Loss of Physiologic Hepatic Blood Flow Control (“Hepatic Arterial Buffer Response”) During CO2-Pneumoperitoneum in the Rat : Anesthesia & Analgesia

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Cardiovascular Anesthesia: Research Report

Loss of Physiologic Hepatic Blood Flow Control (“Hepatic Arterial Buffer Response”) During CO2-Pneumoperitoneum in the Rat

Richter, Sven MD*†,; Olinger, Angela MD‡,; Hildebrandt, Ulrich MD†,; Menger, Michael D. MD*,; Vollmar, Brigitte MD*

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doi: 10.1097/00000539-200110000-00014
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Abstract

Laparoscopic techniques are routine for many surgical procedures. Even extended resections or complex reconstructive operations lasting many hours are performed. Moreover, laparoscopic procedures are even used in patients with impaired organ function or as diagnostic tools in the evaluation of patients with abdominal trauma. The safety of laparoscopy in such patients has been doubted (1–6), as there is evidence of hemodynamic alterations during these procedures (7–9), especially when carbon dioxide is used for induction of pneumoperitoneum (9–13).

The splanchnic microcirculation has been assessed as a major target of circulatory disturbances (7,9,14,15), and animal models have shown diminished portal venous (PV) flow during enhanced intraabdominal pressures (12,13,16,17), possibly leading to decreased liver blood supply and impaired organ function. However, hepatic perfusion is characterized by a unique autoregulatory mechanism, known as the “hepatic arterial buffer response” (HABR). Several studies have demonstrated that under physiological and pathophysiological conditions, alterations of PV flow are counteracted by flow changes of the hepatic artery, thereby maintaining total hepatic blood flow (18–21) to preserve sufficient oxygen supply to the liver (22,23). Reduced PV flow, as during CO2-pneumoperitoneum, can be compensated by increased hepatic arterial (HA) perfusion. However, no study has investigated the existence of the HABR under laparoscopic conditions. We found that under conditions of CO2-pneumoperitoneum in the rat, HA blood flow does not compensate for the intraabdominal pressure-associated reduction of PV inflow, with the consequence of a marked decrease in total liver perfusion, inadequate oxygen supply to tissue, and hepatocellular injury.

Methods

Experiments were performed in accordance with the German legislation on protection of animals and the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

After overnight fasting with free access to tap water, Sprague-Dawley rats of either sex (378 ± 20 g) were anesthetized with pentobarbital; supplemental doses (10 mg/kg IP) were given during the experiment to maintain sufficient anesthetic depth as determined by the absence of changes in blood pressure and heart rate on intermittent tail clamp testing. Animals were placed in the supine position on a heating pad, maintaining body temperature at 36°C–37°C, and catheters were placed in the right carotid artery and jugular vein for continuous monitoring of mean arterial pressure and fluid substitution with saline solution (6 mL · kg−1 · h−1).

After tracheotomy, the animals were mechanically ventilated with room air (tidal volume, 1 mL/100 g bw, 45 strokes/min), and ventilation variables were guided by blood gas analysis, which was performed repeat-edly throughout the experiment. For counteracting systemic effects of CO2 reabsorbed from the CO2-pneumoperitoneum, Pco2 values were adjusted below 55 mm Hg by increasing the respiratory frequency up to 70 strokes/min. In contrast, base excess was not corrected by bicarbonate infusion, so that metabolic acidosis as a consequence of increased intraabdominal pressure and/or CO2-pneumoperitoneum was tolerated.

After midline laparotomy, microsurgical preparation for assessment of liver blood flow was performed similarly to the method described in detail by Lautt (18) in cats. An ultrasonic flowprobe (0.5V; Transonic Systems, Ithaca, NY) was placed around the celiac artery, and all other branches, including the splenic artery, the left gastric artery, and the gastroduodenal artery, were ligated so that all blood entering the hepatic artery was derived from the celiac artery. Likewise, a second flowprobe (1.5R; Transonic Systems) was positioned around the superior mesenteric artery, and all other inlet arteries to the splanchnic system (i.e., the inferior mesenteric artery and anastomoses with rectal arteries) were ligated. Thus, all blood entering the splanchnic microcirculation and flowing into the portal vein was derived solely from the superior mesenteric artery. This experimental approach allowed for simultaneous assessment of HA and PV perfusion by measuring the blood flow in the celiac artery and the superior mesenteric artery, respectively, without the risk of mechanical obstruction or kinking of the referring vessels. This was especially important for the laparoscopic series because intraabdominal gas insufflation may cause distension of the abdomen, but would not allow the repositioning of the probes. The ultrasonic probes were connected to a flowmeter for continuous monitoring of HA and PV blood flow values. A catheter that was advanced via the splenic vein into the portal vein served for continuous monitoring of PV blood pressure.

Hepatic tissue oxygenation (Po2) was assessed by means of a flexible polyethylene microcatheter Clark-type Po2 probe (diameter, 470 μm; length, 300 mm) (LICOX System; GMS, Kiel-Melkendorf, Germany), which was attached between the surface of two adjacent liver lobes and fixed with Histoacryl-glue (B. Braun, Melsungen, Germany). This allowed the LICOX probe to integrate local tissue Po2 values over the tissue area in contact with the 5-mm long Po2-sensitive area near the catheter tip without interference of ambient air or CO2. Online temperature compensation was performed by an additional temperature probe (type K thermocouple probe, LICOX System), which was also positioned and fixed between two adjacent lobes.

In the Laparoscopy group (n = 7), the midline laparotomy was closed with 5–0 Vicryl suture (Ethicon, Norderstedt, Germany), including the peritoneum, all muscle layers, and the fascia, and sealed with Histoacryl glue. The skin was closed with an extra suture. Then, a Veress needle was inserted for induction of CO2-pneumoperitoneum. After connecting a gas insufflation system (Laparoflator 264300 20; Karl Storz, Tuttlingen, Germany), the intraabdominal pressure was increased every 5 min in steps of 2 mm Hg to a pressure of 18 mm Hg before the pneumoperitoneum was deflated. Thereafter, the pneumoperitoneum was set to 18 mm Hg intraabdominal pressure and maintained for 2 h, simulating prolonged operation conditions. Within this time, liver Po2 measurements were performed together with hemodynamic recordings of HA and PV blood flow as well as PV pressure every 30 min before the abdomen was deflated and final measurements were made 30 min afterward.

Control animals (n = 7) served to demonstrate physiologic HABR. Therefore, the abdominal cavity was not sutured, but a micromanipulator-controlled constrictor (5–0 Ethibond; Ethicon) was placed around the superior mesenteric artery, and stepwise reduction of the blood flow in the superior mesenteric artery (equal to PV flow) to 80%, 60%, 40%, and 20% of baseline values was performed every 5 min, before blood flow was restored to baseline conditions by complete release of the tourniquet. In analogy with the Laparoscopy group, PV flow reduction to 20% was maintained for 2 h, with subsequent assessment of hepatic tissue Po2 and hemodynamic variables every 30 min, before the PV tourniquet was finally released. At the end of the experiment, arterial blood samples were taken for spectrophotometric determination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities.

Buffer capacity was calculated as the quotient of changes of HA flow divided by changes of PV flow between the individual steps of either tourniquet-induced or intraabdominal pressure-induced PV flow reduction (buffer capacity = ΔHA flow/ΔPV flow × 100).

All values are expressed as means ± sem. After proving the assumption of normality and homogeneity of variance across groups, differences between groups were calculated using the unpaired Student’s t-tests. Intergroup differences were assessed by one-way analysis of variance (overall differences), followed by the Student-Newman-Keuls’ method for pairwise multiple comparisons. Overall statistical significance was set at P < 0.05. Statistics were performed using the software package SigmaStat (SPSS Inc., Chicago, IL).

Results

In Controls, stepwise reduction of PV flow from 100% (15.0 ± 1.2 mL/min) to 20% (3.0 ± 0.2 mL/min) resulted in a significant HABR, i.e., an increase of HA flow from 4.3 ± 0.7 mL/min (100%) to 9.9 ± 1.7 mL/min (230%) (P < 0.01;Fig. 1A). However, because of the smaller fraction of HA flow contributing to hepatic perfusion, total liver blood flow was reduced from 19.3 ± 1.6 mL/min to 12.9 ± 1.8 mL/min (P < 0.01) during PV tourniquet, representing a reduction of total liver blood flow to 67% of baseline conditions (Fig. 1A). Mean arterial blood pressure increased significantly from 117 ± 3 mm Hg to 127 ± 3 mm Hg (P < 0.01, Fig. 1B). PV pressure was found slightly, but significantly (P < 0.05) decreased during induction of HABR (Fig. 1B).

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Figure 1:
A, hepatic arterial flow (white dots) and total liver blood flow (gray dots) on stepwise reduction of portal venous flow (black dots); B, mean arterial blood pressure (white squares) and portal venous blood pressure (black squares) on stepwise reduction of portal venous flow. Means ± sem.

In contrast to controls, animals that underwent laparoscopy exhibited significantly (P < 0.05) higher arterial Pco2 values (range, 46–54 mm Hg) and lower pH values (range, 7.02–7.19) when compared with corresponding values in Controls (Pco2, 34–47 mm Hg; pH, 7.21–7.30). In the Laparoscopy group, an increase in intraabdominal pressure from 0 to 18 mm Hg led to a significant reduction of PV flow from 13.4 ± 0.8 mL/min to 6.6 ± 1.1 mL/min (P < 0.01, Fig. 2A), which was paralleled by a threefold increase of PV pressure (P < 0.01, Fig. 2B). Regression analysis between intraabdominal and PV pressure revealed a significant (P < 0.01) linear correlation with a regression coefficient of r = 0.997. Importantly, intraabdominal pressure increase-induced PV flow reduction failed to provoke an increase of HA perfusion and even caused a significant decrease of HA flow by ∼50% from 2.4 ± 0.3 mL/min to 1.2 ± 0.5 mL/min, thus presenting a lack of HABR during CO2-pneumoperitoneum (Fig. 2A). Absence of this compensatory mechanism led to a significant reduction of overall liver inflow from 15.3 ± 0.9 mL/min to 7.5 ± 1.4 mL/min (P < 0.01), representing only 49% of baseline liver perfusion (Fig. 2A). Mean arterial blood pressure slightly decreased during intraabdominal pressure increase (Fig. 2B).

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Figure 2:
A, hepatic arterial flow (white dots), portal venous flow (black dots), and total liver blood flow (gray dots) on stepwise increase of intraabdominal pressure; B, mean arterial blood pressure (white squares) and portal venous blood pressure (black squares) on stepwise increase of intraabdominal pressure. Means ± sem.

Within the individual steps of PV flow reduction in Control animals, buffer capacity revealed values between 43% and 49%, indicating a HA flow compensation of nearly 50% for diminished PV flow. In contrast, as the intraabdominal pressure increase in the Laparoscopy group led to a simultaneous decrease of both PV and HA flow, the calculation of the hepatic arterial buffer capacity revealed values of almost zero.

On release of the PV tourniquet in controls, PV flow regained baseline values statistically not significantly different from those seen at the beginning of the experiment. Then, PV flow was again reduced to 20% and maintained for 2 h. During this period, hemodynamic measurements revealed a sustained HABR with an increase of HA flow to approximately 200% of baseline values (Fig. 3A). Release of the tourniquet after the 2 h-period resulted in rapid restoration to normal of both HA and PV flow as well as PV and systemic blood pressure (Fig. 3A, Fig. 3B). Hepatic Po2 was found significantly (P < 0.01) reduced from 29.1 ± 1.8 mm Hg to 19.1 ± 2.3 mm Hg (−35%), but also instantly returned to baseline values after the 2 h-period of PV tourniquet (Fig. 3B).

F3-14
Figure 3:
A, hepatic arterial flow (white dots) and total liver blood flow (gray dots) on reduction of portal venous flow to 20% of baseline values (black dots) for 2 h; B, mean arterial blood pressure (white squares), portal venous blood pressure (black squares), and hepatic tissue Po2 (gray squares) during 2 h of reduced PV flow. Means ± sem.

Two hours of CO2-pneumoperitoneum with 18 mm Hg demonstrated a sustained loss of HABR with a reduction of total liver blood flow to 50% of baseline values (Fig. 4A). Intraabdominal pressure evacuation at the end of the experiment resulted in total restoration of PV and HA perfusion (Fig. 4A). Within the 2 h of CO2-pneumoperitoneum, a progressive and significant (P < 0.05) decrease of hepatic Po2 was observed, averaging values <50% of baseline at the end of the 2 h-period of increased intraabdominal pressure (baseline, 34.1 ± 3.1 mm Hg; 120 min, 16.6 ± 4.3 mm Hg) (Fig. 4B). Notably, subsequent abdominal CO2-desufflation was not associated with a complete restoration of hepatic tissue Po2 despite normal liver blood flow (Fig. 4B).

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Figure 4:
A, hepatic arterial flow (white dots), portal venous flow (black dots), and total liver blood flow (gray dots) during persistently increased intraabdominal pressure to 18 mm Hg for 2 h; B, mean arterial blood pressure (white squares), portal venous blood pressure (black squares), and hepatic tissue Po2 (gray squares) during 2 h of 18 mm Hg intraabdominal pressure elevation. Means ± sem.

Arterial blood sample analysis in Control animals revealed significantly less serum activities of AST (81 ± 8 U/L) and ALT (59 ± 14 U/L) when compared with those obtained from animals undergoing CO2-pneumoperitoneum (AST, 154 ± 24 U/L, P < 0.01; ALT, 136 ± 32 U/L, P < 0.05), indicating moderate hepatic tissue injury in the Laparoscopy group.

Discussion

Recently, hemodynamic alterations during laparoscopic surgery have become an important topic of research. Although a number of experimental studies have focused interest on hepatic function or perfusion during pneumoperitoneum (4,7,9,12,24–26), the HABR as the unique autoregulatory mechanism of hepatic blood flow has not been studied during laparoscopy. In this study, we modified an established rat model for simultaneous measurement of HA and PV flow (21–23), allowing simulation of laparoscopic interventions with increased intraabdominal pressures. As expected (18,20,21), Control animals with tourniquet-induced reduction of PV flow revealed a significant HABR, although the increase of HA flow did not completely compensate for maintenance of total liver blood flow (21,22). Mean arterial pressure increased during step-wise flow reduction of PV flow, probably as a result of increased cardiac afterload during tourniquet of splanchnic perfusion, but also possibly because of a nervous reflex response of impaired liver blood flow.

Intraabdominal insufflation with CO2 reduces PV flow (9,10,12,16,27–29), but others have failed to demonstrate an effect of CO2-pneumoperitoneum on hepatic or splanchnic perfusion (2,15). In our study, PV flow decreased when intraabdominal pressure increased, demonstrating a linear relationship between intraabdominal pressure and PV pressure and a reciprocal correlation between the increase of intraabdominal pressure and PV flow reduction, as reported by others (11,12,16,17,29).

The major finding of our study is that the increase of intraabdominal pressure by CO2-pneumoperitoneum results in loss of HABR. This is in line with the results of an experimental study using lactated Ringer’s solution for enhancing intraabdominal pressure, which demonstrated a decrease of both PV flow and HA flow on pressure values of 20 mm Hg (17). However, Ishizaki et al. (27) demonstrated a maintained HA flow during PV flow reduction on intraabdominal pressure increase to 16 mm Hg, postulating a compensatory mechanism for maintenance of hepatic blood flow. However, preserved HA flow during PV flow reduction does not reconstitute total liver blood flow; therefore, the term “compensatory” seems inappropriate in this context. Moreover, in a further study, the same authors reported that “hepatic arterial flow had a tendency to decrease” on PV flow reduction during CO2-pneumoperitoneum (10). Others (2,9,24) showed either a decrease of HA flow and maintenance of PV flow during CO2-pneumoperitoneum (9), no influence on HA and PV flow (2), or a slight increase of both HA and PV flow (24). Using an intraabdominal reservoir bag, Masey et al. (16) demonstrated reduced PV flow during intraabdominal pressure increase to 15, 20, and 25 mm Hg, which was accompanied with a significant increase of HA flow to values of more than 200% of baseline HA flow. However, although these data suggest an autoregulatory compensation of liver blood flow by the hepatic artery, the increase of HA perfusion had already reached its maximum at 15 mm Hg pneumoperitoneum, with no further increase at higher levels of intraabdominal pressure and, thus, PV flow reduction. Therefore, these data do not reveal a genuine “HABR,” as this term defines a strict reciprocal relationship between PV and HA flow (18,21).

The controversial results derived from the above mentioned studies on HA perfusion during enhanced intraabdominal pressure could presumably result from different animal models (24), as blood flow analysis has been performed during intraabdominal pressure increase in dogs (10,27), pigs (2,9,17,24), or neonatal lambs (16). Although measuring HA flow in rats under laparoscopic conditions has been considered to be impossible (13), we established a rat model serving for simultaneous measurement of HA and PV blood flow during extended periods of pneumoperitoneum. We are aware that the influence of enhanced intraabdominal pressure may be overestimated in small animals, especially in loose skin animals with thin abdominal muscle layers, such as the rat. Moreover, different anesthetic regimes may influence HA and/or PV blood flow (24,30), as well as fluid substitution (2), changes in body position (9,24), and different Pco2 levels may affect liver perfusion (31). Acidosis, as observed in the present study, seems to deteriorate perfusion control of the liver, i.e., loss of the HABR. Acidosis may–in part–be caused by local intraabdominal CO2-accumulation, but particularly results from intraabdominal hypertension with longitudinal stretch-associated narrowing of vessel diameters, decrease of blood flow, and thus local hypoxia (17,26). This view is further underlined by studies demonstrating splanchnic hypoperfusion regardless of whether gasless intraabdominal pressure increase (16,17) or insufflation of CO2, N2O, helium, or argon for induction of pneumoperitoneum (2,8,9,13,25) was performed.

Beside hemodynamic variables, hepatic function during and after laparoscopic surgery has been examined in a number of clinical studies, and AST and ALT serum activities were found to be increased as a result of intraabdominal pressure increase (3,5,6,32,33). In the present study, similarly increased AST/ALT levels occurred in parallel with impaired hepatic tissue oxygenation during CO2-pneumoperitoneum. Laparoscopic interventions, generally considered to be less harmful than conventional surgery, may be of some risk when pneumoperitoneum of long duration is applied (3,5), in patients with compromised liver function (1,3,5), or in elderly subjects (6). Therefore, a selective setting, including low-pressure pneumoperitoneum with intermittent deflation at distinct time points or even a gasless abdominal wall lift may be recommended for safe laparoscopic interventions in critically ill patients, unless intraoperative monitoring of liver perfusion or hepatic tissue oxygenation is available.

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