¶ HL, XWM, and YY are co-first authors on this work.
The authors have declared that no competing interests exist.
Conceived and designed the experiments: YL. Performed the experiments: HL XWM YY. Analyzed the data: HL XWM YY. Contributed reagents/materials/analysis tools: JX KH JSC. Contributed to the writing of the manuscript: HL XWM YY.
The aim of this study is to accurately assess whether the duration of intraoperative carbon dioxide pneumoperitoneum (CDP) is associated with the induction of hepatic injury.
We conducted a systematic review of PubMed, Embase, and Cochrane Library databases (through February 2014) to identify case-match studies that compared high-pressure CDP with low-pressure CDP or varied the duration of CDP in patients who underwent abdominal surgery. The outcome of interest was postoperative liver function (ALT, AST, TB).
Eleven comparative studies involving 2,235 participants were included. Overall, levels of ALT, AST, and TB (on postoperative days 1, 3, and 7) were significantly elevated in the study groups. However, the results of the subanalyses of those who underwent laparoscopic colorectal cancer resection (LCR) versus open colorectal cancer resection (OCR) and those who underwent laparoscopic gastric bypass (LGBP) versus open gastric bypass (OGBP) were inconsistent.
The current evidence suggests that the duration of CDP during laparoscopic abdominal surgery may be associated with hepatic injury. Additional large-scale, randomized, controlled trials are urgently needed to further confirm this.
Laparoscopic surgery is one of the most significant surgical advances of the twentieth century. Its numerous advantages are well known: shorter hospital stays and convalescence, limited postoperative pain, more rapid recovery, and a reduction in complications and lost working days
With the increasing use of laparoscopic surgery, new concerns have arisen regarding the effects of CDP on cardiovascular and respiratory systems. An important hemodynamic change is the transient reduction in hepatic blood flow caused by CDP. In 1994, Halevy et al.
To date, conflicting results have been reported regarding the effects of CDP on splanchnic and liver perfusion. Most reports have suggested that there is a direct correlation between duration of CDP and hepatic injury
We assumed that the duration of CDP would be associated with hepatic injury in those who underwent laparoscopic abdominal surgery. Then, we performed a systematic meta-analysis to evaluate this assumption.
The Pubmed, Embase, and Cochrane Library electronic databases were searched for comparative studies published up to February 2014. The following medical subject heading (MeSH) terms and words were used for the search in all possible combinations: “pneumoperitoneum,” “insufflation,” “aeroperitoneum,” “liver function,” and “hepatic function.” A filter for identifying comparable studies recommended by the Cochrane Collaboration was used to filter out non-randomized studies in Pubmed and Embase
Studies were considered eligible if they met the following inclusion criteria: Study design—case-match design (random controlled trials or controlled clinical trials); population—patients undergoing laparoscopic abdominal surgery; intervention—some period of CDP in the intraoperative period; comparator—patients undergoing laparoscopic abdominal surgery with lower pressure CDP or patients undergoing open abdominal surgery; and all included studies had to report at least one of the following postoperative outcome measures: ALT, AST, TB, ALP, GGT, and Alb.
Studies were excluded if any of the following criteria were met: not a case-match design, animal experiment, primary outcome was not the one of interest, interventions other than duration of CDP, raw data could not be extracted in an appropriate format and could not be obtained from the authors or other published results.
Data were independently extracted from all eligible publications by two investigators (Hao Lai and Xianwei Mo) according to the aforementioned inclusion criteria. Disagreements were resolved by discussion during a consensus meeting with a third reviewer (Yuan Lin). Data extracted included first author's last name, year of publication, study design, country, type of surgery, patient population, type of CDP, and postoperative results of liver function (ALT, AST, TB, ALP, GGT, LDH, and Alb).
Outcome variables were considered suitable for analysis if they met the following criteria: continuous outcomes were reported as means and standard deviations, and the same variables were reported for a minimum of five comparison groups and a minimum of two days postoperatively. Three outcome variables were considered the most suitable for analysis: postoperative results for ALT (days 1, 3, 7), AST (days 1, 3, 7), and TB (days 1, 3, 7).
Risk of bias was evaluated by the reviewers using the Cochrane Handbook for Systematic Reviews of Interventions
Statistical analysis for continuous variables was performed using the standard mean difference (SMD) and a random-effects or fixed-effects model was used depending on the presence or absence of heterogeneity. We used the
The characteristics of the 11 studies included, which were published between 2003 and 2013, are presented in
First author | Study design | Country | Patients population | Type of surgery | Type of CDP | Inclusion criteria | Exclusion criteria |
Tan2003 | RCT | China | 143 VS 40 143 VS 40 18 VS 23 | LC VS OC (group 1) LC VS OC (group 2) LCR VS OCR | 12–14 mmHg VS open 12–14 mmHg VS open 12–14 mmHg VS open | Patients had normal values of serum liver enzymes preoperative | Patients who underwent ERCP or EST within one week preoperative; Patients who developed complications which might cause serum liver enzymes elevated |
Gupta2013 | RCT | India | 51 VS 50 | LC VS LC | 14 mmHg VS 8 mmHg | Patients with normal preoperative LFTs | Patients with a history of jaundice, with common bile duct stones, or with abnormal preoperative LFTs |
Güven2007 | CCT | Turkey | 267 VS 54 | LC VS OC | 12–14 mmHg VS open | Patients with fully completed data on results of liver function test | Patients who with disease which might cause serum liver enzymes elevated preoperative |
Hasukic2005 | RCT | Tuzla | 25 VS 25 | LC VS LC | 14 mmHg VS 7 mmHg | Patients without history of previous liver diseases and exhibited normal values on preoperative liver function tests. | Patients who with disease which might cause serum liver enzymes elevated preoperative; age ≤18 years, pregnancy and lactation, previous extensive abdominal surgery, and an ASA grade of 3 or more. |
Eryılmaz2012 | RCT | Turkey | 23 VS 20 | LC VS LC | 14 mmHg VS 10 mmHg | ASA physical status I or II patients | Patients with liver failure, coagulopathy, and known allergy to medication drugs |
Sakorafas2005 | RCT | Turkey | 72 VS 36 | LC VS OC | 14 mmHg VS open | NA | Patients who with disease or complication which might cause serum liver enzymes elevated in perioperative period |
Jeong2011 | CCT | Korea | 91 VS 124 43 VS 78 | LADG VS ODG LCR VS OCR | 12 mmHg VS open 12 mmHg VS open | NA | Patients underwent any surgical technique which might affect their liver function during surgery. |
Kinjo2011 | CCT | Japan | 199 VS/120 324 VS 56 | LADG VS ODG LCR VS OCR | 8 mmHg VS open 8 mmHg VS open | NA | Patients with liver tumor, hepatic disease or whose liver function were abnormal preoperative |
Yoon2011 | CCT | Korea | 18 VS 32 | LADG VS ODG | 12 mmHg VS open | Liver cirrhosis patients; fatty liver patients, healthy hepatitis B virus carriers; and healthy hepatitis C virus carriers. | NA |
Etoh2007 | CCT | Japan | 147 VS 58 | LADG VS ODG | 10 mmHg VS open | LADG was selected for tumors limited to the mucosal layer or superficial submucosal layer and ODG for those invading deep submucosal layer. | NA |
Nguyen2003 | RCT | USA | 18 VS 18 | LGBP VS OGBP | 15 mmHg VS open | Patients being evaluated for surgical treatment of morbid obesity | Patients who had undergone previous obesity or gastric surgery, had a large abdominal ventral hernia, or a history of cirrhosis |
Note: ASA: American Society of Anesthesiology; LC: laparoscopic cholecystectomy; OC: open cholecystectomy; LCR: laparoscopic colorectal cancer resection; OCR: open colorectal cancer resection; LADG: laparoscopic assisted distal gastrectomy; OADG: open assisted distal gastrectomy; LGBP: laparoscopic gastric bypass; OGBP: open gastric bypass; NA: not available;
(
(a: day 1; b: day 3; c: day 7).
a | Test for heterogeneity | b | Test for heterogeneity | c | Test for heterogeneity | |||||||||
Subgroups | Pools SMDs | Subgroups | Pools SMDs | Subgroups | Pools SMDs | |||||||||
Results for postoperative day 1 | Results for postoperative day 1 | Results for postoperative day 1 | ||||||||||||
LADG vs. ODG | 0.58 (0.43, 0.74) | 0.00 | 86.2% | 0.00 | LADG vs. ODG | 0.51 (0.36, 0.66) | 0.00 | 84.4% | 0.00 | LADG vs. ODG | 0.34 (0.18, 0.51) | 0.00 | 0% | 0.50 |
LC vs. LC | 0.78 (0.48, 1.07) | 0.00 | 34.9% | 0.22 | LC vs. LC | 0.82 (0.52, 1.11) | 0.00 | 69.7% | 0.04 | LC vs. LC | 0.28(−0.01, 0.56) | 0.06 | 34.9% | 0.22 |
LC vs. OC | 1.15 (0.93, 1.36) | 0.00 | 96% | 0.00 | LC vs. OC | 0.97 (0.76, 1.19) | 0.00 | 97.4% | 0.00 | LCR vs. OCR | 0.11(−0.12, 0.33) | 0.35 | 34.2% | 0.22 |
LCR vs. OCR | −0.02 (−0.23, 0.20) | 0.86 | 75.7% | 0.02 | LCR vs. OCR | 0.05 (−0.16, 0.26) | 0.64 | 0% | 0.43 | Overall | 0.26 (0.15, 0.39) | 0.00 | 12.6% | 0.33 |
LGBP vs. OGBP | −0.04(−0.70, 0.61) | 0.90 | - | - | LGBP vs. OGBP | −0.21(−0.87,0.61) | 0.44 | - | - | |||||
Overall | 0.58 (0.48, 0.68) | 0.00 | 91.3% | 0.00 | Overall | 0.53 (0.43, 0.63) | 0.00 | 91.6% | 0.00 | |||||
Results for postoperative day 3 | Results for postoperative day 3 | Results for postoperative day 3 | ||||||||||||
LADG vs. ODG | 0.31 (0.12, 0.49) | 0.00 | 0% | 0.39 | LADG vs. ODG | 0.35 (0.19, 0.50) | 0.00 | 85.4% | 0.00 | LADG vs. ODG | 0.38(0.22, 0.55) | 0.00 | 0% | 0.55 |
LC vs. OC | 4.39 (3.67, 5.10) | 0.00 | - | - | LC vs. OC | 4.43 (3.71, 5.14) | 0.00 | - | - | LCR vs. OCR | 0.08(−0.15, 0.30) | 0.50 | 0% | 0.37 |
LCR vs. OCR | −0.36 (−0.14, 0.59) | 0.00 | 33.1% | 0.22 | LCR vs. OCR | 0.09 (−0.14, 0.32) | 0.44 | 0% | 0.83 | Overall | 0.39 (0.27, 0.52) | 0.00 | 38.6% | 0.16 |
Overall | 0.48 (0.34, 0.62) | 0.00 | 95.9% | 0.00 | Overall | 0.39 (0.27, 0.52) | 0.00 | 96.5% | 0.00 | |||||
Results for postoperative day 7 | Results for postoperative day 7 | Results for postoperative day 7 | ||||||||||||
LADG vs. ODG | 0.34 (0.18, 0.50) | 0.00 | 61.2% | 0.05 | LADG vs. ODG | 0.09(−0.06, 0.23) | 0.00 | 0% | 0.87 | LADG vs. ODG | 0.22(0.06, 0.38) | 0.01 | 73% | 0.01 |
LC vs. LC | 0.32 (−0.08, 0.71) | 0.11 | - | - | LC vs. LC | 0.35 (−0.04, 0.74) | 0.08 | - | - | LC vs. LC | −0.06(−0.45,0.34) | 0.78 | - | - |
LC vs. OC | 0.53 (0.31, 0.75) | 0.00 | 96% | 0.00 | LC vs. OC | 0.41 (0.19, 0.63) | 0.00 | 96.7% | 0.00 | LCR vs. OCR | 0.18(−0.05, 0.41) | 0.12 | 76.8% | 0.04 |
LCR vs. OCR | 0.34 (0.15, 0.53) | 0.00 | 38.3% | 0.20 | LCR vs. OCR | 0.12 (−0.10, 0.33) | 0.29 | 31.6% | 0.23 | Overall | 0.18 (0.06, 0.30) | 0.00 | 64.8% | 0.01 |
Overall | 0.38 (0.28, 0.48) | 0.00 | 84.1% | 0.00 | Overall | 0.53 (0.43, 0.63) | 0.00 | 85.9% | 0.00 |
Four studies evaluated ALT results on postoperative day 3
In the analyses above, there was a high degree of heterogeneity across trials. Publication bias was not evident in the results of postoperative day 1 (
a. Sensitivity analysis. b. Funnel plot analysis to detect publication bias for ALT results on postoperative day 3; each point represents a separate study for the indicated association. c, Funnel plot analysis to detect publication bias for AST results on postoperative day 3; each point represents a separate study for the indicated association.
(
(a: day 1; b: day 3; c: day 7).
Results on postoperative day 3 were reported in four studies
Eleven studies evaluated AST results on postoperative day 7
In these analyses, there was evidence of significant heterogeneity across the trials. No publication bias was detected, with the exception of the results for postoperative day 3 (P = 0.04,
(
(a: day 1; b: day 3; c: day 7).
The inclusion criteria for this meta-analysis were subjected to a sensitivity analysis to determine whether modification of the inclusion criteria of the meta-analysis affected the results (
Funnel plots of the studies included in our outcome analysis of the postoperative results regarding ALT, AST, and TB were prepared to assess publication bias. The funnel plot showed the CI and effect estimate. The latter showed a symmetrical distribution around the effect estimate, thereby indicating that publication bias was likely minimal for the results evaluating postoperative liver function in patients who underwent laparoscopic abdominal surgery (
However, publication bias was evident in the ALT (
Presently, the association between the duration of CDP in laparoscopic abdominal surgery and hepatic injury is not fully understood. Increasing evidence suggests that the duration of CDP may be associated with reduced hepatic blood flow and induce hepatic injury. However, other studies have suggested that elevated liver enzyme values may be caused by direct liver manipulation or aberrant hepatic artery ligation rather than CDP
“The higher the pressure, the better the view” used to be the axiom of surgeons who needed adequate exposure for laparoscopic procedures. To provide good exposure of the surgical field, generally 10 to 15 mmHg pressure ranges are used during pneumoperitoneum
Generally, this effect might be positively correlated with the pressure of CDP and its duration
We performed a sensitivity analysis on the subgroup analyses. The LCR versus OCR subgroup analysis always produced contrary results. The study conducted by Kinjo
Explanations for these differing results of the subgroup analyses may include that the small numbers of cases in some studies and the limited number of trials in the subgroup analyses increased the possibility that chance alone accounted for the results. Additionally, the CDP used for patients in the study groups was not uniform. For example, three studies involved LCR versus OCR, and these showed inconsistent results
We included several abdominal surgeries and then performed subgroup analyses regarding the duration of CDP according to type of surgery or control group. There is sufficient evidence in the 11 comparative studies to conclude that the duration of CDP is associated with the induction of hepatic injury in patients undergoing laparoscopic abdominal surgery.
To the best of our knowledge, this is the first reported meta-analysis to systematically evaluate the relationship between the duration of CDP and hepatic injury and to demonstrate a significant effect in this regard. Despite the variation in the results of individual studies, the accumulating evidence and large sample provided the statistical power to produce more precise and reliable efficiency estimates. Overall, the published evidence supports the assumption that the duration of CDP is associated with the induction of hepatic injury. Therefore, surgeons should pay attention to the following take home messages. First, surgeons should be cautious before planning to perform laparoscopic abdominal surgery in patients with known hepatic insufficiency. Second, we recommend using low pressure CDP (10 mmHg or lower), particularly for those undergoing prolonged laparoscopic surgery. This is because low-pressure CDP is not only feasible for decreasing hemodynamic variations but also add on to already existing benefits of endoscopic surgery
Our meta-analysis has several limitations. First, the interesting aspect of our study is the significance of this transient abnormality of liver enzymes and its clinical impact. Most studies reported that a transient increase in serum transaminase activities was most prominent on postoperative day 1, but returned to normal levels within several days after surgery
The current evidence suggests that the duration of CDP during laparoscopic abdominal surgery may be associated with hepatic injury. Additional large-scale, randomized, controlled trials are urgently needed to further confirm this.
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