Effects of Prolonged Pneumoperitoneum on Hepatic Perfusion During Laparoscopy Lisette T

ORIGINAL ARTICLE

Effects of Prolonged Pneumoperitoneum on Hepatic Perfusion During Laparoscopy Lisette T. Hoekstra, MD,∗ Anthony T. Ruys, MD,∗ Dan M. J. Milstein, MD, PhD,† Gan van Samkar, MD,‡ Mark I. van Berge Henegouwen, MD, PhD,∗ Michal Heger, PhD,∗ Joanne Verheij, MD, PhD,§ and Thomas M. van Gulik, MD, PhD∗

toneal pressures during PP are higher (14 mm Hg) than the nor- Objective: To assess the influence of prolonged pneumoperitoneum (PP) on mal pressure in the hepatic portal system (7–10 mm Hg) and may, liver function and perfusion in a clinically relevant porcine model of laparo- therefore, cause changes in liver portal blood flow and, consequently, scopic abdominal insufflation. hepatic function. Indeed, elevations in aspartate aminotransferases Background: PP during laparoscopic surgery produces increased intra- and alanine aminotransferases levels have been reported after la- abdominal pressure, which potentially influences hepatic function and mi- paroscopic operations; however, these elevations were transient and crocirculatory perfusion. returned to normal within the first 3 postoperative days.4–6 Methods: Six pigs (49.6 ± 5.8 kg) underwent laparoscopic intra-abdominal Several studies described the effects of PP on intra-abdominal insufflation with 14 mm Hg CO gas for 6 hours, followed by a recovery period 2 blood flow and reported diminished blood flow in the portal vein and of 6 hours. Two animals were subjected to 25 mm Hg CO gas. Hemodynamic 2 the hepatic artery.1,7–10 Because these studies focused on the effects parameters were monitored, and damage parameters in the blood were mea- of blood flow after 1 hour of PP,2 interesting questions emerged: first, sured to assess liver injury. Liver total blood flow and function were determined to which extent does diminished blood flow influence liver function? by the indocyanine green (ICG) clearance test. Intraoperative hepatic hemo- And, second, what are the consequences after prolonged PP? The dynamics were measured by simultaneous reflectance spectrophotometry (ve- indocyanine green (ICG) clearance test is the most frequently used nous oxygen saturation StO and relative tissue hemoglobin concentration 2 test for determining liver total blood flow and function11,12 and has rHb) and laser Doppler flowmetry (blood flow and flow velocity). Postmortem previously been shown to be significantly reduced after 1 hour of PP, liver samples were collected for histological evaluation. suggesting a decrease of liver function.9 However, it has been shown Results: A decrease in microvascular perfusion was observed during PP.After that this short-lived decline in liver function is associated with only 6 hours of PP,ICG clearance increased (P < 0.001), indicating a compensatory a transient elevation of liver enzymes (aspartate aminotransferases improvement of overall liver blood flow resulting in concomitantly improved and alanine aminotransferases). With laparoscopic liver resection, microcirculatory perfusion (P = 0.024). Minimal parenchymal damage (as- however, the duration of PP increases with longer periods of surgery. partate aminotransferase) of the liver was seen after 6 hours of PP (P = In addition to its effects on blood flow and liver function, the impact of 0.006), which seemed related to PP pressure. Minor histological damage was continuous insufflation on hepatic microcirculation, as the principal observed. site of metabolic exchange between the blood and tissue parenchymal Conclusions: The liver sustains no additional damage due to prolonged PP cells, is also essential for assessing the influence of prolonged PP. during laparoscopic surgery. Our findings suggest that prolonged PP does These issues become more relevant with laparoscopic liver resection not hamper liver function or cause liver damage after extended laparoscopic in which the liver may be subjected to additional injury when applying procedures. vascular inflow occlusion (Pringle maneuver). (Ann Surg 2012;00:1–6) The Oxygen to See is an instrument designed to perform simultaneous laser Doppler flowmetry and tissue spectrophotometry, using a single compact probe to detect microperfusion parameters.13 dvantages of laparoscopic surgery are well recognized and in- This device is capable of intraoperatively providing the characteris- A clude reduced postoperative pain, shorter length of hospital stay, tics of hepatic microcirculation.14,15 The Oxygen to See system has and superior cosmetic results.1,2 Within the field of liver surgery, been extensively used for the determination of microcirculatory pa- the use of laparoscopy has increased substantially in recent years.3 rameters in a wide range of surgical procedures in maxillofacial,16 Disadvantages associated with laparoscopic surgery include pro- cardiothoracic,17,18 plastic,19,20 and neurosurgical21,22 specialties. longed operation times and elevations in intra-abdominal pressure. This study was undertaken to investigate the influence of Laparoscopic operations require insufflation of the abdominal cavity prolonged PP on liver function and hepatic microcirculatory param- (pneumoperitoneum, PP) with carbon dioxide (CO2) gas to achieve eters in a clinically relevant porcine model of extended abdominal adequate surgical exposure for instrumentation and surgical maneu- insufflation. vers. However, PP obviously produces elevated intra-abdominal pressure with continuous compression of intra-abdominal organs, which METHODS potentially influences hepatic microcirculatory perfusion. Intraperi- The study protocol was approved by the institutional Animal Experimentation Committee of the Academic Medical Center of the From the Departments of ∗Surgery (Surgical Laboratory); †Translational Physiol- University of Amsterdam. Care and handling of the animals were ogy; ‡Anaesthesiology; and §Pathology, Academic Medical Center, University in accordance with the European guidelines for the Institutional and of Amsterdam, Amsterdam, The Netherlands. Animal Care and Use committees. Disclosure: The authors declare no conflict of interest. Reprints: Thomas M. van Gulik, MD, PhD, Department of Surgery (Surgical Lab- oratory), Academic Medical Center, University of Amsterdam, Meibergdreef Animals 9, 1105 AZ Amsterdam, The Netherlands. E-mail: [email protected]. Twelve female Landrace pigs (van Beek, The Netherlands) Copyright C 2012 by Lippincott Williams & Wilkins ISSN: 0003-4932/12/00000-0001 with a mean body weight of 47.0 ± 1.7 kg were used in this study. DOI: 10.1097/SLA.0b013e31825d5b2b All animals were allowed to feed and drink ad libitum and remained r Annals of Surgery Volume 00, Number 00, 2012 www.annalsofsurgery.com | 1

quarantined 1 week before the start of the investigation to permit nik GmbH, Giessen, Germany). At the end of each experiment, all adaptation to environmental conditions. All experiments were initi- animals were killed by infusion of KCl (60–90 mmol) under gen- ated in the morning after an overnight fast. An intramuscular injection eral anesthesia. For histological examination, postmortem biopsies of premedication consisting of ketamine (Nimatek; Eurovet, Bladel, of both the left and right liver lobes were obtained. An overview of The Netherlands; 15 mg/kg of body weight), midazolam (Dormicum; the experimental design and measurement time points is presented in Actavis, Hafnarfjordur, Iceland; 1.5 mg/kg of body weight), Figure 1. and atropine sulfate (Pharmachemie, Haarlem, The Netherlands; 0.01 mg/kg of body weight) was administered before induction of Assessment of Hepatic Function and Perfusion anesthesia. The pigs were resting in a dorsally recumbent position on the operating table, and core body temperature was maintained Hepatic Function at 37◦C for the duration of the experimental procedures. All animals Hepatic function was determined using laboratory measure- were orotracheally intubated. Before surgery, the animals received ments and the ICG clearance test. The levels of aspartate aminotrans- γ bolus doses of ketamine, midazolam, sufentanil (Hameln Pharma- ferases, alanine aminotransferases, alkaline phosphatase, and GT ceuticals, Hameln, Germany), and pancuronium bromide (Pavulon; were determined as liver damage parameters. ICG clearance was de- Organon, Oss, The Netherlands). Anesthesia was continued with termined by the LiMON method. A 0.5 mg/kg of ICG solution (ICG- sufentanil (5–8 μg/kg/h of body weight), ketamine (10–14 mg/kg/h of PULSION; Medical Systems AG, Munich, Germany) dissolved in 5 body weight), midazolam (1–1.5 mg/kg/h of body weight), and pan- mL of sterile distilled water was injected in the left peripheral ear curonium bromide (0.10–0.15 mg/kg/h of body weight) intravenously. vein in all animals and for all measurements of liver perfusion. The LiMON device (LiMON, Pulsion Medical Systems AG, Munich, Ger- Anesthesia was maintained with oxygen and/or air FiO2 45% O2 (1.5– 3 L/min). All animals received 0.9% NaCl (Baxter, Utrecht, The many) measures ICG elimination by pulse spectrophotometry. Details 23 Netherlands; 8–10 mL/kg/h) and 6% elohaes (Tetraspan, Braun, Mel- of this technique have been described elsewhere. Briefly, accurate sungen, Germany; 2–3 mL/kg/h) for electrolyte and metabolic home- and continuous recording of ICG blood levels was possible using a ostasis. Glucose 20% (Baxter Benelux, Brussel, Belgium) was given dichromatic densitometer, placed on the tail of the pig. Liver blood intravenously to maintain glucose levels between 5 and 10 mmol/L. flow and function were determined by calculating the ICG clearance Catheters were placed in the brachial artery, popliteal artery, and from the ICG retention rate 15 minutes after administration. As ICG jugular vein, respectively, to continuously monitor heart rate, mean clearance depends on liver perfusion, it is also a parameter of total arterial blood pressure, and central venous pressure and for collec- liver blood flow. tion of blood samples. Open introduction was performed for bladder catheterization and placement of a 10-mm trocar in the abdomen for Hepatic Microperfusion Assessments laparoscopy, followed by closure of the abdominal wall. Hepatic microperfusion parameters were assessed using Oxy- gen to See. The Oxygen to See device (Type LW 1/1-/1/1, LEA Experimental Design Medizintechnik GmbH, Giessen, Germany) combines laser Doppler Six animals underwent laparoscopic intra-abdominal insuffla- flowmetry and tissue spectrophotometry in 1 flat probe (LF1.027, tion for 6 hours via a 10-mm trocar (Olympus, Zoeterwoude, The LEA Medizintechnik GmbH, Giessen, Germany) and detects a Netherlands) with CO2 gas (14 mm Hg), followed by a recovery wide range of microperfusion parameters. The optical methods period of 6 hours. Two animals were subjected to 25 mm Hg intra- for measuring these parameters have been previously described in abdominal insufflation during 6 hours and were observed over a sim- ulated recovery phase of 2 hours. Four pigs served as controls and did not undergo intra-abdominal insufflation. Hemodynamic parameters, such as arterial oxygen saturation (SpO2), heart rate, mean arterial blood pressure, central venous pressure, rectal temperature, and respiratory minute volume were continuously recorded. Arterial blood gas samples derived from the brachial artery were collected every hour and were analyzed using an automated analyzer (Blood Gas, Oximeter, and Electrolyte Systems, Acid Base Laboratory, Ra- diometer Medical, Copenhagen, Denmark), and measurements were obtained for pH, oxygen saturation, carbon dioxide, sodium, potas- sium, and hemoglobin. Glucose levels were also determined every hour. The experiments started after a stabilization period of 60 minutes (0 mm Hg), in which baseline values were recorded. After 6 hours of insufflation (14 or 25 mm Hg), blood samples were collected for the determination of liver injury parameters and measurements of liver function using the ICG clearance test. Post-PP FIGURE 1. Timeline of experimental design (in 14 mm Hg PP recovery measurements were performed at 2 and 6 hours. Aspartate group). All animals were subjected to the same procedures. aminotransferases, alanine aminotransferases, alkaline phosphatase, • Continuous assessments: hemodynamics; gamma-glutamyltranspherase (γ GT), bilirubin, lactate, and lactate • Every hour: blood gas analysis, glucose levels; dehydrogenase levels were evaluated by routine clinical chemistry for • Baseline measurements: continuous Oxygen to See, and after the assessment of liver function. The left peripheral ear vein was can- 1 hour, blood samples (liver function), and ICG clearance; nulated for the administration of ICG solution for assessment of liver • Repeated measurements after 6, 8, and 12 hours: function. Hepatic hemodynamics were examined continuously for • Continuous Oxygen to See, the entire duration of the protocol by simultaneous reflectance spec- • Blood samples for liver function, and trophotometry (StO2, and rHb) and laser Doppler flowmetry (blood • ICG clearance; and flow and flow velocity), using Oxygen to See (LEA Medizintech- • 12 hours: liver biopsy for histological examination.

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Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. r Annals of Surgery Volume 00, Number 00, 2012 Effects of Prolonged Pneumoperitoneum on Hepatic Perfusion

detail.13,15,24–28 The Oxygen to See probe was inserted in a sterile bag (Ultracover; Microtek Medical B.V., Zuthpen, The Netherlands) that exactly matched the probe dimensions and was subsequently ﬁxed to the left lateral liver lobe with Histoacryl (Aesculap, Tuttlin- gen, Germany) after a small midline laparotomy. Once the Oxygen to See probe was positioned and ﬁxed, the abdominal wall was closed using Vicryl Plus sutures (2-0 FS-1 and CTX 1; Johnson&Johnson, St-Stevens-Woluwe, Belgium) in 2 layers to prevent leakage of CO2 gas. Hepatic microperfusion parameters were measured continuously for the entire duration of the experimental procedure.

Histology In all animals, postmortem biopsies were obtained from the FIGURE 2. Central venous pressure increased significantly dur- middle of the right and left lobes of the liver. Hematoxylin and eosin- ing insufflation and returned to baseline during desufflation in stained sections were blindly evaluated by a liver pathologist expe- ∗ the 14 and 25 mm Hg groups [ P < 0.01 for 3 and 6 hours of rienced in liver disease. Steatosis was estimated as the percentage PP vs baseline in both groups; †P < 0.001 for 0 and 2 hours of of involved hepatocytes: grade 0 (absent; <5%), grade I (mild; 5%– recovery vs 6 hours of PP in both groups and 6 hours recovery 33%), grade II (moderate; 33%–66%), or grade III (severe; >66%).29 vs 6 hours of PP in the 14 mm Hg group]. Portal inflammation was arbitrarily graded as follows: 0 (absent), 1 (mild), 2 (moderate), or 3 (severe). Sinusoidal dilation (with and without congestion) was graded as follows: 0 (absent), 1 (mild; involving pressure was significantly higher in the 25 mm Hg group than in the one third or less of the centrolobular area), 2 (moderate; involvement 14 mm Hg group (P < 0.001). two third or less of the parenchyma), or 3 (severe; involving more 30 than two third of the liver parenchyma). Intralobular inflammation Blood Gas Analysis and lytic necrosis were graded as follows: 0 (not present), 1 (<2foci The levels of pCO increased significantly during PP (base- per ×objective), 2 (2–4 foci per ×10 objective), 3 (5–10 foci per ×10 2 line 36.7 ± 0.7 mm Hg vs 46.1 ± 1.1 mm Hg after 6 hours of PP, objective), and 4 (>10 foci per ×10 objective). Portal edema was P = 0.019), which is related to the CO gas used for PP. This re- scored as the percentage of the portal tracts involved: 0 (not present), 2 sulted in respiratory acidosis and, consequently, a decrease in pH and 1(<25%), 2 (25%–50%), 3 (50%–75%), and 4 (>75%). The pres- pO values. pH decreased significantly from 7.49 ± 0.01 at base- ence of areas with confluent necrosis of the parenchyma was scored 2 line to 7.41 ± 0.01 after 6 hours of PP (P < 0.05). Baseline mean as follows: 0 (absent), 1 (affecting <25%), 2 (affecting 25%–50%), pO was 247.5 ± 5.9 mm Hg and after 6 hours of PP decreased to 3 (affecting 50%–75%), and 4 (affecting >75%). Centrolobular is- 2 202.7 ± 4.9 mm Hg (P < 0.05). Similar findings were observed for chemic changes were evaluated separately as follows: 0 (not present), PP at 25 mm Hg but with greater differences. A pCO baseline value 1 (mild; <50% of central veins affected), or 2 (moderate; >50% of 2 of 48.4 ± 22.1 mm Hg was observed, which increased to 66.1 ± 35.6 central veins affected). mm Hg after 6 hours of PP (NS); pH at baseline was 7.47 ± 0.08 and decreased to 7.35 ± 0.12 after 6 hours of PP (NS), whereas Statistical Analysis pO2 decreased from baseline 192.8 ± 27.1 mm Hg to 180.9 ± 34.5 The differences between the groups were compared using the 2- mm Hg after PP (NS). After desufflation, a significant decrease of tailed unpaired Student t test for parametric data. The Mann-Whitney pCO2 was observed in the 14 mm Hg PP group at 0, 2, and 6 hours U test was used for nonparamateric data. Analysis of variance, using of recovery as compared with 6 hours of PP. As a consequence, pO2 a linear mixed model for repeated measurements, was performed for and pH increased significantly after desufflation in the same group. the comparison of several time points within groups. The relationship Figure 3 shows the overall results of blood gas analysis. between the presence of PP and hemodynamic parameters was studied χ 2 χ 2 by the test. Results of histology were determined by the test and Biochemical Parameters the Fisher exact test, where appropriate. Correlation between variables The mean baseline aspartate aminotransferases level was was tested using the Pearson r correlation coefficient. The results were 36.5 ± 3.8 U/L in the 14 mm Hg PP group (Fig. 4). A marginal, considered to be of statistical significance when P < 0.05. All data but statistically significant, increase in aspartate aminotransferases analyses were performed using PASW Statistics (Version 18.0) for was found after 6 hours of PP (57.0 ± 16.6 U/L, P = 0.006). The Windows (SPSS Inc, Chicago, IL). Values are expressed as means ± elevated aspartate aminotransferases values persisted during the re- SD. covery period, whereas alanine aminotransferases levels did not show any statistically significant differences (results not shown). In the RESULTS 25 mm Hg PP group, the liver damage parameter aspartate amino- Hemodynamic Parameters transferases also increased (baseline: 38.8 ± 11.7 U/L; 6 hours of PP: There were no significant differences in mean arterial blood 69.0 ± 46.7, P = 0.001). Aspartate aminotransferases levels were pressure between all groups during insufflation or in the recovery significantly higher in the 25 mm Hg PP group after 6 hours of PP period (results not shown). Central venous pressure increased signif- than in the 14 mm Hg PP group (P = 0.001). icantly during insufflation (baseline 6.0 ± 0.4 mm Hg vs 11.0 ± 0.5 mm Hg after 6 hours of PP, P < 0.01) and returned to baseline after Liver Perfusion and Microcirculation desufflation in the 14 mm Hg group (Fig. 2). The same trend was seen ICG clearance increased significantly after 6 hours of PP and in the 25 mm Hg PP group, with a baseline value of 7.5 ± 0.7 mm Hg continued to increase during desufflation (∗P < 0.001 for 6 hours increasing to 14.8 ± 3.1 mm Hg after 6 hours of PP and returning to of PP and 2 hours of recovery vs baseline; Fig. 5), suggesting an 8.5 ± 1.2 after 2 hours of recovery (P < 0.001 between 6 hours of improved total liver blood flow over time. The profile of ICG clearance PP and 2 hours of recovery). After 6 hours of PP, the central venous in the 25 mm Hg group was comparable with ICG clearance at 14

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FIGURE 4. Changes in aspartate aminotransferases as a function of intra-abdominal pressure (PP) and time. Aspartate aminotransferases increased after 6 hours of PP (∗P = 0.006) in the 14 mm Hg PP group. The elevated aspartate aminotransferases levels persisted during the recovery period (†P = 0.008). In the 25 mm Hg PP group, aspartate aminotransferases also increased after 6 hours of PP and was signiﬁcantly higher than that in the 14 mm Hg PP group (‡P = 0.001).

FIGURE 5. ICG clearance increased significantly during insuf- FIGURE 3. A, The levels of pCO increased significantly during 6 flation in the 14 mm Hg PP group, which continued during 2 ∗ hours of PP (∗P < 0.05 for 3 and 6 hours of PP vs baseline) in the desufflation ( P < 0.001 for 6 hours of PP and 2 hours of 14 mm Hg PP group. After desufflation, a significant decrease recovery vs baseline; †P = 0.017 for 6 hours of recovery vs of pCO2 was observed at 0, 2, and 6 hours of recovery as baseline). In the 25 mm Hg PP group, ICG clearance signifi- compared with 6 hours of PP (†P < 0.01). B, As a consequence, cantly increased at 2 hours of recovery compared with baseline ∗ ‡ = pO2 decreased significantly during insufflation ( P < 0.05 for ( P 0.006). No significant differences in ICG clearance were 3 and 6 hours of PP vs baseline) in the 14 mm Hg PP group, observed in the 14 and 25 mm Hg PP groups. after which an increase was observed after desufflation (∗P < 0.05 for 2 and 6 hours of recovery vs 6 hours of PP), as well as for pH. C, ∗P < 0.05 for 3 and 6 hours of PP vs baseline and 0 Blood flow velocity also slightly decreased during 6 hours of and 2 hours of recovery vs 6 hours of PP. PP (NS, Fig. 6B). Oxygen saturation was elevated after an insufflation period of 6 hours, which subsequently normalized in the recovery period (14 mm Hg PP group). There were no significant differences mm Hg (5.4% ± 0.4% baseline, 7.1% ± 1.2% after 6 hours of PP, between the 14 and 25 mm Hg PP groups. and 8.8% ± 0.07% after 2 hours of recovery, P = 0.006 for 2 hours of recovery vs baseline). No significant differences in ICG clearance Histology were observed between the 14 and 25 mm Hg PP groups. No significant differences were seen for any of the histological During PP, the measurements of hepatic microcirculation parameters evaluated between the right and left liver lobes of the showed a decreased intrahepatic flow in both groups, with a more same pig or between the 14 and 25 mm Hg PP groups at all time prominent decrease observed in the pigs undergoing 25 mm Hg of PP. points. No steatosis or centrolobular ischemic changes were found An almost immediate restoration (P = 0.024) in hepatic microcircu- in any animal; portal and lobular inflammation was mild in all pigs. latory blood flow was found after desufflation in the pigs undergoing Sinusoidal dilatation in both groups ranged from 0 to 2 (median grade 14 mm Hg of PP (Fig. 6A), with a similar profile in the pigs that 2), focal lytic necrosis from 0 to 1 (median 0), portal edema from 1 underwent 25 mmHg of PP. After 2 and 6 hours of recovery, hepatic to 3 (median grade 1), and confluent necrosis from 0 to 1 (median microcirculatory blood flow was not significantly changed. grade 0) (NS, within or between groups).

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which microvascular perfusion decreased during 6 hours of PP as the intra-abdominal pressure increased, with a concomitant increase in microcirculatory parameters after desufflation, and increased ICG clearance. Some recent experimental studies have demonstrated an impairment of liver function after PP. Hepatic injury was shown after 60 to 90 minutes of PP in rat models.34,35 Also liver regeneration rate was impaired, and oxidative stress and hepatocellular damage increased in rats undergoing PP before hepatectomy.36 These findings are not in accordance with our study. However, these differences may be explained by the choice of animal model, of which the porcine model obviously is more compatible with the clinical situation. Us- ing a swine model too, Nsadi et al37 reported no hepatocellular injury or microcirculatory changes in pigs undergoing PP, which is in line with our results. Yet, with the application of portal triad clamping, the authors found increased hepatocellular damage parameters and an increased necrotic index. These results suggest caution when com- bining PP with portal triad clamping. In literature, only 1 clinical study demonstrated the feasibility of Oxygen to See for intraoperative evaluation of hepatic microcirculation.14 Studies focusing on hepatic perfusion during prolonged PP and its effect on liver function are lacking. With this in mind, it is important to consider some weaknesses of the Oxygen to See device. First, disturbances through motion can falsify values for relative microcirculatory blood flow and velocity. This problem can be resolved by immobilizing the Oxygen to See probe on the FIGURE 6. A, A decrease in microcirculatory blood flow was liver surface, as was taken care of in our study. Second, there are observed during 6 hours of PP in both groups, with restora- no absolute values for single parameters and therefore the measured 14 tion of microcirculatory flow after desufflation (∗P = 0.024). values cannot be interpreted without baseline values. In all ani- B, Blood flow velocity decreased during 6 hours of PP with a mals of this study, baseline measurements were obtained to assess transient increase after desufflation (NS). changes in hepatic microcirculation while each animal served as its own control. Third, if the probe is not properly affixed, stray light can influence oxygen saturation and hemoglobin concentration values. DISCUSSION In this study, the probe was isolated from any external light sources We determined the effect of prolonged PP on liver func- because the abdomen was closed after the placement of the trocar for tion and perfusion in a porcine model of laparoscopic abdominal laparoscopy. Several other methods for evaluation of liver perfusion insufflation. The results of our study show a decrease in microvas- have been used, such as a transonic hepatic blood flow measurement, cular perfusion during PP, which was restored after desufflation. A intravital fluorescence microscopy, or transesophageal Doppler ultra- concomitant increase of the ICG clearance rate was observed after PP, sonography. However, because most of these techniques are invasive, which remained, on average, increased during desufflation, indicating they are less useful for evaluating liver perfusion in a (pre)clinical a compensatory improvement of overall liver blood flow. Increased setting. total liver blood flow of the liver, hence, contributed to the restora- Not only the level of intra-abdominal pressure during laparo- tion of microcirculatory perfusion. Our results demonstrate that under scopic surgery is responsible for changes in liver function and per- these circumstances, the liver sustains limited parenchymal damage, fusion but also the duration of PP influences (micro)circulatory as concluded from marginally elevated aspartate aminotransferases hemodynamics.38 Hypoxia due to elevated levels of carbon diox- levels in the blood and the absence of major histological injury after ide potentially triggers vasoregulatory mechanisms and alters blood prolonged PP (14 mm Hg). pressure, and thus, deprives the liver of the much needed oxygen We used the Oxygen to See probe to assess hepatic microcir- to support the rich metabolism of the liver. One study evaluated the culatory blood flow after prolonged PP.To our knowledge, no studies effects of 15 mm Hg of intra-abdominal pressure over a period of 24 have correlated the effects of PP on hepatic function as measured by hours and reported a reduction in function and morphological changes ICG clearance and on liver microcirculation. A significant negative in the liver, lungs, kidneys, and bowel.38 Serum alanine aminotrans- correlation was seen for ICG clearance and microvascular blood flow ferases and alkaline phosphatase levels were significantly elevated, after 6 hours of PP (r =−0.813, P = 0.049) in the 14 mm Hg PP and low-grade liver necrosis was observed. No literature currently group, with a similar profile in the 25 mm Hg PP group after 6 hours exists establishing the effects of prolonged PP on hepatic perfusion of PP (r =−1.000, P < 0.01). A negative correlation was also ob- and liver damage. In this study, we chose a clinically relevant PP time served between ICG clearance and blood flow velocity after 6 hours of 6 hours representing the duration of several complex abdominal of PP (r =−1.000, P < 0.01). No other significant differences were laparoscopic procedures used today, such as major liver resections of found. 3 Couinaud segments or more. It is important to consider that clearance of ICG from the blood In conclusion, a decrease in liver microvascular perfusion was depends on total blood flow of the liver. Therefore, the ICG clearance detected during 6 hours of PP. After desufflation, hepatic microcircu- rate also reflects total liver circulatory dynamics.31,32 Several authors latory blood flow was restored with a concomitant increase of ICG report a decrease in liver blood flow, as intra-abdominal pressure clearance, indicating a compensatory improvement of overall liver increased in pigs with different cutoff values for intra-abdominal blood flow. The liver thereby sustained limited parenchymal damage pressure.9,33 This finding is in line with the results of this study in during PP, which was related to PP pressure. Our findings suggest

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