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To determine whether first-line treatment with percutaneous or surgical drainage of liver abscesses larger than 5 cm results in better clinical outcome.Pyogenic liver abscesses larger than 5 cm are currently treated by intravenous antibiotics and either percutaneous (PD) or surgical drainage (SD). Percutaneous techniques have been increasingly performed in place of open drainage as first-line treatment. This paradigm shift has been fueled by the drive for low-risk and less-invasive procedures and the surgical option being reserved for percutaneous failures. Yet there is a lack of data to support percutaneous drainage over open surgical drainage as first-line treatment.Over a 3-year period, 80 patients with liver abscesses larger than 5 cm amenable to PD and SD were included in the study. This situation was possible as 1 team of surgeons favored the use of PD and 1 team favored the use of SD as first-line treatment. The treatment outcomes in both groups were compared, and clinical end-points included time to defervescence of fever, failure of treatment, secondary procedures, hospital stay, morbidity, and mortality.PD was performed in 36 patients and SD in 44 patients as first-line treatment. Clinical, laboratory, and abscess parameters were comparable in both groups. Sixty-four of 80 patients (80%) had multiloculated abscess. The time to defervescence of fever was not statistically significant (PD versus SD, 4.85 versus 4.38 days; P = 0.09). However, SD had less treatment failures (3 versus 10, P = 0.013), less requirement for secondary procedures (5 versus 13, P = 0.01), and shorter length of hospital stay (8 versus 11 days, P = 0.03). There was no difference in morbidity or mortality rates.The results of our study show that for large liver abscesses more than 5 cm, SD provides better clinical outcomes than PD in terms of treatment success, number of secondary procedures, and hospital stay with comparable morbidity and mortality rates. SD should be considered as first-line treatment of large liver abscesses.