TY - JOUR
AU - Kokudo, N
AB - Abstract Background Previous RCTs have failed to demonstrate the usefulness of combining energy devices with the conventional clamp crushing method to reduce blood loss during liver transection. Here, the combination of an ultrasonically activated device (UAD) and a bipolar vessel-sealing device (BVSD) with crush clamping was investigated. Methods Patients scheduled to undergo hepatectomy at the University of Tokyo Hospital or Nihon University Itabashi Hospital were eligible for this parallel-group, single-blinded randomized study. Patients were assigned to a control group (no energy device used), an UAD group or a BVSD group. The primary endpoint was the volume of blood loss during liver transection. Outcomes of the control group and the combined energy device groups (UAD plus BVSD) were first compared. Pairwise comparisons among the three groups were made for outcomes for which the combined energy device group was superior to the control group. Results A total of 380 patients were enrolled between July 2012 and May 2014; 116 patients in the control group, 122 in the UAD group and 123 in the BVSD group were included in the final analysis. Median blood loss during liver transection was lower in the combined energy device group (245 patients) than in the control group (116 patients): median 190 (range 0–3575) versus 230 (range 3–1570) ml (P = 0·048). Pairwise comparison revealed that blood loss was lower in the BVSD group than in the control group (P = 0·043). Conclusion The use of energy devices combined with crush clamping reduced blood loss during liver transection. Registration number: C000008372 (www.umin.ac.jp/ctr/index.htm). Introduction A variety of techniques and devices are available to reduce blood loss and improve safety when performing hepatectomy1. The clamp crushing method was first described in the 1970 s2, followed by reports on the development of the ultrasonic dissector3, water jet dissector4, argon beam coagulator5, harmonic scalpel6, microwave coagulator7 and bipolar vessel-sealing device (BVSD)8. Although numerous studies have evaluated the usefulness of these devices9, RCTs have failed to demonstrate a benefit compared with the clamp crushing method10–12. Three RCTs conducted at the University of Tokyo Hospital also failed to demonstrate a benefit of using an ultrasonic dissector13, saline-linked radiofrequency coagulator14 or BVSD15. Thus, previous meta-analyses16–18 have concluded that the clamp crushing method without the use of an energy device should be the standard for liver transection. More recently, improvements in energy devices have been made, and the ultrasonically activated device (UAD) and BVSD are now used widely. The presently used UAD (Harmonic FOCUSTM Long Curved Shears; Ethicon Endo-Surgery Inc., Cincinnati, Ohio, USA) is longer than the previous model, allowing for secure cutting and sealing, even in remote areas. Equally, the BVSD (LigaSureTM Small Jaw; Covidien, Dublin, Ireland) provides a quicker and more secure seal when used in combination with a new energy platform (ForceTriadTM Energy Platform; Covidien)19,20. Its improved design also reduces instrument exchanges19. Both of these devices were used at the University of Tokyo Hospital before the start of the present trial, and safety and haemostatic performances of these two devices found to be almost the same. A recent RCT21 concluded that energy devices were useful for shortening liver transection time and reducing the incidence of bile leakage21. However, their usefulness in reducing blood loss, an important short-term outcome in hepatectomy22,23, has not yet been demonstrated. The present RCT was designed to test the hypothesis that the use of an UAD or BVSD in combination with the clamp crushing method might reduce blood loss during liver transection, compared with the standard clamp crushing method without the use of an energy device. Methods The study protocol was approved by the institutional review board of the University of Tokyo Hospital. An English-language protocol summary was submitted (registration ID C000008372) to the Clinical Trials Registry managed by the University Hospital Medical Information Network in Japan (http://www.umin.ac.jp/ctr/index.htm). Patients scheduled to undergo open liver resection between July 2012 and May 2014 for primary or metastatic liver tumours at the University of Tokyo Hospital or Nihon University Itabashi Hospital were eligible for this two-centre, single-blinded, parallel-group RCT. Other inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0–2 and the fulfilment of Makuuchi's criteria24. Patients with any of the following were excluded: scheduled for laparoscopic liver resection; need for bilioenteric reconstruction; other malignant disease outside the liver; expected difficulty with inflow occlusion during liver transection because of severe adhesions or other cause; living liver donors for liver transplantation; and severe co-morbidity, such as renal dysfunction (estimated glomerular filtration rate 20 ml per min per 1·73 m2 or less), cardiovascular disease (necessitating intervention or an ejection fraction of no more than 50 per cent), or a respiratory disorder (vital capacity below 60 per cent or forced expiratory volume in 1 s less than 50 per cent). In addition, patients who required the resection of another organ (except cholecystectomy) because of liver tumour invasion, or a simultaneous primary lesion, metastatic lesion or non-malignant disease, were excluded. Both treatment centres participating in this study are university hospitals located in Tokyo, Japan. More than 200 hepatectomies (including hepatectomies with bilioenteric reconstruction, laparoscopic liver resection, and the procurement of living donor grafts for liver transplantation) are performed at each centre every year. This study was conducted in accordance with the Declaration of Helsinki. Before enrolment, all participating patients provided written informed consent. Assignment The doctors in charge were required to enrol all eligible patients before the day of surgery. After obtaining informed consent, the participants were assigned randomly (1 : 1 : 1 ratio) to the control group (crush clamping without the use of an energy device for liver transection), the UAD group or the BVSD group. The assignments were generated using an internet-accessed randomization system (VIEDOCTM) supported by PCG Solutions (Uppsala, Sweden). The allocation sequence was concealed by the system. The randomization was performed according to the stochastic minimization procedure with the following stratification factors: indocyanine green retention rate at 15 min (ICG-R15 below 20 per cent, or 20 per cent or above), number of tumours (solitary or multiple) and centre (University of Tokyo Hospital or Nihon University Itabashi Hospital). The energy device group was formed by combining the UAD and BVSD groups. In this study, group assignment was not masked for the surgeons and investigators, but the allocation was concealed for the participants. Surgical procedures The surgical procedures were selected according to a previously described algorithm24. Pringle's manoeuvre (15 min clamping and 5 min release) was applied for intermittent inflow occlusion from the beginning to the end of liver transection in all patients (liver transection time was equal to liver ischaemia time). In the control group, after cauterizing the liver capsule, the liver parenchyma was fractured with a forceps13–15. Vessels were ligated with 3/0 or 4/0 silk sutures. Small vessels and minor oozing were cauterized by electrical cautery. In the UAD group, after the liver capsule had been cauterized or sealed and cut with the UAD, the liver parenchyma was fractured with a forceps or the UAD. In the BVSD, after cauterizing the liver capsule, the liver parenchyma was fractured with forceps in the same manner as in the control group. If the remaining structures, including the portal triads and/or hepatic veins, were less than approximately 2 mm in diameter, they were sealed and cut with the UAD or BVSD, appropriate to the group assignment. Vessels larger than 2 mm in diameter were ligated and divided in the conventional manner15. Minor oozing was cauterized by electrical cautery. In all groups, macroscopically observed points of bile leakage were sutured with braided absorbable sutures. Bleeding points were also sutured with braided non-absorbable sutures if cauterization was not effective. To ensure haemostasis, fibrin glue (Beriplast® P; CSL Behring, King of Prussia, Pennsylvania, USA) was spread routinely on the cut surface of the liver. One drainage tube was placed on every cut surface, and the total bilirubin level of drained fluid was measured on the first and third days after surgery. The drain was removed on or after postoperative day 3 if the bilirubin level in the drainage fluid was lower than 3 mg/dl and the total amount of drained fluid less than 500 ml/day. Endpoints The primary endpoint was the volume of blood loss during liver transection. Blood loss was calculated by adding the weight of blood absorbed by gauzes and the amount of blood collected in the suction bottle. Blood loss during the transection phase was measured separately from that during the other surgical phases. Secondary endpoints were: liver transection time; transection speed; total duration of surgery; total intraoperative blood loss; intraoperative red blood cell transfusion volume; length of postoperative hospital stay; mortality; postoperative levels of serum alanine aminotransferase; postoperative liver function as estimated by serum levels of total bilirubin and prothrombin time on the third and seventh postoperative days; and the incidence of major complications such as bile leakage, bleeding by the third postoperative day, pleural effusion, abscess formation and other infections. The transection speed (cm2/min) was calculated as transection area divided by transection time. The size of the transection area (cm2) was estimated using Adobe Photoshop Elements® 11 software (Adobe System, San Jose, California, USA) based on the shape of the transection plane, which was traced on to a piece of paper13–15. Bile leakage was considered only when clinically significant, that is grade B or C, according to the definition of the International Study Group of Liver Surgery25. Postoperative bleeding necessitating relaparotomy, pleural effusion requiring percutaneous drainage, abscess formation requiring percutaneous drainage or relaparotomy, other infections resulting in a temperature higher than 38°C and necessitating administration of antibiotic drugs, and any other life-threatening events were defined as major complications, according to the Clavien–Dindo classification26. Statistical analysis Outcomes were first compared between the control and combined energy device groups. Pairwise comparisons of outcomes among the three randomization groups were made only where outcomes for the energy device group were superior to those of the control group; for multiplicity adjustment, the fixed sequence testing approach was used. A sample size calculation was performed for these comparisons. In a previous study conducted at the University of Tokyo Hospital15, the mean and median blood losses during liver transection were 462 and 315 ml respectively. The amount of blood loss during liver transection followed a normal logarithmic distribution (mean(s.d.) 5·73(1·01) after logarithmic transformation). A blood loss reduction of more than 100 ml (approximately 30 per cent of the total amount) was considered meaningful clinically; therefore, it was hypothesized that median blood loss during transection would be 315 ml in the control group and that the median value in the UAD or BVSD group would be at least 100 ml less (215 and 200 ml respectively). The sample size required to detect this difference using a one-way ANOVA model for logarithmically transformed data with a standard deviation of 1·01 was calculated to be 111 patients in each group. This sample size would enable the detection of a statistically significant difference between the control and combined energy device groups, or differences between the UAD or BVSD group and the control group, with a type 1 error of 5 per cent and a statistical power of 80 per cent. To compare the outcomes of each device group with that of the control group, the sample allocation was set at a 1 : 1 : 1 ratio, and the total number of participants required was calculated to be 333. Allowing for a 10 per cent drop-out rate, the target number was initially set at 350. However, the number of drop-outs was larger than expected, and the target number was finally changed to 380 in expectation of a 15 per cent drop-out rate. Although a comparison of outcomes between the UAD and BVSD groups was planned, the statistical power was insufficient for such a comparison. An interim analysis was not scheduled, and premature termination of the study was to be considered only if serious adverse events occurred, as specified in the study protocol. The institution of the corresponding author (Hepato-Biliary-Pancreatic Surgery Division, University of Tokyo) collected the data, which were analysed by a blinded statistician. Surgical endpoints in the control and energy device groups were compared using Fisher's exact test for categorical variables. For continuous data, means of surgical endpoints in each group were compared using a one-way ANOVA after logarithmic transformation. All pairwise comparisons between the control, UAD and BVSD groups were based on the Tukey–Kramer method after logarithmic transformation. For the primary endpoint, subgroup analyses were performed for comparison between the control group and groups superior to the control group to assess whether the results were applicable in various situations. Subgroups were formed based on ICG-R15 value, number of tumours and extent of hepatectomy (major or minor). In each subgroup, the differences between mean outcomes and 95 per cent confidence intervals (c.i.) of the difference were presented without logarithmic transformation to clarify the difference. P values of differences between mean outcomes were calculated using the t test after logarithmic transformation. All analyses were performed on an intention-to-treat basis. A statistical analysis plan was created before data analysis, and all analyses were conducted according to this plan. Statistical significance was defined as P < 0·050. All statistical calculations were performed using SAS® 9.3 software (SAS Institute, Cary, North Carolina, USA). Results A total of 492 consecutive patients were potentially eligible for the study. Of these, 112 were excluded and the remaining 380 patients were enrolled (Fig. 1). As surgery was cancelled for three patients before randomization, 377 patients were randomized. After randomization, two patients were found not to meet the eligibility criteria. Of the remaining 375 patients, 122 were assigned to the control group, 128 to the UAD group and 125 to the BVSD group. Surgery was cancelled for some patients after the preoperative conference, and hepatic resection was abandoned in some others after exploratory laparotomy. Finally, 116 patients in the control group, 122 in the UAD group and 123 in the BVSD group were included in the intention-to-treat analysis. A BVSD was used in one patient in the control group to stop bleeding from the Spiegel lobe. The combined energy device group comprised the UAD plus BVSD groups (245 patients). Fig. 1 Open in new tabDownload slide Flow diagram for the trial. UAD, ultrasonically activated device; BVSD, bipolar vessel-sealing device Background patient characteristics were similar in the control and combined energy device groups, except for the proportion of patients who received a thoracotomy and presence of liver cirrhosis (Table 1). The proportion of patients with a thoracotomy tended to be higher in the control group. Table 1 Background characteristics of the control and combined energy device groups . Control (n = 116) . Energy device (n = 245) . Age (years)* 69 (34–85) 69 (29–87) Sex ratio (M : F) 88 : 28 179 : 66 BMI (kg/m2)* 23 (17–35) 23 (15–39) Disease Primary liver tumour 84 (72·4) 171 (69·8) Metastatic liver tumour 32 (27·6) 74 (30·2) No. of tumours Solitary tumour 71 (61·2) 152 (62·0) Multiple tumours 45 (38·8) 93 (38·0) Maximum diameter (mm)* 30 (6–180) 25 (7–220) Repeat hepatic resection Yes 32 (27·6) 64 (26·1) No 84 (72·4) 181 (73·9) Type of hepatic resection Major 17 (14·7) 40 (16·3) Minor 99 (85·3) 205 (83·7) Thoracotomy added 38 (32·8) 48 (19·6) ICG-R15 (%)* 10·5 (1·8–54·0) 11 (0·7–41·7) Background liver Cirrhosis 17 (14·7) 61 (24·9) No cirrhosis 99 (85·3) 184 (75·1) Preoperative chemotherapy 12 (10·3) 39 (15·9) Serum alanine aminotransferase (units/l)* 29 (7–157) 24 (6–202) Serum total bilirubin (mg/dl)* 0·7 (0·2–1·4) 0·7 (0·2–2·2) . Control (n = 116) . Energy device (n = 245) . Age (years)* 69 (34–85) 69 (29–87) Sex ratio (M : F) 88 : 28 179 : 66 BMI (kg/m2)* 23 (17–35) 23 (15–39) Disease Primary liver tumour 84 (72·4) 171 (69·8) Metastatic liver tumour 32 (27·6) 74 (30·2) No. of tumours Solitary tumour 71 (61·2) 152 (62·0) Multiple tumours 45 (38·8) 93 (38·0) Maximum diameter (mm)* 30 (6–180) 25 (7–220) Repeat hepatic resection Yes 32 (27·6) 64 (26·1) No 84 (72·4) 181 (73·9) Type of hepatic resection Major 17 (14·7) 40 (16·3) Minor 99 (85·3) 205 (83·7) Thoracotomy added 38 (32·8) 48 (19·6) ICG-R15 (%)* 10·5 (1·8–54·0) 11 (0·7–41·7) Background liver Cirrhosis 17 (14·7) 61 (24·9) No cirrhosis 99 (85·3) 184 (75·1) Preoperative chemotherapy 12 (10·3) 39 (15·9) Serum alanine aminotransferase (units/l)* 29 (7–157) 24 (6–202) Serum total bilirubin (mg/dl)* 0·7 (0·2–1·4) 0·7 (0·2–2·2) Values in parentheses are percentages unless indicated otherewise; * values are median (range). Major hepatectomy defined as resection of three or more Couinaud segments. ICG-R15, indocyanine green retention rate at 15 min. Open in new tab Table 1 Background characteristics of the control and combined energy device groups . Control (n = 116) . Energy device (n = 245) . Age (years)* 69 (34–85) 69 (29–87) Sex ratio (M : F) 88 : 28 179 : 66 BMI (kg/m2)* 23 (17–35) 23 (15–39) Disease Primary liver tumour 84 (72·4) 171 (69·8) Metastatic liver tumour 32 (27·6) 74 (30·2) No. of tumours Solitary tumour 71 (61·2) 152 (62·0) Multiple tumours 45 (38·8) 93 (38·0) Maximum diameter (mm)* 30 (6–180) 25 (7–220) Repeat hepatic resection Yes 32 (27·6) 64 (26·1) No 84 (72·4) 181 (73·9) Type of hepatic resection Major 17 (14·7) 40 (16·3) Minor 99 (85·3) 205 (83·7) Thoracotomy added 38 (32·8) 48 (19·6) ICG-R15 (%)* 10·5 (1·8–54·0) 11 (0·7–41·7) Background liver Cirrhosis 17 (14·7) 61 (24·9) No cirrhosis 99 (85·3) 184 (75·1) Preoperative chemotherapy 12 (10·3) 39 (15·9) Serum alanine aminotransferase (units/l)* 29 (7–157) 24 (6–202) Serum total bilirubin (mg/dl)* 0·7 (0·2–1·4) 0·7 (0·2–2·2) . Control (n = 116) . Energy device (n = 245) . Age (years)* 69 (34–85) 69 (29–87) Sex ratio (M : F) 88 : 28 179 : 66 BMI (kg/m2)* 23 (17–35) 23 (15–39) Disease Primary liver tumour 84 (72·4) 171 (69·8) Metastatic liver tumour 32 (27·6) 74 (30·2) No. of tumours Solitary tumour 71 (61·2) 152 (62·0) Multiple tumours 45 (38·8) 93 (38·0) Maximum diameter (mm)* 30 (6–180) 25 (7–220) Repeat hepatic resection Yes 32 (27·6) 64 (26·1) No 84 (72·4) 181 (73·9) Type of hepatic resection Major 17 (14·7) 40 (16·3) Minor 99 (85·3) 205 (83·7) Thoracotomy added 38 (32·8) 48 (19·6) ICG-R15 (%)* 10·5 (1·8–54·0) 11 (0·7–41·7) Background liver Cirrhosis 17 (14·7) 61 (24·9) No cirrhosis 99 (85·3) 184 (75·1) Preoperative chemotherapy 12 (10·3) 39 (15·9) Serum alanine aminotransferase (units/l)* 29 (7–157) 24 (6–202) Serum total bilirubin (mg/dl)* 0·7 (0·2–1·4) 0·7 (0·2–2·2) Values in parentheses are percentages unless indicated otherewise; * values are median (range). Major hepatectomy defined as resection of three or more Couinaud segments. ICG-R15, indocyanine green retention rate at 15 min. Open in new tab Perioperative outcomes were first compared between the control and combined energy device groups (Table 2). Median blood loss during liver transection was lower in the energy device group: 190 (range 0–3575) ml compared with 230 (3–1570) ml in the control group (P = 0·048). The difference in mean blood loss during liver transection between these groups after logarithmic transformation was 0·327 (95 per cent c.i. 0·003 to 0·651). The blood loss per transection area during liver transection was also lower in the energy device group: 3·19 (0–53·06) versus 4·07 (0·11–58·82) ml/cm2 (P = 0·027). Median transection time was shorter with use of an energy device than without: 56 (8–183) versus 68 (9–211) min respectively (P = 0·003). Transection speed was also faster in the energy device group: 1·11 (0·06–3·68) cm2/min versus 0·86 (0·07–3·06) cm2/min in the control group (P = 0·004). Use of an energy device was associated with a lower median serum alanine aminotransferase level on the third postoperative day: 114 (7–1212) versus 134 (31–920) units/l (P = 0·008). Table 2 Comparison of perioperative outcomes between the control and combined energy device groups . Control (n = 116) . Energy device (n = 245) . P† . Blood loss* Total (ml) 460 (35–4840) 340 (5–5103) 0·086‡ During transection (ml) 230 (3–1570) 190 (0–3575) 0·048‡ Per transection area (ml/cm2) 4·07 (0·11–58·82) 3·19 (0–53·06) 0·027‡ Liver transection* Time (min) 68 (9–211) 56 (8–183) 0·003‡ Area (cm2) 56 (3–183) 62 (1–275) 0·747‡ Speed (cm2/min) 0·86 (0·07–3·06) 1·11 (0·06–3·68) 0·004‡ Duration of operation (min)* 327 (109–669) 300 (91–839) 0·096‡ Red blood cell transfusion 7 (6·0) 14 (5·7) 1·000 Plasma transfusion 14 (12·1) 28 (11·4) 0·986 Serum alanine aminotransferase on POD 3 (units/l)* 134 (31–920) 114 (7–1212) 0·008‡ Serum total bilirubin on POD 3 (mg/dl)* 0·8 (0·4–2·0) 0·8 (0·3–4·4) 0·548‡ Postoperative adverse events Bile leakage 8 (6·9) 10 (4·1) 0·371 Pleural effusion 18 (15·5) 27 (11·0) 0·300 Abscess 4 (3·4) 3 (1·2) 0·306 Bleeding 2 (1·7) 4 (1·6) 1·000 Infection 14 (12·1) 23 (9·4) 0·542 Clavien–Dindo classification (≥ grade III) 24 (20·7) 37 (15·1) 0·242 Death 0 (0) 2 (0·8) 0·920 Duration of hospital stay (days)* 11(7–45) 11 (7–97) 0·691‡ . Control (n = 116) . Energy device (n = 245) . P† . Blood loss* Total (ml) 460 (35–4840) 340 (5–5103) 0·086‡ During transection (ml) 230 (3–1570) 190 (0–3575) 0·048‡ Per transection area (ml/cm2) 4·07 (0·11–58·82) 3·19 (0–53·06) 0·027‡ Liver transection* Time (min) 68 (9–211) 56 (8–183) 0·003‡ Area (cm2) 56 (3–183) 62 (1–275) 0·747‡ Speed (cm2/min) 0·86 (0·07–3·06) 1·11 (0·06–3·68) 0·004‡ Duration of operation (min)* 327 (109–669) 300 (91–839) 0·096‡ Red blood cell transfusion 7 (6·0) 14 (5·7) 1·000 Plasma transfusion 14 (12·1) 28 (11·4) 0·986 Serum alanine aminotransferase on POD 3 (units/l)* 134 (31–920) 114 (7–1212) 0·008‡ Serum total bilirubin on POD 3 (mg/dl)* 0·8 (0·4–2·0) 0·8 (0·3–4·4) 0·548‡ Postoperative adverse events Bile leakage 8 (6·9) 10 (4·1) 0·371 Pleural effusion 18 (15·5) 27 (11·0) 0·300 Abscess 4 (3·4) 3 (1·2) 0·306 Bleeding 2 (1·7) 4 (1·6) 1·000 Infection 14 (12·1) 23 (9·4) 0·542 Clavien–Dindo classification (≥ grade III) 24 (20·7) 37 (15·1) 0·242 Death 0 (0) 2 (0·8) 0·920 Duration of hospital stay (days)* 11(7–45) 11 (7–97) 0·691‡ Values in parentheses are percentages unless indicated otherewise; * values are median (range). POD, postoperative day. † Fisher's exact test, except ‡ contrast-based test after a one-way ANOVA for logarithmically transformed data. Open in new tab Table 2 Comparison of perioperative outcomes between the control and combined energy device groups . Control (n = 116) . Energy device (n = 245) . P† . Blood loss* Total (ml) 460 (35–4840) 340 (5–5103) 0·086‡ During transection (ml) 230 (3–1570) 190 (0–3575) 0·048‡ Per transection area (ml/cm2) 4·07 (0·11–58·82) 3·19 (0–53·06) 0·027‡ Liver transection* Time (min) 68 (9–211) 56 (8–183) 0·003‡ Area (cm2) 56 (3–183) 62 (1–275) 0·747‡ Speed (cm2/min) 0·86 (0·07–3·06) 1·11 (0·06–3·68) 0·004‡ Duration of operation (min)* 327 (109–669) 300 (91–839) 0·096‡ Red blood cell transfusion 7 (6·0) 14 (5·7) 1·000 Plasma transfusion 14 (12·1) 28 (11·4) 0·986 Serum alanine aminotransferase on POD 3 (units/l)* 134 (31–920) 114 (7–1212) 0·008‡ Serum total bilirubin on POD 3 (mg/dl)* 0·8 (0·4–2·0) 0·8 (0·3–4·4) 0·548‡ Postoperative adverse events Bile leakage 8 (6·9) 10 (4·1) 0·371 Pleural effusion 18 (15·5) 27 (11·0) 0·300 Abscess 4 (3·4) 3 (1·2) 0·306 Bleeding 2 (1·7) 4 (1·6) 1·000 Infection 14 (12·1) 23 (9·4) 0·542 Clavien–Dindo classification (≥ grade III) 24 (20·7) 37 (15·1) 0·242 Death 0 (0) 2 (0·8) 0·920 Duration of hospital stay (days)* 11(7–45) 11 (7–97) 0·691‡ . Control (n = 116) . Energy device (n = 245) . P† . Blood loss* Total (ml) 460 (35–4840) 340 (5–5103) 0·086‡ During transection (ml) 230 (3–1570) 190 (0–3575) 0·048‡ Per transection area (ml/cm2) 4·07 (0·11–58·82) 3·19 (0–53·06) 0·027‡ Liver transection* Time (min) 68 (9–211) 56 (8–183) 0·003‡ Area (cm2) 56 (3–183) 62 (1–275) 0·747‡ Speed (cm2/min) 0·86 (0·07–3·06) 1·11 (0·06–3·68) 0·004‡ Duration of operation (min)* 327 (109–669) 300 (91–839) 0·096‡ Red blood cell transfusion 7 (6·0) 14 (5·7) 1·000 Plasma transfusion 14 (12·1) 28 (11·4) 0·986 Serum alanine aminotransferase on POD 3 (units/l)* 134 (31–920) 114 (7–1212) 0·008‡ Serum total bilirubin on POD 3 (mg/dl)* 0·8 (0·4–2·0) 0·8 (0·3–4·4) 0·548‡ Postoperative adverse events Bile leakage 8 (6·9) 10 (4·1) 0·371 Pleural effusion 18 (15·5) 27 (11·0) 0·300 Abscess 4 (3·4) 3 (1·2) 0·306 Bleeding 2 (1·7) 4 (1·6) 1·000 Infection 14 (12·1) 23 (9·4) 0·542 Clavien–Dindo classification (≥ grade III) 24 (20·7) 37 (15·1) 0·242 Death 0 (0) 2 (0·8) 0·920 Duration of hospital stay (days)* 11(7–45) 11 (7–97) 0·691‡ Values in parentheses are percentages unless indicated otherewise; * values are median (range). POD, postoperative day. † Fisher's exact test, except ‡ contrast-based test after a one-way ANOVA for logarithmically transformed data. Open in new tab There was no difference in incidence of postoperative adverse events between the control and combined energy device groups. Two deaths occurred in this trial. One patient in the UAD group developed postoperative pneumonia, followed by severe liver failure, and one in the BVSD died from portal vein thrombosis. No serious adverse events were related directly to the study intervention. As significant differences between the control group and the combined energy device group were seen for five outcomes, including the primary endpoint (Table 2), comparisons were also made between the control, UAD and BVSD groups. Patient background characteristics were similar among these three groups, except for age and the proportion of patients who had a thoracotomy (Table S1, supporting information). Perioperative outcomes for the three groups are summarized in Table S2 (supporting information). The volume of blood loss was lowest in the BVSD group followed by the UAD group and then the control group. The results of pairwise comparisons are shown in Table 3. As for the volume of blood loss during transection, the BVSD was superior to the control group (P = 0·043). The difference in the mean blood loss during transection between the control and BVSD groups after logarithmic transformation was 0·456 (95 per cent c.i. 0·011 to 0·900). That for the control and UAD groups was 0·199 (−0·248 to 0·646), and that for the UAD and BVSD groups was 0·257 (−0·183 to 0·698). Table 3 Pairwise comparisons . P for pairwise comparison* . . Control versus UAD . Control versus BVSD . UAD versus BVSD . Blood loss During transection 0·549 0·043 0·356 Per transection area 0·543 0·015 0·184 Liver transection Time 0·028 0·018 0·990 Speed 0·021 0·045 0·952 Serum alanine aminotransferase on POD 3 0·031 0·088 0·900 . P for pairwise comparison* . . Control versus UAD . Control versus BVSD . UAD versus BVSD . Blood loss During transection 0·549 0·043 0·356 Per transection area 0·543 0·015 0·184 Liver transection Time 0·028 0·018 0·990 Speed 0·021 0·045 0·952 Serum alanine aminotransferase on POD 3 0·031 0·088 0·900 Pairwise comparisons were conducted only for outcomes where the combined energy device group was superior to the control group. UAD, ultrasonically activated device; BVSD, bipolar vessel-sealing device; POD, postoperative day. * Tukey–Kramer method after logarithmic transformation. Open in new tab Table 3 Pairwise comparisons . P for pairwise comparison* . . Control versus UAD . Control versus BVSD . UAD versus BVSD . Blood loss During transection 0·549 0·043 0·356 Per transection area 0·543 0·015 0·184 Liver transection Time 0·028 0·018 0·990 Speed 0·021 0·045 0·952 Serum alanine aminotransferase on POD 3 0·031 0·088 0·900 . P for pairwise comparison* . . Control versus UAD . Control versus BVSD . UAD versus BVSD . Blood loss During transection 0·549 0·043 0·356 Per transection area 0·543 0·015 0·184 Liver transection Time 0·028 0·018 0·990 Speed 0·021 0·045 0·952 Serum alanine aminotransferase on POD 3 0·031 0·088 0·900 Pairwise comparisons were conducted only for outcomes where the combined energy device group was superior to the control group. UAD, ultrasonically activated device; BVSD, bipolar vessel-sealing device; POD, postoperative day. * Tukey–Kramer method after logarithmic transformation. Open in new tab Comparisons for the primary endpoint revealed that the combined energy device and BVSD groups were superior to the control group (Tables 2 and 3). Subgroup analyses were conducted to assess the generalizability of these results (Figs 2 and 3). The results for the subset with an ICG-R15 below 20 per cent or solitary tumour and those having minor hepatectomy were consistent with the overall results in both comparisons as the differences between groups in the means of the primary endpoint were mostly positive and the P values were small. However, for patients with an ICG-R15 of 20 per cent and above or multiple tumours and those undergoing major hepatectomy, a reduction in blood loss was not seen in either the combined energy device or BVSD group. Fig. 2 Open in new tabDownload slide Subgroup analysis for the primary endpoint: comparison between control and combined energy device groups. ICG-R15, indocyanine green retention rate at 15 min. *t test after logarithmic transformation Fig. 3 Open in new tabDownload slide Subgroup analysis for the primary endpoint: comparison between control and bipolar vessel-sealing device (BVSD) groups. ICG-R15, indocyanine green retention rate at 15 min. *t test after logarithmic transformation Discussion In the present study, the use of the UAD or BVSD in combination with the clamp crushing method reduced blood loss during liver transection, compared with clamp crushing without the use of an energy device. This trial has confirmed the potential benefit of energy devices in reducing blood loss. The improved performance of these more recently launched devices may explain why the present trial was able to confirm this benefit. Compared with the conventional haemostatic procedure (ligation), energy devices seem to have two advantages. First, the haemostatic performance is not influenced by the skill of the assistant surgeons. Ligation can be difficult when vessels are small and the surgical field is narrow, whereas energy devices can easily seal such vessels. The second advantage is a shorter transection time. In some patients, oozing persists from the transection plane or hepatic veins even after careful haemostatic procedures. In the present trial, energy devices were used for vessels smaller than 2 mm. Larger vessels were ligated in all groups because treating such vessels using an energy device is associated with a risk of rebleeding or bile leakage. Haemostasis of small vessels is also important because the source of such bleeding can be difficult to identify. Furthermore, bleeding makes it difficult to identify other vessels in the transection plane and may lead to injury of larger vessels and major complications. Blood loss during transection and total blood loss decreased by 40 and 120 ml respectively with the use of an energy device. These volume reductions are relatively small and seem to be due mainly to the relatively low blood loss in this trial, compared with previously reported data. As hypothesized, the volume reduction in this trial was approximately 30 per cent, which was clinically meaningful. In interpreting the present results, differences in the background characteristics must be taken into account. The use of a thoracotomy may have implied a wider surgical field to be controlled by secure ligation in more patients in the control group. Regarding background liver status, although patients were stratified according to ICG-R15 value, more patients in the combined energy device group had cirrhosis. This difference would not have been advantageous for this group as cirrhosis is known to increase blood loss. As for secondary endpoints, transection speed was faster with use of an energy device, as described previously11,21. Advances in the BVSD have enabled a quicker seal and a reduction in the need to exchange devices19,20. Vessels could be sealed and cut equally quickly using the BVSD and the 2010 UAD model. The incidence of major complications did not differ between groups, indicating that the use of energy devices to seal vessels less than 2 mm in diameter was as safe as the conventional procedure (ligation). Although recent studies21,27,28 have demonstrated that thin bile ducts can be sealed safely, early investigation29,30 reported an increased risk of bile leakage from major bile ducts. Therefore, the use of energy devices to seal thick bile ducts may require careful attention. Blood loss during the non-transection phase of the procedure was lower in the combined energy device group than in the control group. As this trial was designed to detect the difference in blood loss during transection, definite conclusions on the haemostatic performance of the energy devices during steps other than transection cannot be drawn. However, these devices might also be useful for stopping bleeding or lymphorrhoea from fragile fat tissue, lymph nodes and the soft tissue of adhesions. Subgroup analyses revealed lower blood loss in the combined energy device group for patients with an ICG-R15 of less than 20 per cent or solitary tumours and those undergoing minor hepatectomy. Because these three factors are associated with less blood loss, the advantage of energy devices may decrease in difficult cases. In the present trial, the number of patients in each subset was too small for valid comparison. Pairwise comparisons indicated that the amount of blood lost during transection was lower in the BVSD group than in the control group. Median blood loss was lowest in the BVSD group, suggesting that this device may help to create a more secure seal than the UAD. Direct comparison between the UAD and BVSD groups, however, revealed no significant difference. The present trial was conducted at two centres, and the hepatectomies were performed in the same manner. Careful attention is required when generalizing the results of this study for application at other centres with different protocols. The catalogue prices of the disposable UAD and BVSD hand pieces used in this trial are both approximately €540 per unit. Although it depends on social circumstances whether this price is considered high or low, these devices seem to be worth the cost. Acknowledgements The authors thank Y. Sugawara, T. Aoki, J. Kaneko, N. Akamatsu, T. Ishizawa, H. Nakayama, A. Kanamoto, N. Yoshida, A. Miyazaki and Y. Hagiwara for their contribution to this study. Disclosure: The authors declare no conflict of interest. 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Google Scholar PubMed OpenURL Placeholder Text WorldCat © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd
TI - Randomized clinical trial comparing two vessel-sealing devices with crush clamping during liver transection
JO - British Journal of Surgery
DO - 10.1002/bjs.10297
DA - 2016-11-30
UR - https://www.deepdyve.com/lp/oxford-university-press/randomized-clinical-trial-comparing-two-vessel-sealing-devices-with-E8of67nJS9
SP - 1795
EP - 1803
VL - 103
IS - 13
DP - DeepDyve
ER -