helps in prevention of AKI/ severe renal dysfunction in term neonates with severe birth asphyxia (moderate quality evidence) without increasing the risk of complications and without affecting all-cause mortality (very low-quality evidence). Trial registration number CRD 42017073600. INTRODUCTION Acute kidney injury (AKI) is defined as a rapid loss in kidney function (hours to days), resulting in derangements in fluid balance, electrolytes and waste products. 1 AKI may result from impaired renal perfusion, exposure to nephrotoxic drugs, sepsis or ischaemia during surgery, such as cardio- pulmonary bypass. 2 In a recent prospective national cohort study using electronic alert system, the inci- dence of hospital and community acquired AKI in children was found to be 40.1% and 29.4%, respec- tively. 3 The reported incidence of neonatal AKI ranges from 8.4% to 34.5% 3–5 and is associated with increased mortality, longer duration of hospital stay and an increased cost. 6 7 A systematic review of large cohort studies conducted between 2004 to 2012 showed a pooled incidence of AKI in 33.7% children and a pooled mortality rate of 13.8%. 8 Despite increased mortality, there are few modali- ties for prevention and treatment of AKI. Some of the previous studies and randomised controlled trials (RCTs) have shown renoprotec- tive role of theophylline and aminophylline in term 9–13 and preterm neonates with severe birth asphyxia, 14 children undergoing cardiac surgery 15 16 and in preterm neonates with respiratory distress syndrome. 17 A previous systematic review had shown improved outcome with use of a single dose of theophylline. 18 Since then, two RCTs have been published. 9 19 The previous review focused mainly on neonates with severe birth asphyxia; the description of outcome data was limited, and treatment emergent complications were excluded from the final meta-analysis. Thus, we conducted this updated systematic review including RCTs and quasirandomised trials to explore the present evidence for the use of adenosine antagonists for prevention of AKI. We used the Grading of Recom- mendations, Assessment, Development and Evalua- tion (GRADE) 20 approach to rate quality of evidence for primary outcomes and present our results with GRADE summary tables, which was also lacking in the previous systematic review. What is already known on this topic? ► Acute kidney injury (AKI) is associated with increased mortality, longer duration of hospital stay and an increased cost. ► Care for neonates and children with AKI remains supportive. What this study adds? ► A single dose of adenosine antagonists reduces the incidence of AKI in term neonates with severe birth asphyxia by 60% without increasing the risk of complications (moderate quality evidence). ► Prophylactic theophylline given to neonates with severe birth asphyxia also decreases serum creatinine, maintains negative fuid balance and increases glomerular fltration rate. on 24 February 2019 by guest. 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