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Learn more: PMC Disclaimer | PMC Copyright Notice Sci Rep . 2026 Mar 8;16:12622. doi: 10.1038/s41598-026-42933-x Search in PMC Search in PubMed View in NLM Catalog Add to search Effects of a Pringle maneuver on jejunal mucosal oxygenation and blood flow in a porcine model Selina Sartori Selina Sartori 1 Department of Anesthesiology and Critical Care Medicine, Graz Medical University, Auenbruggerplatz 5, Graz, A-8036 Austria Find articles by Selina Sartori 1, # , Werner Pajk Werner Pajk 2 Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, Innsbruck, A-6020 Austria Find articles by Werner Pajk 2, # , Axel Kleinsasser Axel Kleinsasser 2 Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, Innsbruck, A-6020 Austria Find articles by Axel Kleinsasser 2 , Hanno Ulmer Hanno Ulmer 3 Institute of Clinical Epidemiology, Health Economics, Medical Statistics and Informatics, Public Health, Innsbruck Medical University, Anichstrasse 35, Innsbruck, A-6020 Austria Find articles by Hanno Ulmer 3 , Peter Modler Peter Modler 4 Traunkreis Vet Clinic, Tierklinik Sattledt; Kirchdorferstrasse 7, Sattledt, A-4642 Austria Find articles by Peter Modler 4 , Bernhard Poidinger Bernhard Poidinger 5 Institute of Anesthesiology and Critical Care Medicine, Klinikum Wels, Grieskirchner Str. 42, Wels, 4600 Austria Find articles by Bernhard Poidinger 5 , Oskar Kotzinger Oskar Kotzinger 5 Institute of Anesthesiology and Critical Care Medicine, Klinikum Wels, Grieskirchner Str. 42, Wels, 4600 Austria Find articles by Oskar Kotzinger 5 , Hans Knotzer Hans Knotzer 5 Institute of Anesthesiology and Critical Care Medicine, Klinikum Wels, Grieskirchner Str. 42, Wels, 4600 Austria Find articles by Hans Knotzer 5, ✉ , Walter Hasibeder Walter Hasibeder 6 Department of Anesthesiology and Critical Care Medicine, Krankenhaus St. Vinzenz in Zams; Sanatoriumsstrasse 43, Zams, A-6511, Austria Find articles by Walter Hasibeder 6 Author information Article notes Copyright and License information 1 Department of Anesthesiology and Critical Care Medicine, Graz Medical University, Auenbruggerplatz 5, Graz, A-8036 Austria 2 Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, Innsbruck, A-6020 Austria 3 Institute of Clinical Epidemiology, Health Economics, Medical Statistics and Informatics, Public Health, Innsbruck Medical University, Anichstrasse 35, Innsbruck, A-6020 Austria 4 Traunkreis Vet Clinic, Tierklinik Sattledt; Kirchdorferstrasse 7, Sattledt, A-4642 Austria 5 Institute of Anesthesiology and Critical Care Medicine, Klinikum Wels, Grieskirchner Str. 42, Wels, 4600 Austria 6 Department of Anesthesiology and Critical Care Medicine, Krankenhaus St. Vinzenz in Zams; Sanatoriumsstrasse 43, Zams, A-6511, Austria ✉ Corresponding author. # Contributed equally. Received 2025 Nov 27; Accepted 2026 Feb 28; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13086847 PMID: 41796174 Abstract The Pringle maneuver is routinely used during hepatic surgery to reduce blood loss. However, its hemodynamic effects on extrahepatic organs—especially the gut—remain poorly understood. This study investigates the impact of 20- and 40-minute continuous Pringle maneuver on jejunal mucosal oxygenation and microcirculatory blood flow in a porcine model. Twenty-three anesthetized pigs were randomized into three groups: 20-minute Pringle maneuver (A, n = 7), 40-minute Pringle maneuver (B, n = 7), and control (C, n = 9). Systemic hemodynamics, mesenteric and portal blood flow, mucosal tissue oxygen tension (PO₂muc), mucosal hemoglobin oxygen saturation (HbO₂muc), and jejunal microvascular blood flow were measured at baseline, during Pringle maneuver (groups A and B), and at multiple time points up to 100 min after reperfusion. Intestinal acid-base status and oxygen transport variables were also analyzed. Following Pringle maneuver, systemic hemodynamic instability and hyperlactatemia were more pronounced and sustained in group B. Although mesenteric and portal blood flow normalized post-reperfusion, PO₂muc and HbO₂muc remained significantly reduced in both intervention groups compared to controls. This impairment was significantly greater and more persistent in the 40-minute group. Microvascular flow partially recovered after Pringle maneuver, but mucosal oxygenation did not, indicating a dissociation between perfusion and oxygen delivery/utilization. Continuous Pringle maneuver induces duration-dependent impairments in jejunal mucosal oxygenation, despite recovery of macro- and microcirculatory blood flow. These findings highlight the predominance of reperfusion injury over ischemic hypoperfusion in splanchnic tissues with a dissociation between flow and oxygenation and suggest that prolonged Pringle maneuver may compromise intestinal barrier integrity and promote systemic inflammation. Keywords: Pringle maneuver, Microcirculation, Intestinal oxygenation, Reperfusion injury, Pig model Subject terms: Gastroenterology, Medical research, Physiology Introduction In 1908, James Hogarth Pringle first described a technique to minimize blood loss during hepatic surgery by clamping the vascular pedicle 1 . In this surgical maneuver the hepatoduodenal ligament is totally clamped interrupting the blood flow through the hepatic artery and the portal vein. Due to the Pringle maneuver blood loss during hepatic transection is minimized. A possible advantage during surgery, as the amount of operative blood loss influences both the short- and long-term outcome of patients undergoing liver resection 2 . Intermittent Pringle maneuver has become the most preferred and commonly used technique 3 . In this technique inflow clamping time ranges from 5 to 40 min, followed by reperfusion for periods of 5 to 20 min 4 , 5 . Results of studies examine the blood loss and transection time of an intermittent Pringle maneuver have yield heterogeneous results 6 – 8 . So a clear positive effect of this technique remains speculative and a meta-analysis does not recommend the intermittent Pringle maneuver as a routine use 9 . Besides direct damage of hepatocytes due to clamping and reperfusion damage, portal stasis may lead to intestinal congestion with temporary ischemia and reperfusion injury of the most vulnerable part of the intestine, the gut mucosa. Animal models of hemorrhagic shock, endotoxinemia and ischemia/reperfusion injury have demonstrated that mucosal tissue oxygen partial pressure and microcirculatory hemoglobin oxygen saturation are significantly decreased during low flow states 10 – 12 . Furthermore, intestinal mucosal damage occurs not only during the hypoperfused state but also immediately after reperfusion, caused by a phenomenon known as reperfusion injury 13 . As a consequence, small bowel congestion induced by a Pringle maneuver of 30 min duration results in gut barrier failure by significantly increasing bacterial translocation and endotoxinemia in rats 14 . The objective of this study was to assess the impact on mucosal tissue oxygenation and microcirculatory blood flow within the jejunal mucosa in pigs subjected to a Pringle maneuver lasting either 20–40 min. Our additional, specific hypothesis was that the duration of the clamping period significantly influences the depression of microcirculatory blood flow and tissue oxygenation during reperfusion. The novelty of the present study lies on the direct measurement of tissue oxygen tension and microcirculatory haemoglobin oxygen saturation of the gut mucosa during reperfusion related to macro- and microcirculatory blood flow. Material & methods Animal preparation The experimental protocol was approved by the Federal Ministry of Science and Research in Vienna, Austria with the official number TV-Nr. 66.011/16-Pr/4/99. Animals were managed in accordance with the American Physiological Society institutional guidelines and the Position of the American Heart Association on Research Animal Use, as adopted on November 11, 1984. General anesthesia was used in all surgical interventions, all unnecessary suffering was avoided, and research was terminated if unnecessary pain or distress resulted. Our animal facilities meet the standards of the American Association for Accreditation of Laboratory Animal Care. The pigs were obtained from an official institution for keeping and distribution of laboratory animals (Dr. Viktor Klima). The accomodation of the experimental animals complies with the requirements oft he European Directive 2010/63/EU, in particular with regard to space requirements, social contact and species-appropriate environment. Animal care and use was performed by qualified individuals, supervised by an veterinarian, and all facilities and transportation complied with current legal requirements and guidelines. The animal experiment ist reported in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE 2.0) guidelines 15 . Twenty-three domestic pigs (35–40 kg body weight) of either sex were fasted overnight, but had free access to water. The animals were anesthetized with ketamine HCL (20 mg∙kg − 1 ) i.m. Tracheas of the animals were intubated, and lungs were mechanically ventilated with a positive endexpiratory pressure of 5 cm H 2 O (mbar). Tidal volume and respiratory frequency were adjusted to maintain an arterial PCO 2 of 35–45 mm Hg at baseline; fractional inspiratory oxygen concentration was primary set at 0.3, and further adjusted to achieve an arterial oxygen tension between 100 and 150 mm Hg. Anesthesia was maintained using a continuous infusion of midazolam (0.5 mg∙kg − 1 ∙h − 1 ) and fentanyl (10 µg∙kg − 1 ∙h − 1 ). If hemodynamic variables or clinical evaluation indicated an inadequate depth of anesthesia, additional bolus of midazolam (5 mg) and fentanyl (100 µg) was administered. The right carotid artery was cannulated for arterial blood pressure measurements and for obtaining arterial blood samples. A balloon - tipped thermodilution pulmonary artery catheter (Swan-Ganz CCOmbo, Baxter Healthcare, Irvine, CA) was inserted via the right internal jugular vein for measuring cardiac index, central venous pressure, pulmonary arterial pressure, pulmonary artery occlusion pressure, central blood temperature and for collecting mixed venous blood samples. Ringer´s lactate solution and modified gelatine (Gelofusin ® ; mol wt 22600) were given throughout the study period to maintain the central venous pressure between 10 and 12 mmHg. Midline laparotomy was performed. The arteria mesenterica superior and vena portae were dissected for blood flow measuring and a 20-F silicone rubber tie was wrapped around the hepatoduodenal ligament as a tourniquet clamp to perform the Pringle manoeuvre. A 16 – gauge catheter (Baxter Healthcare, Irvine, CA) was placed in the superior mesenteric vein for intermittent blood sampling. To expose part of the mucosa for tissue oxygenation measurements, a 20 cm antimesenteric enterotomy was performed in the mid-jejunum. The boundary of the mucosa was sutured to the oval opening of a cork plate. The intestine was reintroduced into the abdominal cavity except for the exposed mucosa. The temperature of the preparation was maintained at 37 °C by covering the preparation with a plastic box including a temperature sensor and a servo-controlled heated water bath. Mucosal surface temperature was measured intermittently. Measurement techniques Arterial, pulmonary artery, and central venous pressure were measured using three Statham P10EZ pressure transducers (Spectramed-Statham, Bilthoven, Netherlands). Cardiac output was determined by the thermodilution method. Heart rate, blood pressure, central venous pressure, pulmonary artery pressure, and core temperature were continuously recorded on a Horizon 2000 Monitor connected to an Omnicorder 8M14 (Mennen Medical, Clarence, NY). Zero reference for all pressures was mid-chest position. Arterial, central venous, mesenteric venous blood gases, and acid – base status were determined using an AVL 995 automatic blood gas analyzer (AVL Biomedical Instruments, Graz, Austria). Blood hemoglobin O 2 saturation (HbO 2 ) was measured with a hemoximeter (Cooximeter, AVL Biomedical Instruments, Graz). Blood hemoglobin concentration was assessed using the cyanomethemoglobin method. Systemic and mesenteric venous lactate was measured by using an Accusport automatic blood lactate analyzer (Accusport, Boehringer Mannheim, Germany). A Transonic Animal Research Flowmeter (Transonic, Ithaca, USA) was used for measuring mesenteric arterial and portal venous blood flow. The measuring principle is based on the use of flow-sensors, which are connected to the flow detection unit via a flexible cable. Two ultrasonic transducers within the flow-sensor body transmit ultrasound through a rectangular sensing window and sense volume flow passing through the window. The electronic flow detection unit automatically identifies the scaling factor and individual calibration factor of the flowprobe connected to it. Measurements of jejunal mucosal tissue oxygenation and microvascular blood flow The methodology for measurement of mucosal tissue oxygen tensions (PO 2muc ) and mucosal microvascular haemoglobin oxygen saturation (HbO 2muc ) has been described in detail in previous studies 11 , 12 , 16 . Briefly, PO 2muc was measured by Clark-type multiwire surface electrodes (Eschweiler, Kiel, Germany). These electrodes were calibrated using natriumdithionid and room air in a water bath warmed to 37 °C. One sensor (electrode) consists of eight platinum wires, each of which has a diameter of 15 μm representing an individual measuring point and one Ag-AgCl reference electrode. An Erlangen microlight guide spectrophotometer (Diehl, Nürnberg, Germany) was used for measuring HbO 2muc . The measuring principle is based on the use of one illuminating and six detecting microlight guides (each 250 μm diam) and a rapidly rotating band-pass interference filter disk for the generation of monochromatic light in 2-nm wavelength steps within the spectral range of 502–628 nm representing 64 different wavelengths. Laser doppler flow measurements were used to assess jejunal microvascular blood flow (Periflux 4001; Perimed; Järfella; Schweden). Laser-Doppler measurements are based on the principle that light scattered by moving red cells experiences a frequency shift that is proportional to the velocity of the red blood cells. The Periflux 4001 uses laser light with a wavelength of 770 to 790 nm. A fiberoptic guidewire which conducts laser light to the tissue and carries backscattered light to a photodetector was placed on the mucosal surface. Jejunal microvascular blood flow is recorded in relative perfusion units (PU). Tissue oxygen tension and blood flow sensors were fittet into small polyvinylchloride rings surrounded by transparent thin silicone rubber patch, approximately 2 cm in diameter, and they were kept in place on the gut mucosal surface simply by adhesion force. In this manuscript, the term ‘mucosal tissue oxygenation’ is used to describe the functional oxygen status of the jejunal mucosa, as assessed by mucosal tissue oxygen tension (PO₂muc) and microvascular hemoglobin oxygen saturation (HbO₂muc). Experimental protocol Animals were randomised into three groups. 20 min pringle group (A; n = 7), 40 min pringle group (B; n = 7), and control group (C; n = 9). Baseline measurements of systemic and local hemodynamics, arterial, mixed venous, and mesenteric venous blood gas analysis and hemoglobin oxygen saturation measurements, PO 2muc , HbO 2muc , and perfusion units (PU) were performed after animal preparation and 45 min resting period. Systemic oxygen delivery, systemic oxygen consumption and systemic- and intestinal oxygen extraction ratio were calculated. After baseline measurement the pringle maneuver was performed in group A for 20 min and in group B for 40 min. In both, group A and group B, one measurement during the pringle maneuver was performed. Further measurements were done immediately after opening of the portal vein and were repeated at 20, 40, 60, 80, and 100 min. In group C measurements were done in the same periods without intervention. Additionally, mesenteric venous and arterial blood samples were taken for lactate measurement at baseline, immediately after, 80, and 100 min after opening the clamping. At the end of the experiment, deeply anesthetized animals were euthanized by central venous bolus of 40 mM potassium chloride. Analysis of data Systemic oxygen delivery, oxygen consumption, systemic and mesenteric oxygen extraction ratio were calculated according to standard formulas. PO 2muc and HbO 2muc were recorded at each measurement point for a period of at least 100 s. LDF measurements were performed for a period of 300 s. Mean values were used for statistical comparison. Statistics. Due to the exploratory and mechanistic nature of this large-animal study and the lack of reliable prior effect size estimates for jejunal mucosal oxygenation during Pringle maneuver, no formal a priori sample size calculation was performed. For systemic and local hemodynamics, oxygen transport, systemic and mesenteric venous acid-base status, blood gas variables, PO 2muc, HbO 2muc , LDF and mesenteric oxygen extraction ratio, repeated measures analysis of variance (ANOVA) were performed. Post hoc pairwise comparisons were conducted using Bonferroni correction for multiple comparisons. A P-value of ≤ 0.05 was considered statistically significant. Data are presented as mean values ± standard deviation. Results Twenty-five test animals were used for this experiment. Two animals were excluded from the analysis because of significant intra-operative hemorrhage and failure in data recording, respectively. A total of 23 pigs were used for statistical analysis (group A: 7; group B: 7; and group C: 9 animals). There were no statistically significant differences in base-line variables between the three groups (Tables 1 and 2 ; Fig. 1 ). Table 1. Systemic hemodynamics and oxygen transport variables in 20 min pringle group (A; n = 7), 40 min pringle group (B; n = 7) and control group (C; n = 9). Time (min) M1 M2 M3 M4 M5 M6 M7 M8 Time Effect ( p ) Time-Group Interaction ( p ) 0 10 30 (A, C) 50 (B) 50 (A, C) 70 (B) 70 (A, C) 90 (B) 90 (A, C) 110 (B) 110 (A, C) 130 (B) 130 (A, C) 150 (B) Baseline Pringle Pringle open HR A 138 (±13) 131 (±8) 128 (±5) 131 (±9)* 128 (± 12)* 118 (±10) 115 (±13) 104 (±7) # <0.001 0.002 B 143 (±23) 142 (±21) 142 (±20) 151 (±20) 149 (±32)* 143 (±27)* 146 (±29) 142 (±26) C 127 (±16) 123 (±13) 120 (±11) 115 (±9) 107 (±8) 103 (±7) # 106 (±13) 107 (±14) MAP (mmHg) A 91 (±11) 76 (±14) 51 (±5) # * 81 (±8)* 83 (±8)* 84 (±8) 85 (±10) 84 (±10)* <0.001 <0.001 B 100 (±4) 85 (±7) # 42 (±9) # * 68 (±9) # * 72 (±15) # * 75 (±15) # * 74 (±16)* 80 (±11) # * C 100 (±15) 103 (±16) 106 (±14) 107 (±13) 106 (±15) 106 (±15) 104 (±13) 107 (±13) PAP (mmHg) A 26 (±4) 17 (±4) # 18 (±6) 28 (±5) 26 (±6) 25 (±2) 25 (±3) 21 (±4) <0.001 0.658 B 29 (±5) 19 (±5) 18 (±4) 30 (±5) 27 (±6) 27 (±5) 22 (±4) 25 (±4) C 23 (±3) 23 (±5) 23 (±4) 24 (±3) 23 (±4) 23 (±3) 22 (±3) 24 (±3) PCWP (mmHg) A 12 (±2) 9 (±3) 8 (±4) 13 (±4) 13 (±4) 12 (±3) 12 (±2) 11 (±2) 0.004 0.694 B 14 (±2) 10 (±3) 12 (±4) 14 (±1) 13 (±2) 12 (±3) 11 (±3) 13 (±2) C 12 (±2) 13 (±3) 13 (±2) 13 (±2) 12 (±2) 12 (±2) 11 (±2) 12 (±2) CI (mL/kg/min) A 227 (±59) 145 (±22) 171 (±49) 217 (±55) 201 (±45) 184 (±32) 166 (±32) 151 (±30) <0.001 0.643 B 270 (±38) 171 (±41) # 141 (±26) # 216 (±24) 204 (±42) 202 (±34) 190 (±44) 185 (±24) # C 211 (±31) 210 (±30) 197 (±23) 196 (±27) 170 (±21) 171 (±20) 167 (±20) # 173 (±23) DO 2 (mL/kg/min) A 19.3 (±4.4) 11.0 (±2.5) # 14.4 (±1.9) 15.6 (±2.8) 15.1 (±2.3) 13.6 (±2.6) 11.7 (±1.8) # 11.2 (±1.3) # <0.001 0.219 B 22.1 (±4.4) 12.8 (±2.7) # 10.2 (±2.7) # 17.4 (±1.9) 16.2 (±4.3) 16.7 (±4.6) 16.6 (±6.4) 15.3 (±4.9) C 18.4 (±2.1) 18.2 (±2.0) 16.4 (±1.6) 15.9 (±1.7) 13.9 (±1.8) # 14.2 (±1.8) # 14.0 (±2.4) # 14.5 (±2.2) # VO 2 (mL/kg/min) A 5.4 (±1.2) 3.6 (±1.3) 5.6 (±1.3) 5.9 (±1.5) 5.7 (±1.1) 5.3 (±1.2) 5.2 (±0.6) 4.8 (±1.1) <0.001 0.490 B 5.6 (±0.9) 3.6 (±0.7) # 4.9 (±0.9) 5.2 (±0.8) 5.8 (±1.1) 6.5 (±1.2) 6.6 (±1.9) 6.6 (±0.6) C 5.1 (0.6) 5.4 (±1.0) 5.2 (±0.5) 5.2 (±0.9) 4.8 (±0.6) 4.8 (±0.7) 4.9 (±0.8) 5.0(±0.9) ERsys A 0.29 (±0.05) 0.30 (±0.06) 0.39 (±0.11) 0.38 (±0.06) 0.38 (±0.07) 0.39 (±0.08) 0.42 (±0.09) 0.43 (±0.08) # <0.001 0.107 B 0.28 (±0.04) 0.29 (±0.06) 0.51 (±0.10) # 0.34 (±0.09) 0.37 (±0.06) 0.41 (±0.10) 0.42 (±0.10) 0.42 (±0.09) C 0.30 (±0.04) 0.30 (±0.05) 0.32 (±0.04) 0.33 (±0.03) 0.34 (±0.04) 0.34 (±0.05) 0.34 (±0.03) 0.33 (±0.04) pO 2 (mmHg) A 135 (±16) 137 (±19) 125 (±15) 129 (±14) 126 (±17) 134 (±12) 133 (±15) 134 (±11) 0.017 0.220 B 123 (±11) 134 (±12) 105 (±23) 120 (±9) 119 (±10) 118 (±8) 123 (±4) 126 (±4) C 130 (±10) 136 (±18) 134 (±14) 134 (±17) 132 (±15) 129 (±16) 130 (±14) 130 (±13) pCO 2 (mmHg) A 36 (±4) 30 (±3) 47 (±4) # * 38 (±3) 38 (±4) 34 (±2) 33 (±3) 31 (±4) <0.001 0.006 B 40 (±7) 35 (±9) 55 (±8)* 49 (±11) 45 (±8) 44 (±8)* 36 (±7) 37 (±3) C 35 (±3) 36 (±4) 34 (±3) 34 (±3) 34 (±2) 34 (±2) 35 (±2) 35 (±2) Art pH A 7.38 (±0.02) 7.39 (±0.02) 7.14 (±0.02) # * 7.23 (±0.03) # * 7.27 (±0.04) # * 7.32 (±0.02) # * 7.35 (±0.04) 7.37 (±0.02) <0.001 <0.001 B 7.32 (±0.03) 7.37 (±0.04) 7.08 (±0.12) # * 7.07 (±0.05) # * 7.13 (±0.04) # * 7.16 (±0.04) # * 7.25 (±0.04)* 7.25 (±0.02) # * C 7.40 (±0.05) 7.38 (±0.04) 7.41 (±0.04) 7.40 (±0.04) 7.41 (±0.03) 7.41 (±0.03) 7.41 (±0.04) 7.41 (±0.04) Art Lac (mMol/L) A 4.3 (±0.7) 7.8 (±1.5) # 5.1 (±0.9) 3.7 (±1.5) <0.001 <0.001 B 4.1 (±2.0) 9.7 (±2.7) # 7.8 (±1.6) 6.5 (±1.5) C 3.5 (±1.5) 3.0 (±1.2) 2.2 (±0.6) 1.8 (±0.4) Open in a new tab *Significant Bonferroni corrected post hoc group comparison. # Significant Bonferroni corrected post hoc baseline comparison. HR, heart rate; MAP, mean arterial blood pressure; PAP, mean pulmonary artery blood pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; DO 2 , systemic oxygen delivery; VO 2 , systemic oxygen consuption, ERsys, systemic oxygen extraction ratio, pO 2 , systemic arterial oxygen tension; pCO 2 , systemic arterial carbon dioxide tension; art pH, arterial pH; art Lac, arterial serum lactate. Table 2. Mesenteric (BFMes) and portal blood flow (BFPort), intestinal pH (Int pH), pO 2 (Int pO 2 ) and pCO 2 (Int pCO 2 ), splanchnic oxygen delivery (DO 2spl ), consumption (VO 2 spl) and extraction ratio (ERspl), blood flow in perfusion units (PU) in 20 min pringle group (A; n = 7), 40 min pringle group (B; n = 7) and control group (C; n = 9). Time (min) M1 M2 M3 M4 M5 M6 M7 M8 Time Effect ( p ) Time-Group Interaction ( p ) 0 10 30 (A, C) 50 (B) 50 (A, C) 70 (B) 70 (A, C) 90 (B) 90 (A, C) 110 (B) 110 (A, C) 130 (B) 130 (A, C) 150 (B) Baseline Pringle Pringle open BFMes (ml/min/kg) A 0.03 (±0.01) 0.01 (±0.00) # 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.02 (±0.01) 0.03 (±0.00) 0.02 (±0.00) <0.001 0.090 B 0.03 (±0.01) 0.01 (±0.00) # 0.03 (±0.01) 0.04 (±0.01) 0.04 (±0.00) 0.04 (±0.00) 0.03 (±0.01) 0.04 (±0.00) C 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) BFPort (ml/min/kg) A 0.03 (±0.01) 0.00 (±0.00) # 0.03 (±0.01) 0.04 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) <0.001 0.279 B 0.04 (±0.01) 0.00 (±0.00) # 0.02 (±0.01) # 0.04 (±0.01) 0.04 (±0.01) 0.04 (±0.01) 0.03 (±0.01) 0.03 (±0.01) C 0.04 (±0.01) 0.04 (±0.01) 0.03 (±0.01) 0.04 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) 0.03 (±0.01) Int pH A 7.30 (±0.04) 7.24 (±0.08) 6.98 (±0.05) # * 7.14 (±0.03) # * 7.18 (±0.03) # * 7.22 (±0.05)* 7.26 (±0.05)* 7.29 (±0.05) <0.001 <0.001 B 7.26 (±0.03) 7.26 (±0.04)* 6.78 (±0.06) # * 6.99 (±0.05) # * 7.05 (±0.04) # * 7.09 (±0.05) # * 7.16 (±0.04) # * 7.18 (±0.02) # * C 7.35 (±0.05) 7.34 (±0.03) 7.35 (±0.03) 7.36 (±0.03) 7.35 (0.04) 7.35 (0.04) 7.35 (±0.03) 7.34 (±0.03) Int pO 2 (mmHg) A 50 (±5) 39 (±9) 58 (±6) 50 (±8) 48 (±6) 46 (±7) 47 (±8) 44 (±7) <0.001 0.189 B 53 (±3) 47 (±11) 53 (±9) 58 (±7) 57 (±8) 56 (±7) 51 (±8) 51 (±8) C 50 (±4) 49 (±3) 49 (±5) 49 (±4) 49 (±3) 49 (±3) 48 (±3) 48 (±3) Int pCO 2 (mmHg) A 43 (±5) 45 (±6) 81 (±12) # * 52 (±4) # * 50 (±3)* 46 (±3) 45 (±4) 44 (±4) <0.001 <0.001 B 49 (±7) 44 (±3) 110 (±11) # * 66 (±14)* 59 (±12)* 54 (±9)* 51 (±7)* 49 (±5) C 42 (±3) 43 (±2) 39 (±5) 40 (±3) 42 (±2) 43 (±3) 42 (±2) 43 (±2) DO 2 spl (mL/kg/min) A 10.9 (±2.5) 0.0 (±0.0) # 10.9 (±2.7) 9.6 (±2.7) 9.5 (±2.0) 8.4 (±1.6) 7.9 (±1.6) 7.9 (±1.4) <0.001 0.022 B 12.5 (±2.9) 0.0 (+0.1) # 6.6 (±3.0) 11.5 (±2.2) 11.4 (±2.2) 11.6 (±2.6) 11.0 (±1.9) 11.0 (±1.5) C 12.1 (±2.0) 11.5 (±2.2) 11.0 (±2.1) 11.3 (±2.6) 10.9 (±2.5) 10.9 (±2.2) 10.9 (±2.4) 10.9 (±2.4) VO 2 spl (mL/kg/min) A 3.9 (±0.9) 0.0 (±0.0) # 5.1 (±1.7) 4.2 (±1.6) 4.3 (±1.0) 4.0 (±1.1) 3.7 (±1.0) 3.6 (±1.0) <0.001 0.863 B 4.3 (±1.2) 0.0 (±0.0) # 4.0 (±2.1) 4.3 (±1.6) 4.4 (±1.5) 4.4 (±1.5) 4.8 (±1.4) 4.5 (±1.8) C 4.1 (±0.9) 4.1 (±1.0) 4.1 (±1.2) 3.9 (±0.9) 3.8 (±0.9) 3.6 (±0.7) 3.8 (±1.1) 3.7 (±1.1) ERspl A 0.37 (±0.09) 0.61 (±0.21) 0.45 (±0.11) 0.43 (±0.11) 0.47 (±0.12) 0.48 (±0.15) 0.48 (±0.14) 0.47 (±0.15) 0.001 0.063 B 0.34 (±0.02) 0.46 (±0.16) 0.60 (±0.08) # 0.39 (±0.14) 0.39 (±0.12) 0.39 (±0.11) 0.44 (±0.13) 0.43 (±0.15) C 0.34 (±0.06) 0.35 (±0.05) 0.37 (±0.09) 0.35 (±0.08) 0.35 (±0.06) 0.34 (±0.06) 0.35 (±0.07) 0.34 (±0.07) PU A 132 (±37) 54 (±12) # 120 (±44) 97 (±21) 128 (±36) 141 (±68) 102 (±20) 95 (±21) <0.001 0.431 B 222 (±62) 64 (±28) # 81 (±61) 95 (±37) # 117 (±53) 104 (±29) # 90 (±25) # 99 (±17) # C 153 (±74) 156 (±59) 146 (±39) 126 (±21) 110 (±31) 112 (±31) 105 (±41) 98 (±35) Spl Lac (mMol/L) A 4.7 (±1.1) 9.0 (±1.5) # * 5.1 (±1.2)* 3.6 (±0.8)* <0.001 <0.001 B 4.0 (±1.8) 10.6 (±2.52) # * 7.7 (±1.3) # * 6.3 (±1.4)* C 3.5 (±1.3) 2.8 (±1.2) 2.2 (±0.6) 1.8 (±0.5) # Open in a new tab *Significant Bonferroni corrected post hoc group comparison. # Significant Bonferroni corrected post hoc baseline comparison. Fig. 1. Open in a new tab Mucosal tissue oxygen tension and microvascular hemoglobin oxygen saturation in 20 min pringle group (A; n = 7), 40 min pringle group (B; n = 7) and control group (C; n = 9). *Significant Bonferroni corrected post hoc group comparison. # Significant Bonferroni corrected post hoc baseline comparison. Systemic variables The initial response after opening of the Pringle maneuver was characterized by a drop of mean arterial blood pressure (Table 1 ). Especially, group B developed a significant decrease in mean arterial blood pressure after opening of the clamp which persisted throughout the study period and did not reach baseline values until the end of the experiment. This drop in blood pressure was accompanied by an increase in arterial carbon dioxide partial pressure, a decrease in arterial pH and by a rise in arterial lactate values (Table 1 ). The increase in arterial lactate levels was particularly prominent and sustained in group B compared to group A. Intestinal variables Following hepatoduodenal ligament clamping blood flow in the mesenteric artery decreased significantly but partially recovered again after clamp removal (Table 2 ). The opening of the clamp led to a wash out of mesenteric venous carbon dioxide and an increase in mesenteric venous lactate level and a drop in mesenteric venous pH (Table 2 ). In group B this lactate acidosis was more prominent compared to group A. Jejunal microcirculatory alterations during and after Pringle maneuver Jejunal microvascular blood flow decreased during the Pringle maneuver and increased after clamp release; however, in the 40-minute Pringle group, flow values did not consistently return to baseline or control levels (Table 2 ). Jejunal microvascular HbO 2 and mucosal tissue oxygenation decreased after clamping in both groups A and B compared to group C (Fig. 1 ). Although mesenteric arterial, portal venous - and jejunal microvascular blood flow partially restored after de-clamping (Table 2 ), both jejunal mucosal tissue oxygen tension and microvascular hemoglobin oxygen saturation, recovered only slowly and never reached the level of animals in group C (Table 2 ; Fig. 1 ). This impairment in jejunal mucosal oxygenation was more prominent in group B when compared to group A. Discussion In this porcine animal model, Pringle maneuver performed either for 20 min, or 40 min resulted in pathologic alterations of the jejunal microcirculation. Although jejunal microvascular blood flow increased after reperfusion, particularly in the 20-minute group, this improvement was incomplete in animals subjected to 40 min of continuous portal triad clamping. Despite a partially restoration in mesenteric artery and jejunal microvascular blood flow, reperfusion after Pringle maneuver resulted in a significant impairment in mucosal tissue oxygenation and jejunal hemoglobin oxygen saturation. This deterioration was more pronounced in the group which had a longer vascular clamping time of 40 min compared of 20 min Pringle maneuver. The novelty of the present study lies on the one hand in the direct measurement of tissue oxygen tension and microcirculatory haemoglobin oxygen saturation of the gut mucosa and on the other hand of the dissociation between restored macro- and microcirculatory blood flow during reperfusion and tissue oxygenation. In the literature, it is noted that the Pringle maneuver results in a reduction in cardiac output and an increase in mean arterial blood pressure 17 . The reduction in cardiac output is attributed to the decline of venous backflow mainly from the splanchnic region, while the increase in arterial pressure is due to systemic vasoconstriction during the clamping period 18 . In the present study, we observed a decrease in cardiac output during the Pringle maneuver, which is indeed explainable by the mechanism of diminished venous return to the heart. However, we did not observe an increase in blood pressure, which is easily explainable by the preload-dependency of cardiac stroke volume. This observation is consistent with another animal study on pigs in which a Pringle maneuver was performed laparoscopically 19 . After the beginning of the Pringle maneuver, cardiac index and mean arterial and central venous pressure decreased significantly, whereas the heart rate increased. In line with this investigation, our experiment demonstrated a drop in systemic vascular resistance and a persistently elevated heart rate after discontinuation of the Pringle maneuver. This drop in systemic vascular resistance can be explained by the hemodynamic effects due to a reperfusion syndrome 20 . Especially in animals with an ischemia time of 40 min mean arterial pressure was significantly decreased throughout the study period after opening the clamping and did not return to base-line values. Through reperfusion, arterial carbon dioxide and accumulated lactate were increasingly transported into the systemic circulation after clamp release 21 . Although the blood flow returns to baseline level in both the mesenteric artery and the portal vein after opening of the clamp, ensuring a normal oxygen delivery to the intestines, the metabolic lactic acidosis in the splanchnic area persists. These are clear indications of an ischemia-reperfusion problem 22 . The increased mesenteric-to-arterial lactate gradient after prolonged portal clamping is most pronounced during the clamping phase, indicating substantial regional lactate production that preceded and likely contributed to the observed systemic arterial hyperlactatemia. The present animal experiment reflects reperfusion injury after intestinal congestion, a clinically common problem that causes severe damage to the intestinal tract and other organs 23 . While congestion itself causes tissue damage and increased intestinal permeability, reperfusion frequently exacerbates this effect 24 . Studies have shown that compared to intestinal ischemia, intestinal congestion is more likely to cause severe tissue damage and recovers slowly. In addition, the degree of damage increases with increasing duration of congestion 25 . Although both, ischemia and congestion cause tissue hypoxia, congestion adds additional stress due to increased hydrostatic pressure in the outflow vasculature and increased accumulation of metabolites in the capillaries in intestinal tissue 26 , 27 . Consequently, the extent of tissue destruction and impairment of oxygen delivery to the intestinal mucosa is greater in congestion than in ischemia. In recent years, increasing attention has been directed towards the effect of ischemia-reperfusion injury on the epithelial barrier function 28 , 29 . The intestine has a complex barrier consisting of mechanical, chemical, immunological and biological protective mechanisms. This barrier prevents the penetration of pathogens and harmful substances. Intestinal congestion-reperfusion injury destroys this barrier, which leads to increased permeability. Bacteria, toxins and other harmful substances enter the bloodstream and trigger a systemic inflammatory reaction that can lead to serious illnesses such as sepsis and organ failure 23 . In contrast to this scientific focus on epithelial barrier function, our experimental animal model concentrates on the immediate effects of congestion/reperfusion injury on the oxygen supply to the jejunal mucosa. The damage caused by ischemia-reperfusion syndrome has a direct impact on the oxygenation of the intestinal mucosa despite a partial restoration of blood flow in both the macrocirculation and jejunal microcirculation. Other pathomechanisms that occur due to ischemia-reperfusion injury in the acute setting include shunt phenomena and heterogeneous blood flow in the microcirculation 30 , 31 . An experiment with rats demonstrated severe microcirculatory impairment after prolonged ischemia of the superior mesenteric artery of 60 min and subsequent reperfusion 30 . This was manifested by a reduced flow velocity in the venules, increased leukocyte adhesion and a metabolic acidosis. The results showed that shunting and heterogenous blood flow of the microcirculation play an important role in the pathology of mesenteric ischemia and exacerbate poor outcome. In a clinical study involving 15 patients, the effects of a Pringle maneuver during liver resections on the hepatic microcirculation were investigated 31 . Microvascular blood flows were measured using vital microscopy. Interestingly, eight patients showed partial maintenance of microcirculation despite ischemia/reperfusion injury (“partial responders”), while in seven patients blood flow was completely stopped (“full responders”). The functional capillary density and the measured microcirculatory blood flow were significantly higher in the partial responders than in the full responders. The results suggest that patients may react differently to an ischemia/reperfusion event. In our study, no significant differences in microcirculatory parameters were observed within a group, which is probably due to the consistent and uniform study design. Of pathophysiological interest are also inflammatory mechanisms that cause an impairment of the oxygen supply to the intestinal mucosa. In an animal study, the effect of ischemic events and reperfusion on intestinal microcirculation and leukocyte-endothelial interactions in rats were investigated 32 . After ischemic phases of different lengths (15, 30–60 min) followed by 2 h of reperfusion, there was a sharp decrease in venular blood flow without changes in vessel diameter. Blood flow decreased to 40% (15 min), 25% (30 min) or below 10% (60 min) of the initial value. Concurrently with the decrease in blood flow, leukocyte-endothelial interactions increased 5- to 10-fold in the 15- and 30-minute groups. However, this could not be verified in the 60-minute group due to severely reduced perfusion. After 60 min of ischemia, the reperfusion phase led to death. This observation corresponds well with the present study, in which we observed a time-dependent deterioration of the mucosal oxygen supply. One important factor that plays a decisive role in the severity of impairment of mucosal oxygen supply is duration of ischemia. As clearly demonstrated in our study, a longer ischemic phase causes a more pronounced impairment of mucosal oxygen supply to the jejunum. This result is consistent with the work of Ikeda and colleagues 33 . Histological, immunohistochemical, and molecular biological methods were used at various time intervals after interruption and restoration of blood flow in the small intestine of rats. The results showed that significant damage of over 80% of the mucosal cells occurs after just 30 min of ischemia. Several further animal studies have investigated the effects of ischemia/reperfusion injury in both continuous and intermittent Pringle maneuvers 34 – 37 . All studies indicate that, depending on the duration of the continuous Pringle maneuver, significant cell damage occurs in the liver itself as well as in the intestine. Initial intestinal damage was observed after approximately 40 min of continuous occlusion, particularly in vulnerable organs such as the intestinal mucosa. These data are consistent with the results of the present study, which revealed significantly impaired microcirculatory oxygen prameters after 40 min of clamping than after 20 min. From a translational perspective these animal experiment data should be interpreted with caution. However, the complication rate in humans also increases over time with continuous ischemia 38 . It has therefore been recommended to prefer an intermittent Pringle maneuver when ischemia is expected to last > 60 min and to limit continuous Pringle maneuvers to a maximum of 60 min in order to avoid ischemic damage, especially in extrahepatic organs such as the intestine 38 . However, considering the data of our study, ischemia and reperfusion-related damage to the intestinal mucosa should be expected after a much shorter clamping period in order to avoid associated problems. Limitations Some limitations of our experiment should be noted. First, this study was conducted in healthy pigs, and we cannot conclude that similar effects can be observed in a compromised intestinal tract with pre-existing microcirculatory impairment. Second, these results can only be extrapolated to humans and particularly to patients with preexisting disease with great caution. Nonetheless, the digestive tracts of pigs resemble that of humans in terms of anatomical structure, comparable absorption mechanisms, portal vein system, and comparable digestive physiology 39 . Furthermore, systemic hemodynamic, systemic oxygen transport, and microcirculatory physiology are comparable in pigs and humans 11 , 12 . These aspects make the pig a widely used model in gastrointestinal, surgical, and hemodynamic studies. Another aspect is the lack of histological assessment of intestinal tissue. However, the primary aim of the present study was to characterize early functional alterations in mucosal oxygenation and microcirculatory behaviour during and shortly after reperfusion, rather than structural end-organ damage. Histological injury typically represents a later-stage consequence of ischemia–reperfusion, whereas our experimental design focused on the immediate pathophysiological mechanisms that precede overt tissue destruction. Indeed, previous experimental work has already demonstrated substantial mucosal damage after comparable ischemic durations 33 . Our findings extend these observations by showing that clinically relevant clamping times (20–40 min) are sufficient to induce persistent functional oxygen deficits, even in the absence of demonstrable perfusion failure. Furthermore, measurements of endotoxemia, cytokine profiles, or intestinal injury markers would further enhance the translational relevance of the study. These parameters were, however, beyond the predefined scope of this experiment, which was designed to investigate physiological and microcirculatory mechanisms rather than systemic inflammatory consequences. This study does not aim to replace histological or inflammatory assessments but complements them by identifying early functional vulnerability. Conclusion Pringle maneuver in healthy pigs performed either for 20–40 min resulted in pathologic alterations of the jejunal mucosal oxygenation and microcirculatory bloodflow. Despite restoration of systemic hemodynamics and systemic oxygen supply, there were time dependent significant impairments in mucosal oxygenation of the jejunum. The restoration of microcirculatory blood flow with simultaneous impairment of mucosal oxygenation is a clear indication of the dominance of reperfusion injury after congestion independent of restored blood flow. Furthermore, the extent of damage increases with extended duration of congestion. Acknowledgements Not applicable. Abbreviations ANOVA Analysis of variance HbO 2muc Mucosal microvascular. Hemoglobin oxygen saturation LDF Laser Doppler flowmeter PO2 muc Mucosal tissue oxygen tension PU Perfusion units Author contributions Selina Sartori: Conceptualization, Project administration, WritingWerner Pajk: Investigation, Methodology, Writing review and editingAxel Kleinsasser: Writing review and editingHanno Ulmer: Data curation, Formal analysis, Methodology, ValidationPeter Modler: Writing review and editingBernhard Poidinger: Writing review and editingOskar Kotzinger: Writing review and editingHans Knotzer: Conceptualization, Investigation, Writing orginial-draftWalter Hasibeder: Conceptualization, Investigation, Supervision, Writing review and editing. Funding Not applicable. Data availability The data will be made available from the corresponding author upon reasonable request. Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate The experimental protocol was approved by the Federal Ministry of Science and Research in Vienna, Austria with the official number TV-Nr. 66.011/16-Pr/4/99. Consent for publication All authors read and approved the submitted manuscript. Footnotes Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Selina Sartori and Werner Pajk contributed equally to this work. References 1. Pringle, J. H. V. Notes on the arrest of hepatic hemorrhage due to trauma. Ann. Surg. 48 , 541–549 (1908). [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. Ito, H. et al. Effect of postoperative morbidity on long-term survival after hepatic resection for metastatic colorectal cancer. Ann. Surg. 247 , 994–1002 (2008). [ DOI ] [ PubMed ] [ Google Scholar ] 3. van der Bilt, J. D., Livestro, D. P., Borren, A., van Hillegersberg, R. & Borel Rinkes, I. H. 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