Abstract Laparoscopic liver resection is being safely performed by surgeons worldwide for multiple indications. When compared to open liver resection, laparoscopic liver resection is associated with improvements in short-term outcomes such as decreased blood loss, transfusion rate, perioperative complications, length of stay, and overall cost. When laparoscopic is performed for malignancies such as hepatocellular carcinoma and metastatic colorectal cancer, oncological adequacy needs to be assured in order to avoid detrimental effects in long-term outcomes such as disease-free survival and overall survival. Current evidence suggests that in wellselected patients, the long-term oncologic outcomes achieved with laparoscopic liver resection are equivalent to those obtained with open liver resection. To date, there are no published randomized trials comparing laparoscopic to open liver resection, although two trials are ongoing. Keywords Laparoscopic liver resection • Laparoscopic hepatectomy • Hepatocellular carcinoma • Metastatic colorectal cancer • Liver tumor Introduction Laparoscopic liver resection s have been performed for several indications, including both benign lesions and malignancies, with low morbidity and mortality [ 1 , 2 ]. When compared to open resections, laparoscopic liver resection s are associated with decreased LOS, postoperative pain and complications [ 3 – 6 ]. Yet, when laparoscopic liver resections are used for the treatment of malignancies, concerns about the rates of positive margins and failure to recognize occult metastases have caused some to question the oncologic adequacy of the procedure [ 7 ]. Because oncologic A. Gleisner • D. A. Geller (*) Department of Surgery , University of Pittsburgh , 3459 Fifth Avenue , Pittsburgh , PA 15213-2582 , USA e-mail: [email protected] 114 adequacy infl uences important long-term outcomes , such as recurrence and longterm survival , patient selection for laparoscopic liver resection is premised upon understanding which surgical indications are most likely to afford the improved short-term outcomes associated with the laparoscopic technique without compromising the oncologic adequacy of the procedure. This chapter addresses situations in which laparoscopic surgery is preferred over open liver resection, with discussion focused on the short-term outcomes of laparoscopic liver resection when compared to open liver resection for both benign and malignant liver disease as well as longterm outcomes for the most common primary liver malignancy and metastatic disease—hepatocellular carcinoma (HCC) and metastatic colorectal cancer to the liver (mCRC), respectively. Search Strategy A literature search of publications from 2001 to 2014 was performed to identify published data on laparoscopic liver resection using the PICO outline [ 8 ] (Table 10.1 ). Databases searched were PubMed, Embase, Science Citation Index and Cochrane Evidence Based Medicine , restricted for publications in English language. Terms used in the search were “laparoscopic liver resection ,” “ laparoscopic hepatectomy ,” AND “ open liver resection ,” “open hepatectomy ,” AND (“intraoperative complications” OR “perioperative complications” OR “postoperative complications” OR “ overall survival ” OR “disease-free survival ” OR “long-term” OR “ outcomes ”). Articles were excluded if they were review articles or non- comparative. There were no randomized trials. We included 32 cohort studies and 3 meta- analyses that were classifi ed using the GRADE system [ 9 ]. Table 10.1 PICO table for laparoscopic liver resection P (Patients) I (Intervention) C (Comparator group) O (Outcomes measured) Patients with multiple indications for liver resection; patients with indication for liver resection for hepatocellular carcinoma and for metastatic colorectal cancer Laparoscopic liver resection Open liver resection Short-term: EBL, transfusion rate, postoperative morbidity and mortality, LOS, surgical margins, cost Long-term: overall survival and disease-free survival for resection of malignancies A. Gleisner and D.A. Geller 115 Results Short-Term Outcomes of Laparoscopic Liver Resection Several cohort studies have compared the perioperative outcomes of patients submitted to laparoscopic liver resection with those of patients who underwent open liver resection . In a study examining the comparative benefi ts of laparoscopic vs. open hepatectomy , Nguyen et al. analyzed 31 case-cohort matched comparative studies that compared laparoscopic liver resection in 1,146 patients to open liver resection in 1,327 patients [ 3 ]. The short-term benefi ts of laparoscopic liver resection were signifi cantly less blood loss (14 studies), less pRBC transfusions (4 studies), less post-operative pain /narcotic use (8 studies), quicker resumption of diet (8 studies), less overall morbidity (7 studies), and shorter length of stay (24 studies). For HCC and mCRC, there was no difference in 3- or 5-year overall survival when compared with well-matched open hepatic resection cases. Thus, the short-term benefi ts of laparoscopic liver resection were realized without compromising longterm oncologic outcomes. Several recent meta-analyses have addressed short-term benefi ts of laparoscopic liver resection compared to open liver resection by analyzing comparative series [ 4 – 6 ] (Table 10.2 ). These studies have included liver resections for multiple indications as well as those specifi cally performed for HCC and mCRC. Rao et al. [ 5 ] included 32 studies published between 1998 and 2009, including excision of malignant lesions, benign lesions or both, as well as one study in which the indication was live liver donation for transplantation. Most studies described different types of liver resections and matched the laparoscopic and open resection groups based on characteristics of the patients (i.e. age, gender, presence of cirrhosis and ASA classifi cation), the lesions (i.e. size, location and etiology) and related to the operation (i.e. type of resection). A total of 2,466 patients were included, 1,161 (47.1 %) in the laparoscopic group and 1,305 (52.9 %) in the open group. Laparoscopic liver resection was associated with decreased postoperative morbidity (Odds Ratio [OR] 0.62; 95 % Confi dence Interval [CI] 0.20–0.76), decreased length of stay (LOS) (Weighted mean difference [WMD] −2.96; 95 % CI −3.70 to −2.22 days) and decreased need for blood transfusion (OR 0.36; 95 % CI 0.23–0.74). The incidence of positive surgical margins for the resection of malignant lesions was also lower in the laparoscopic group (OR 0.30; 95 % CI 0.20–0.76), according to the data in 6 of the 32 studies. Mortality rate was reported in 18 of the 32 studies and was not signifi cantly different between both groups (p = 0.80). Yin and colleagues [ 6 ] included 15 studies published between 2001 and 2011, where laparoscopic liver resection was compared to open resection exclusively for the treatment of HCC. Lesions were either solitary, restricted to the left lateral lobe or the peripheral subcapsular right segments of the liver and were treated by limited resection (three or fewer segments). Among patients treated with laparoscopic resection, there were signifi cant decreases in EBL (WMD −225, 95 % CI −385 to −64 ml), need for blood transfusion (OR 0.36; 95 % CI 0.17–0.74), postoperative 10 When Is Laparoscopic Liver Resection Preferred Over Open Resection? 116 Table 10.2 Short-term outcomes for patients submitted to laparoscopic liver resection Author Number of patients Indication Number of studies (publication year) pOR for postoperative morbidity (95 % CI) EBL (95 % CI) LOS (95 % CI) pOR for Blood Transfusion Study type ( quality of evidence) LLR/OLR Rao (2012) [ 5 ] 1161/1305 Benign/malignant 32 (1998–2009) 0.35 (0.28–0.45) −184 a ml −2.96 (–3.70 to −2.22) a days 0.36 (0.23–0.74) Metaanalysis (moderate) Yin (2013) [ 6 ] 485/753 HCC 15 (2001–2011) 0.37 (0.27–0.52) −225 (−385 to −64) a ml −4.81 (−6.66 to −2.96) a days 0.36 (0.17–0.74) Metaanalysis (moderate) Schiffman (2014) [ 4 ] 242/368 mCRC 8 (2009–2013) 0.70 (0.52–0.96) −0.70 (0 to −1.41) b −1.50 (−2.60 to −0.41) b 0.51 (0.32–0.81) Metaanalysis (moderate) LLR laparoscopic liver resection , OLR open liver resection , HCC hepatocellular carcinoma, mCRC metastatic colorectal cancer , pOR pooled odds ratio, CI confi dence interval, EBL estimated blood loss, LOS length of stay a Weighted mean difference b Standard mean difference A. Gleisner and D.A. Geller 117 complications (OR 0.37; 95 % CI 0.27–0.52) and LOS (WMD −4.81; 95 % CI −6.66 to −2.96 days). There was no signifi cant difference in the rate of negative margins (OR 1.63; 95 % CI 0.82–3.22). The most recent meta-analysis, by Schiffman and colleagues [ 4 ], summarized data published between 2009 and 2013 that compared laparoscopic surgery to open resection for the treatment of hepatic mCRC. Only matched cohorts were included, resulting in 8 studies with 242 patients submitted to laparoscopic surgery and 368 patients submitted to open resection. The fi ndings also showed improvement in perioperative outcomes for patients who underwent laparoscopic surgery, including reduced EBL (standard mean difference [SMD] – 0.70; 95 % CI 0 to −1.41), need for blood transfusion (OR 0.51; 95 % CI 0.32–0.81), postoperative morbidity (OR 0.70; 95 % CI 0.52–0.96) and LOS (SMD −1.50; 95 % CI −2.60 to −0.41). Although there is some redundancy in the articles included in the three metaanalyses, the effect of laparoscopic surgery in the perioperative outcomes is consistent and with large magnitude. It is possible, however, that important confounders have not been accounted for in these observational studies. For example, more accessible lesions may have been chosen for the laparoscopic approach, which could result in overestimation of its effect. Additionally, the determination of how accessible a tumor is can be hard to measure and varies considerably among surgeons. Further, inherent selection bias exists even in well-matched case cohort series. In addition to the favorable perioperative outcomes associated with laparoscopic liver resection , there is evidence suggesting laparoscopic liver resection s may be more cost-effective as well. In a retrospective cohort study, Vanounou and colleagues [ 10 ] found that laparoscopic left lateral sectionectomy was $1,527–2,939 more cost effective per patient compared to open left lateral sectionectomy. Bhojani and colleagues [ 11 ] reported results from 57 patients who underwent attempted laparoscopic resection matched to 2 open cases for multiple parameters including the number of segments removed. Eight (14 %) cases were converted to open and most perioperative outcomes were similar between the two groups. The median cost for laparoscopic surgery was lower when compared to open resections ($11,376 vs $12,523), but the difference did not achieve statistical signifi cance (p = 0.077). Another retrospective cohort by Cannon and colleagues [ 12 ] found an overall decrease in cost of liver resections performed laparoscopically (weighted average mean cost [WAMC] of $58,401 versus $69,728 for open resections). However, when only right hepatectomies were considered, the laparoscopic approach actually resulted in increased cost (WAMC $69,544 versus $68,266 for open resection), despite the fact that the patients in the laparoscopic group were more likely to have an “on course” hospitalization—suggesting that the cost effectiveness of laparoscopic surgery may vary according to the complexity of the procedure. 10 When Is Laparoscopic Liver Resection Preferred Over Open Resection? 118 Long-Term Outcomes in Laparoscopic Liver Resection Evaluation of the oncological adequacy of the laparoscopic approach to liver resection is crucial when this technique is applied to the treatment of malignancies. Concerns are mainly related to the rate of negative margins achieved and the ability to recognize occult metastasis, which would result in decreases in the disease-free and overall survival . Hepatocellular Carcinoma Several studies have reported long-term results on cohorts of patients who underwent laparoscopic resection of HCC. These studies included retrospective or prospective cohorts of patients submitted to laparoscopic surgery compared to retrospective cohorts of patients submitted to open resection (Table 10.3 ). With the exception of one study, which reported a signifi cantly higher 3-year survival rate for those submitted to laparoscopic resection (89 % versus 55 % in the open resection group) [ 13 ], no signifi cant differences in disease-free or overall survival were observed. The largest study, by Ker and colleagues, [ 14 ] included 116 patients submitted to laparoscopic resection and 208 patients submitted to open resection. Overall survival was comparable between both groups (3- and 5-year overall survival 70 % and 62 % for laparoscopic and 76 % and 72 % for open resection). The meta-analysis by Yin and colleagues [ 6 ] included 12 studies that reported long-term outcomes of patients operated for HCC. The pooled hazard ratio (HR) for 3- and 5-year overall survival for laparoscopic surgery was 0.98 (95 % CI 0.72–1.33) and 0.99 (95 % CI 0.74–1.33), respectively. Similarly, the pooled HR for 3- and 5-year recurrence free survival was not signifi cantly different for those submitted to laparoscopic surgery when compared to open (HR 1.04; 95 % CI 0.81–1.34 and HR 1.01; 95 % CI 0.75–1.35, respectively). More importantly, no signifi cant heterogeneity was found between the studies. Metastatic Colorectal Cancer Long-term results for patients submitted to laparoscopic and open liver resection for metastatic colorectal cancer are summarized in Table 10.4 . Of the 11 cohort studies identifi ed in the literature review, all but one matched with regard to clinical, tumor and/or procedure-related characteristics, and there were no difference in diseasefree or overall survival between patients in the laparoscopic and open liver resection cohorts. The studies included a minimum of 13 and a maximum of 60 patients in the laparoscopic group. Disease-free survival was reported in seven studies, ranging between 14 % and 63 % in 3-years and 14 % and 42 % in 5-years for those who underwent laparoscopic resection, and between 18 % and 46 % in 3-years and 18 % and 38 % in 5-years for patients who underwent open resection. A. Gleisner and D.A. Geller 119 Table 10.3 Long-term outcomes for patients submitted to laparoscopic liver resection for hepatocellular carcinoma Author Number of patients Median follow-up (months) Median DFS (months) Median OS (months) 3-years DFS (%) 5-years DFS (%) 3-years OS (%) 5-years OS (%) Study type ( quality of evidence) LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR Kim (2014) [ 15 ] 29/29 48/60 NR NR 62/61 54/40 100/92 92/88 Retrospective matched-cohort (low) Cheung (2013) [ 16 ] 32/64 NR 79/29 92/71 73/50 55/44 88/73 77/57 Retrospective matched-cohort (low) Kobayashi (2013) [ 17 ] 56/27 19/68 NR NR 50/62 NR 100/100 NR Retrospective matched-cohort (low) Ker (2011) [ 14 ] 116/208 94/94 NR NR NR NR 70/76 62/72 Retrospective cohort (low) Truant (2011) [ 18 ] 35/53 36/36 NR NR NR 36/34 NR 70/46 Retrospective matched-cohort (low) Lee (2011) [ 19 ] 33/50 35/29 NR NR 51/56 45/56 82/81 76/76 Retrospective matched-cohort (low) Hu (2011) [ 20 ] 30/30 NR NR NR NR NR 76/77 50/53 Retrospective cohort (low) Kim (2011) [ 21 ] 26/29 22/25 NR NR NR 57/56 NR NR Retrospective matched-cohort (low) (continued) 10 When Is Laparoscopic Liver Resection Preferred Over Open Resection? 120 Table 10.3 (continued) Author Number of patients Median follow-up (months) Median DFS (months) Median OS (months) 3-years DFS (%) 5-years DFS (%) 3-years OS (%) 5-years OS (%) Study type ( quality of evidence) LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR Tranchart (2010) [ 22 ] 42/42 30/35 NR NR 61/54 46/37 74/73 60/47 Retrospective matched-cohort (low) Aldrighetti (2010) [ 23 ] 16/16 32/32 23/31 40/48 NR NR NR NR Retrospective matched-cohort (low) Belli (2009) [ 24 ] 54/125 24/24 38 /– 63 /– 52/55 NR 67/63 NR Retrospective matched-cohort (low) Sarpel (2009) [ 25 ] 20/56 24/18 NR NR NR NR NR 95/75 Retrospective matched-cohort (low) Endo (2009) [ 26 ] 10/11 NR NR NR NR 24/19 NR 57/48 Retrospective matched-cohort (low) Lai (2009) [ 27 ] 25/33 29/29 NR NR 52/56 NR 60/60 NR Retrospective matched-cohort (low) Cai (2008) [ 28 ] 31/31 NR NR 70/61 NR NR 67/74 56/54 Retrospective matched-cohort (low) Kaneko (2005) [ 29 ] 30/28 NR NR NR 45/50 31/29 80/77 61/62 Retrospective and prospective matched-cohort (low) A. Gleisner and D.A. Geller 121 Author Number of patients Median follow-up (months) Median DFS (months) Median OS (months) 3-years DFS (%) 5-years DFS (%) 3-years OS (%) 5-years OS (%) Study type ( quality of evidence) LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR Laurent (2003) [ 13 ] 13/13 NR NR NR 56/54 NR 89/55* NR Retrospective and prospective matched-cohort (low) Shimada (2001) [ 30 ] 17/38 17/29 NR NR NR 72/72 NR 48/38 Retrospective and prospective matched-cohort (low) DFS : Disease-free survival , OS Overall survival, LLR laparoscopic liver resection , OLR open liver resection , NR not reported 10 When Is Laparoscopic Liver Resection Preferred Over Open Resection? 122 Table 10.4 Long-term outcomes for patients submitted to laparoscopic liver resection for metastatic colorectal cancer Author Number of patients Median follow-up (mos) Median DFS (mos) Median OS (mos) 3-years DFS (%) 5-years DFS (%) 3-years OS (%) 5-years OS (%) Study type ( quality of evidence) LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR LLR/OLR Montalti (2014) [ 31 ] 57/57 41/54 NR NR 39/42 29/38 75/75 60/65 Retrospective matched-cohort (low) Iwahashi (2014) [ 32 ] 21/21 NR NR NR 14/33 14/25 84/89 42/51 Retrospective matched-cohort (low) Guerron (2013) [ 33 ] 40 /40 16/16 23/ 23 NR NR NR 89/81 (2-years) NR Retrospective matched-cohort (low) Qiu (2013) [ 34 ] 30/30 NR NR NR NR NR NR NR Retrospective matched-cohort (low) Cannon (2012) [ 35 ] 35/140 NR NR NR 37/39 15/22 63/60 36/42 Retrospective matched-cohort (low) Cheung (2013) [ 36 ] 20/40 NR 9.8/10.9 69/42 42/18 42/18 54/65 54/22 Retrospective matched-cohort (low) Topal (2012) [ 37 ] 20/20 NR NR NR NR 43/23 NR 48/46 Retrospective matched-cohort (low) Hu (2012) [ 38 ] 13/13 NR NR NR NR NR 55/54 27/31 Retrospective matched-cohort (low) A. Gleisner and D.A. Geller 123 Nguyen (2011) [ 3 ] 24/25 27/29 NR NR 63/46 NR 75/79 NR Retrospective matched-cohort (low) Abu Hilal (2010) [ 39 ] 50/85 22/22 NR NR NR NR NR NR Retrospective cohort (low) Castaing (2009) [ 40 ] 60/60 30/33 47/40 NR 47/40 35/27 82/70 64/56 Retrospective matched-cohort (low) DFS Disease-free survival , OS Overall survival, LLR laparoscopic liver resection , OLR open liver resection , NR not reported 10 When Is Laparoscopic Liver Resection Preferred Over Open Resection? 124 In the meta-analysis by Schiffman and colleagues [ 4 ], which included eight matched cohort studies comparing laparoscopic versus open resection of colorectal liver metastasis, long-term outcomes were reported in all studies. Again, there were no differences in disease-free and overall survival between laparoscopic and open resection cohorts. The 3- and 5-year mean disease-free survival was 47.1 % and 31.9 % in the laparoscopic group and 40.4 % and 25.5 % in the open resection group. The 3- and 5-year mean overall survival rate was 72.7 % and 51.4 % in the laparoscopic group and 67.2 % and 45.9 % in the open resection group. Importantly, the mean number of metastasis was 1.4 for the laparoscopic group and 1.5 for the open resection group (p = 0.14), implying that the data on long-term results of laparoscopic resection for mCRC cancer is only applicable to patients with limited disease (one or two tumors). Of note, there have been no reports of peritoneal tumor seeding with laparoscopic liver resection of neither HCC nor mCRC. The major limitation of the data on long-term outcomes comparing laparoscopic and open liver resection s is the lack of randomized trials. Despite the fact that most cohorts were matched with regard to signifi cant clinical, tumor and procedurerelated factors, residual confounding and selection bias is certainly a possibility in these observational studies. Recommendations Laparoscopic liver resection is associated with decreased EBL, need for transfusion, perioperative morbidity , and LOS when compared to open liver resection . Although this data is entirely based on observational studies, the magnitude of the effects is high and there is consistency across several studies (evidence quality moderate). The rate of negative margins is at least equivalent between the two techniques (evidence quality low). Laparoscopic surgery seems to be cost-effective, especially for minor liver resections (evidence quality very low). Long-term term outcomes , disease-free survival and overall survival , are equivalent in patients with either HCC or limited (one or ;two lesions) metastatic colorectal cancer submitted to laparoscopic liver resection when compared to open liver resection . Yet, the lack of randomized trials raises concerns regarding selection bias and residual confounding variables. It is plausible that surgeons selected patients with tumors with more favorable characteristics, such as tumor location, for laparoscopic procedures, which would overestimate the treatment effect of the laparoscopic procedure (evidence quality low). We therefore make a weak recommendation for laparoscopic liver resection in patients with liver lesions, including hepatocellular carcinoma and limited metastatic colorectal cancer , for the potential benefi ts in perioperative outcomes and possibly cost, with no evidence showing compromise in long-term outcomes for patients with malignancy. A. Gleisner and D.A. Geller 125 A Personal View of the Data Laparoscopic liver resection s have been performed safely in over 8,000 patients worldwide. Patient selection according to the surgeon’s expertise is key to assure the short-term benefi ts of laparoscopic surgery . The current evidence also suggests long-term outcomes for laparoscopic liver resection are equivalent to those for open liver resections in well-selected patients, when the procedure can be performed without compromising the oncological adequacy. A more precise estimation of the treatment effect of laparoscopic liver resection in short- and long-term outcomes can only be determined by randomized trials, which may be diffi cult to perform when patients have a choice between laparoscopic and open resections. Recommendations • Laparoscopic liver resection should be considered for patients with benign liver lesions, as it is associated with decreased morbidity and LOS (evidence quality moderate; strong recommendation). • Laparoscopic liver resection can be considered for patients with malignancies such as HCC or limited metastatic colorectal lesions (one or two tumors), as it is associated with improved short-term outcomes without detriment to long-term outcomes (evidence quality low; weak recommendation). References 1. Nguyen KT, Gamblin TC, Geller DA. World review of laparoscopic liver resection-2,804 patients. Ann Surg. 2009;250(5):831–41. 2. Reddy SK, Tsung A, Geller DA. Laparoscopic liver resection. World J Surg. 2011;35(7):1478–86. 3. Nguyen KT, Marsh JW, Tsung A, Steel JJ, Gamblin TC, Geller DA. Comparative benefi ts of laparoscopic vs open hepatic resection: a critical appraisal. Arch Surg. 2011;146(3):348–56. 4. Schiffman SC, Kim KH, Tsung A, Marsh JW, Geller DA. 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Abstract Pyogenic liver abscesses are rare but if handled inappropriately can be life-threatening. Early experiences with the management of these liver abscesses yielded high morbidity and mortality. However, over the last three decades, treatment has moved away from surgery as the front-line therapy and has evolved to include less invasive interventional radiologic procedures. This change in paradigm has been accompanied by shorter length of hospital stay and decreased morbidity and mortality. Despite these fi ndings in the general population, patients that develop pyogenic liver abscesses following a liver transplant have a much higher morbidity and mortality, with some ultimately requiring retransplantation. When managed appropriately and in many cases with a multi-modality approach, patients with pyogenic liver abscesses can achieve excellent clinical outcomes. Keywords Liver abscess • Pyogenic • Percutaneous aspiration • Percutaneous drainage • Hepatectomy of liver abscess Introduction Pyogenic liver abscess es are relatively uncommon occurrences, with an incidence ranging from 1.1 to 2.3 cases per 100,000 based on the most recent population- based studies [ 1 , 2 ]. Although liver abscesses are uncommon, if left untreated, risk signifi – cant morbidity and mortality . Liver abscesses were fi rst described by Ochsner and Debakey in 1938, and surgical drainage was the primary treatment recommendation [ 3 ]. Despite intervention, overall mortality was 77 %. Since then, therapy has evolved with the advent of improved diagnostic imaging, antibiotics, and percutaneous intervention and this has improved the mortality in more recent studies to between 6 % and 14 % [ 4 – 6 ]. In the past 30 years, the advent and wide spread acceptance of T. W. Reichman (*) • W. G. Terral Multi-Organ Transplant Institute, Department of Surgery , Ochsner Medical Center , 1514 Jefferson Highway , New Orleans , LA 70121 , USA e-mail: [email protected] 130 percutaneous aspiration and percutaneous drainage along with antibiotic regimens has supplanted surgical intervention as the primary treatment modality. As the etiology of pyogenic liver abscess has evolved, the appropriate treatment modality has evolved as well. Appropriate patient selection based on etiology, nutritional status, abscess characteristics, and institutional interventional options should be considered. This chapter addresses the indications for surgical intervention, percutaneous aspiration or drainage, and antibiotics therapy alone. Search Strategy A literature search of English language publications from 1980 to 2014 was used to identity published data on pyogenic liver abscess using the PICO outline (Table 11.1 ). Databases searched were PubMed, Ovid MEDLINE, and Cochrane Reviews. Terms used in the search were “pyogenic liver abscess, etiology”, “pyogenic liver abscess, treatment”, “pyogenic liver abscess AND percutaneous drainage or percutaneous aspiration ”, “pyogenic abscess, antibiotics”, “pyogenic liver abscess risk”, “pyogenic liver abscess AND surgery versus drainage”. Etiology of Liver Abscesses In review of the etiology by Johannsen et al. and Rahimian et al. abscesses can be classifi ed by the presumed route: biliary, portal venous, hepatic artery, direct extension, and traumatic [ 7 , 8 ]. Biliary causes include suppurative cholangitis , the most common identifi able cause, Caroli’s disease, and Ascaris lumbricoides invasion in the developing world. According to Seeto and Rockey’s review, 52 of 142 identifi – able causes (37 %) were attributed to biliary disease [ 9 ]. Eleven of the 52 had malignant lesions, 31 had cholelithiasis or choledocholithiasis , 8 had strictures, and 2 with biliary cirrhosis . Appendicitis, historically the most common identifi able cause, along with diverticulits, pancreatitis, infl ammatory bowel disease, and abdominal surgery all represent common portal venous causes of abscesses. Again, Seeto and Rockey’s review identifi ed 16 of 142 patients with a portal venous system etiology as the cause for their liver abscess : 5 from diverticulitis, 4 from appendicitis, 3 with perforation of the small bowel, 2 patients with IBD, and 2 with other intra-abdominal infections [ 9 ]. Any systemic bacterial infection can lead to liver abscess, but as found at autopsy, these abscesses are typically micro-abscesses and Table 11.1 PICO table for assessment of treatment of pyogenic liver abscess es P (Patients) I (Intervention) C (Comparator) O (Outcomes) Patients with pyogenic liver abscess Surgical drainage Percutaneous drainage or aspiration, antibiotics alone Mortality, morbidity, resolution of abscess T.W. Reichman and W.G. Terral 131 are not identifi able by imaging. Direct extension includes cholecystitis, perinephric abscesses, and subdiaphragmatic abscesses. Traumatic causes include penetrating trauma but also include ingestion of foreign objects, blunt trauma with resultant infected hepatic hematoma, tumor necrosis, and sickle cell disease. Lastly, cryptogenic liver abscesses have become the most common fi nding and predominated in reviews from both Rahimian et al. and Rockey and Seeto with cryptogenic causes as 48 % and 40 % respectively [ 8 , 9 ]. Predicting Prognosis Several attempts have been made to try to stratify patients into risk categories in attempt to identify patients that might have a higher risk of mortality and/or a more complicated clinical course. Theoretically, stratifying patients should help to identify individuals that warrant more aggressive clinical management of their abscess up front rather then taking a more conservative approach. Chen et al. studied 298 patients with pyogenic liver abscess es with an overall mortality rate of 10 % [ 10 ]. The authors demonstrated by multivariate analysis that the Acute Physiology and Chronic Health Evaluation II (APACHE II score), SAPS II score, the presence of a gas-forming abscess, or an anaerobic infection was associated with higher mortality. These fi ndings were further substantiated in a study by Hsieh et al. which found that a more aggressive approach in patients with APACHE II scores greater than 15 were associated with better clinical outcomes [ 11 ]. In addition to mortality , Alvarez Pérez et al. examined 133 patients in an attempt to identify risk factors associated with a complicated clinical course from a pyogenic abscess [ 12 ]. They found by multivariate analysis that patients that present with shock, a hemoglobin <10 g/dl, an elevated PT (>17) and/or polymicrobial infections were more likely to have a complicated clinical course. In this study, the overall rate of patients with a complicated clinical course was 36 %. In addition, the authors also identifi ed factors that were associated with patient mortality. Pyogenic abscesses associated with a biliary origin, multiple abscesses, a low hemoglobin (<10 g/dl), or an elevated BUN (>28 mg/dL) were associated with death by multivariate analysis. In addition, the presence of shock was the highest predictor of mortality by multivariate analysis with an odds ratio of 22.66. An additional study by Ruiz-Hernández et al. also reported similar fi ndings in that patients that develop sepsis and/or are in septic shock are at high risk of mortality [ 13 ]. Treatment Options Interventions for pyogenic hepatic abscesses range in degree of invasiveness from antibiotic therapy alone to more aggressive therapies such as hepatic resection . Trials comparing methodologies to manage pyogenic liver abscess es are presented in Table 11.2 . 11 Clinical Management of Pyogenic Liver Abscesses 132 Antibiotic Therapy Antibiotic therapy is almost universally used in conjunction with other treatment modalities. However, in the absence of positive blood cultures, the disadvantage to treatment of liver abscess es without any intervention is a lack of the ability to identify the offending organism(s) in which antibiotic therapy can be tailored. Current recommendations for antibiotic treatment of pyogenic hepatic abscesses include empiric coverage of Enterobacteriaceae , enterococci, anaerobes, and in certain situations staphylococci and streptococci. Empiric regimens should include a betalactam/beta-lactamase inhibitor combination, carbapenem, or second-generation cephalosporin with anaerobic coverage. Metronidazole or clindamycin should be included in the antibiotic regimen to cover Bacteroides fragilis if not covered by the initial antibiotic(s). Systemic antifungal agents should also be initiated if a fungal abscess is suspected. Once cultures and sensitivities are available, the antibiotic regimen should be tailored appropriately. The recommended duration of antibiotic therapy should be 4–6 weeks. However, this may potentially be shortened in patients that have undergone drainage and an uncomplicated clinical course [ 14 ]. Earlier reports demonstrated inferior results in patients treated with antibiotics alone versus an intervention plus antibiotics [ 12 ]. However, in appropriately selected patients, antibiotic therapy alone can be effective in the treatment of certain pyogenic abscesses. In a series by Hope et al . the authors stratifi ed 107 patients with pyogenic liver abscess es into 3 categories: (1) <3 cm, (2) Unilocular, >3 cm, and (3) Complex, multilocular, >3 cm [ 15 ]. Patients were also stratifi ed into three treatment algorithms that included one of the following treatment arms: (1) Antibiotics alone, (2) Percutaneous drainage plus antibiotics, or (3) Surgery. In this series, antibiotic therapy alone was effective in 100 % of patients with hepatic abscesses <3 cm in Table 11.2 Trials comparing treatment modalities for pyogenic liver abscess es First author, year Study type n Comparison Outcome Yu, 2004 RCT 64 Percutaneous aspiration vs. qCD Equivalent Zerem, 2007 RCT 60 Percutaneous aspiration vs. CD Improved with CD Rajak, 1998 RCT 50 (11 with PLA) Percutaneous aspiration vs. CD Improved with CD Tan, 2005 RR 80 (PLA >5 cm) CD vs. surgery Improved with Surgery Hsieh, 2008 RR 81 (APACHE II 15) CD vs. surgery Improved with surgery Chou, 1997 RR 483 (single vs. multiple PLA) CD vs. surgery Single = CD Multiple = surgery Hope, 2008 RR 107 Abx vs. CD vs. surgery 3 cm = Abx >3 cm, UL = CD >3 cm, ML = surgery RCT randomized controlled trial, CD catheter drainage, PLA pyogenic liver abscess , RR retrospective review, APACHE II, Abx antibiotics, UL uniloculated, ML multiloculated T.W. Reichman and W.G. Terral 133 size. Hsieh et al. also demonstrated successful treatment of <3 cm abscesses with antibiotics alone, even in patient with high APACHE II scores [ 11 ]. Similarly, Rahimian et al . reported successful treatment of approximately 17 % of their patients (14 of 70 patients) treated for pyogenic liver abscess with no treatment failures requiring additional interventions [ 8 ]. Radiologic Intervention Percutaneous radiologic interventions (e.g. aspiration or placement of an indwelling catheter) are becoming more commonly the modality of choice for patients with pyogenic liver abscesses. Percutaneous interventions serve two purposes: (1) They drain the underlying infection and (2) They provide abscess contents for culture and sensitivity. There have been several studies that have demonstrated similar or decreased mortality rates in patients treated with percutaneous intervention versus open surgical drainage or resection [ 8 , 9 , 12 , 16 ]. The optimal percutaneous approach to abscess drainage (intermittent needle aspiration versus continuous indwelling catheter and drainage) is still debated. Intermittent needle aspiration has the advantage in that it is easier and more cost effective to perform and is also less painful for the patient. The one disadvantage is that it typically requires multiple interventions. In a randomized-controlled trial by Yu et al. the authors compared intermittent needle aspiration to continuous catheter drainage in 64 consecutive patients with a pyogenic liver abscess . There was no statistically signifi cant difference in outcomes from either treatment modality, however, there was a trend toward higher treatment success rate, shorter hospital stay, and lower mortality rate in patients treated with needle aspiration [ 6 ]. However, a similar randomized study by Rajak et al . demonstrated an improved outcome using percutaneous catheters versus needle aspiration. However, this report has been criticized due to the low sample size of confi rmed pyogenic abscesses (n = 11) and the limitation on the number of aspirations allowed (2). A more recent study however appeared to confi rm these fi ndings and again demonstrated improved outcomes with catheter drainage versus intermittent needle aspiration in a randomized controlled trial with no treatment failures occurring in the percutaneous catheter group [ 17 ]. Previously, the effectiveness of catheter-based drainage has been questioned in patients with multiloculated abscesses. However, a recent publication by Liu et al . compared 109 patients with either uniloculated or multiloculated abscesses who were all treated with percutaneous catheter drainage [ 18 ]. Clinical success ranged between 87 and 92 % regardless of whether the patient had single or multiple abscesses or the abscess was uniloculated or multiloculated, indicating potentially all abscesses regardless of their characteristics should have a trial of percutaneous drainage . Overall mortality reported in this series was 3.5 %. However, no comparison to other modalities was made. In a series from Memorial Sloan-Kettering, Mezhir et al . examined their series of hepatic abscesses (n = 51) of which 88 % occurred the setting of a history of cancer . 11 Clinical Management of Pyogenic Liver Abscesses 134 Twenty-two percent of the patient had previously underwent local-regional therapy (transarterial chemoembolization or radiofrequency ablation). Percutaneous drainage was successful in 66 % of patients; 9 % of patients required surgical intervention. The presence of yeast and/or communication with the biliary tree was associated with poorer outcomes . Overall mortality was 26 %, however many of these patients (60 %) died of progression of disease [ 19 ]. Surgical Therapy Prior to the advent of percutaneous radiology-based interventions, surgery was the mainstay of treatment for patients with pyogenic liver abscess es. However, based on review of the current literature, the paradigm has clearly switched from surgical drainage to percutaneous procedures. However, in certain subsets of patients, surgical intervention might still be the most appropriate fi rst line therapy. In patients with large abscesses (>5 cm), there may still be a role for open surgical drainage. Tan et al . compared PD to surgical drainage (SD, 36 patients versus 44 patients, respectively) in patients with pyogenic liver abscesses greater then 5 cm in size [ 20 ]. The authors examined time to defervescence of fever, treatment failure, secondary procedures, length of hospital stay, morbidity and mortality . Of these endpoints, patients that had SD had less treatment failures, less secondary procedures performed, and shorter length of stays. There was no statistical difference between morbidity and mortality. Hope et al . also noted a high treatment failure rate in patients with large, multiloculated abscesses (67 %). In comparison, patients treated with surgery up front had no recurrence of their abscess [ 15 ]. In contrast to this, a recent publication from 2009 noted a 87 % clinical success rate in patients treated percutaneous drainage with an average abscess size of 8.3 cm [ 18 ]. No comparison to other treatment modalities was made in this series. Patients also who score high on a severity-of-disease classifi cation system may also warrant a more aggressive approach. Hsieh et al . compared the outcomes of patients with an APACHE II score that underwent initial percutaneous drainage versus surgical drainage [ 11 ]. The authors found a higher treatment success rate and a lower mortality rate in patients treated initially treated with surgery . In addition, less antibiotic use and a shorter length of stay were also noted in the group in which surgery was performed upfront. Additional clinical fi ndings might also warrant a surgical approach. Chou et al. demonstrated a high failure rate in patients that underwent catheter-based therapy in the setting of multiple abscesses [ 21 ]. The presence of fungus in the abscess culture also appears to increase catheter-based treatment failure. On multivariate analysis, yeast in the abscess culture was identifi ed as a risk factor for treatment failure via a percutaneous approach [ 19 ]. Strong et al . also reviewed there experience with patients treated for abscess and concluded that a non-surgical approach should be undertaken for patients with pyogenic liver abscess es. However, for patients that present with an initial intraperitoneal abscess rupture or in cases of hepatobiliary T.W. Reichman and W.G. Terral 135 pathology causing multiple abscesses above an obstructed duct system, primary surgical treatment of pyogenic liver abscess is likely indicated [ 22 ]. Liver Abscess After Liver Transplantation Although rare, pyogenic liver abscess es following liver transplant ation can be challenging to manage, with many of these occur in the setting of vascular compromise to the liver graft. Hepatic artery thrombosis is almost always the cause and is often associated with biliary tree necrosis and/or biliary stricture s [ 23 ]. Management of these abscesses can be challenging since with a compromised blood supply, the infection is very diffi cult to clear. In addition, clinicians are often faced managing these patients in the setting of chronic immunosuppression. Tachopoulou et al . reviewed their experience at the Cleveland Clinic from 1990 to 2000 in solid organ transplant patients and identifi ed 12 patients, all liver transplant recipients, with hepatic abscesses [ 24 ]. Thirteen patients underwent aspiration of the abscess from which 30 microbial isolates were obtained. Of these, 15 were gram-positive aerobic bacteria, 9 were gram-negative aerobic bacteria, and 3 were anaerobic. All patients except one were initially treated with percutaneous intervention. The overall mortality of the infected patients in this series was 36 %, signifi cantly higher then that reported for non-transplant patients. Five patients required retransplantation. Similarly, Nikeghbalian reviewed their experience and identifi ed 5 patients out of 560 liver transplant recipients with a hepatic abscess. Overall mortality in their series was 40 % [ 25 ]. Personal Experience As detailed by the authors of several of the quoted manuscripts in this chapter, although now rare in the United States, in our experience, pyogenic abscesses when diagnosed can be challenging to manage, often occurring in older, debilitated patients. A combination approach which includes broad-spectrum antibiotics and percutaneous intervention is typically performed. Although it is ideal to obtain cultures prior to the initiation of antibiotic therapy, it is rarely the case as many of these patients present in extremis and empiric antibiotics have already been started prior to any workup being initiated. Once antibiotic therapy has started, percutaneous aspiration plus or minus placement of a pigtail catheter depending on the size of the abscess is almost routinely performed. Patients are typically reimaged 5–7 days following catheter placement to assess for adequate drainage; sooner if the patients clinical course is not improving. Repeat interventions are performed including upsizing of catheters as needed to maximize drainage. Antibiotics are eventually tailored once cultures and sensitivities have been obtained. Surgery is rarely indicated, and is only reserved for patients that have failed multiple attempts at percutaneous interventions. In patients with a prior liver transplant , liver abscess es can be 11 Clinical Management of Pyogenic Liver Abscesses 136 challenging. Hepatic arterial thrombosis should always be ruled out, either by CT angiogram or ultrasound . Interrogation of the biliary system either via MRCP or ERCP should also be performed to rule out biliary necrosis and/or biliary stricturing. In patients that fail intervention, many will require liver retransplantation especially if biliary or vascular complications are present. Summary Excellent outcomes can be obtained from patients with pyogenic liver abscess es when managed appropriately. First-line therapy should include a percutaneous aspiration or trans-catheter drainage of the abscess in order to control the infection and obtain a sample for culture and sensitivity. All patients should be treated with broad spectrum antibiotics which can be tailored to the organism once identifi ed for a duration of 4–6 weeks. Surgery should be reserved for patients that fail fi rst line therapy, but can also be warranted in patients with large (>5 cm) abscesses or patients who present with high APACHE II scores, depending on the experience and expertise of the interventional radiology department. Recommendations • Percutaneous drainage is fi rst line therapy for the treatment of pyogenic liver abscess es and surgical drainage or resection should be considered in patients who fail initial therapy especially in patients with a large, multi-loculated (>5 cm) abscess (evidence quality good – strong recommendation) • Surgery should be considered for patients with high APACHE II scores (evidence quality poor – weak recommendation). • Antibiotics alone are suitable fi rst line therapy for abscesses less then 3 cm, however, aspiration should be considered in order to tailor antibiotics if possible (evidence quality good – strong recommendation) References 1. Hansen PS, Schonheyder HC. Pyogenic hepatic abscess. A 10-year population-based retrospective study. APMIS. 1998;106(3):396–402. 2. Kaplan GG, Gregson DB, Laupland KB. Population-based study of the epidemiology of and the risk factors for pyogenic liver abscess. Clin Gastroenterol Hepatol. 2004;2(11):1032–8. 3. 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