Platelets promote liver regeneration through site-specific serotonin release from dense granules, triggering proliferative signaling in hepatocytes. However, the effects of factors derived from platelet a-granules on liver regeneration are unclear, because a-granules contain bioactive molecules with opposing functions. Because a-granule molecules are stored in separate compartments, it has been suggested that platelets selectively release their a-granule content dependent on the environmental stimulus. Therefore, we investigated the pattern of circulating a-granule molecules during liver regeneration in 157 patients undergoing partial hepatectomy. We measured plasma levels of a-granule-derived factors in the liver vein at the end of liver resection, as well as on the first postoperative day. We observed a rapid accumulation of platelets within the liver after induction of liver regeneration. Platelet count and P-selectin (a ubiquitous cargo of a-granules) were not associated with postoperative liver dysfunction. However, low plasma levels of vascular endothelial growth factor (VEGF), but high levels of thrombospondin 1 (TSP-1), predicted liver dysfunction after resection. Patients with an unfavorable postoperative a-granule release profile (high TSP-1/low VEGF) showed substantially worse postoperative clinical outcomes. The unfavorable postoperative a-granule release profile was associated with increased postoperative portal venous pressure and von Willebrand factor antigen levels as a marker for intrahepatic endothelial dysfunction. Conclusion: The postoperative profile of circulating platelet-derived factors correlates with the ability of the remnant liver to regenerate. Portal venous pressure and intrahepatic endothelial dysfunction might account for the selective granule release profile. Selective modulation of platelet a-granule release in patients may represent an attractive target for therapeutic interventions to improve liver regeneration and clinical outcomes after partial hepatectomy. (HEPATOLOGY 2016;63:1675-1688 P latelets are critically involved not only in hemostasis, but also in inflammation, wound healing and angiogenesis. Through release of their granule content, they orchestrate signal responses in a plethora of target cells, including hepatocytes. Platelets are potent inducers of liver regeneration (LR) after partial hepatectomy and platelet activation as well as granule release increase after liver resection.(1,2) Platelet activation results in the release of dense granules, followed by secretion of a-granule content.(3) Exocytosis of a-granules represents a highly regulated process, involving distinct packaging

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SummaryBackgroundInfusion therapy is one of the most frequently prescribed medications in hospitalized patients. Currently used crystalloid solutes have a variable composition and may therefore influence acid-base status, intracellular and extracellular water content and plasma electrolyte compositions and have a major impact on organ function and outcome. The aim of our study was to investigate whether use of acetate-based balanced crystalloids leads to better hemodynamic stability compared to 0.9% saline.MethodsWe performed a sub-analysis of a prospective, randomized, controlled trial comparing effects of 0.9% saline or an acetate-buffered, balanced crystalloid during the perioperative period in patients with end-stage renal disease undergoing cadaveric renal transplantation. Need for catecholamine therapy and blood pressure were the primary measures.ResultsA total of 150 patients were included in the study of which 76 were randomized to 0.9% saline while 74 received an acetate-buffered balanced crystalloid. Noradrenaline for cardiocirculatory support during surgery was significantly more often administered in the normal saline group, given earlier and with a higher cumulative dose compared to patients receiving an acetate-buffered balanced crystalloid (30% versus 15%, p = 0.027; 68 ± 45 µg/kg versus 75 ± 60 µg/kg, p = 0.0055 and 0.000492 µg/kg body weight/min, ±0.002311 versus 0.000107 µg/kg/min, ±0.00039, p = 0.04, respectively). Mean minimum arterial blood pressure was significantly lower in patients randomized to 0.9% saline than in patients receiving the balanced infusion solution (57.2 [SD 8.7] versus 60.3 [SD 10.2] mm Hg, p = 0.024).ConclusionThe use of an acetate-buffered, balanced infusion solution results in reduced need for use of catecholamines and cumulative catecholamine dose for hemodynamic support and in less occurrence of arterial hypotension in the perioperative period. Further research in the field is strongly encouraged.

Background Perioperative subcutaneous tissue oxygen tension (PsqO2) is substantially reduced in obese surgical patients. Goal-directed fluid therapy optimizes cardiac performance and thus tissue perfusion and oxygen delivery. We therefore tested the hypothesis that intra- and postoperative PsqO2 is significantly reduced in obese patients undergoing standard fluid management compared to goal-directed fluid administration. Methods We randomly assigned 60 obese patients (BMI ≥ 30 kg/m2) undergoing laparoscopic bariatric surgery to receive either esophageal Doppler-guided goal-directed fluid management or conventional fluid treatment. Our primary outcome parameter was intra- and postoperative PsqO2 measured with a polarographic electrode in the subcutaneous tissue of the upper arm. A random effects linear regression model was used to analyze the effect of intervention. Results Overall, mean (± SD) PsqO2 was significantly higher in obese patients receiving goal-directed therapy compared to conventional fluid therapy (65.8 ± 28.0 mmHg vs. 53.7 ± 21.7, respectively; repeated measures design adjusted difference: 13.0 mmHg [95% CI 2.3 to 23.7; p = 0.017]). No effect was seen intraoperatively (69.6 ± 27.9 mmHg vs. 61.4 ± 28.8, difference: 9.7 mmHg [95% CI -3.8 to 23.2; p = 0.160]); however, goal-directed fluid management improved PsqO2 in the early postoperative phase (63.1 ± 27.9 mmHg vs. 48.4 ± 12.5, difference: 14.5 mmHg [95% CI 4.1 to 24.9; p = 0.006]). Intraoperative fluid requirements did not differ between the two groups. Conclusions Goal-directed fluid therapy improved subcutaneous tissue oxygenation in obese patients. This effect was more pronounced in the early postoperative period. Clinical Trial Number and Registry The study was registered at ClinicalTrials.gov (NCT 01052519).

Background The impact of changes in portal pressure before and after liver resection (defined as ΔHVPG) on postoperative kidney function remains unknown. Therefore, we investigated the effect of ΔHVPG on (i) the incidence of postoperative AKI and (ii) the renin-angiotensin system (RAAS) and sympathetic nervous system (SNS) activity. Methods We included 30 patients undergoing partial liver resection. Our primary outcome was postoperative AKI according to KDIGO criteria. For our secondary outcome we assessed the plasma renin, aldosterone, noradrenaline, adrenaline, dopamine and vasopressin concentrations prior and 2 h after induction of anaesthesia, on the first and fifth postoperative day. HVPG was measured prior and immediately after liver resection. Results ΔHVPG could be measured in 21 patients with 12 patients HVPG showing increases in HVPG (∆HVPG≥1 mmHg) while 9 patients remained stable. AKI developed in 7/12 of patients with increasing HVPG, but only in 2/9 of patients with stable ΔHVPG (p = 0.302). Noradrenalin levels were significantly higher in patients with increasing ΔHVPG than in patients with stable ΔHVPG. (p = 0.009). Biomarkers reflecting RAAS and SNS activity remained similar in patients with increasing vs. stable ΔHVPG. Conclusions Patients with increased HVPG had higher postoperative creatinine concentrations, however, the incidence of AKI was similar between patients with increased versus stable HVPG.

Background: The impact of changes in portal pressure before and after liver resection (defined as ΔHVPG) on postoperative renal function remains unknown. Therefore, we investigated the effect of ΔHVPG on (i) the incidence of postoperative AKI and (ii) the renin-angiotensin system (RAAS) and sympathetic nervous system (SNS) activity. Methods: We included 30 patients undergoing partial liver resection. Our primary outcome was postoperative AKI according to KDIGO criteria. For our secondary outcome we assessed the plasma renin, aldosterone, noradrenaline, adrenaline, dopamine and vasopressin concentrations prior and 2 hours after induction of anaesthesia, on the first and fifth postoperative day. HVPG was measured prior and immediately after liver resection.Results: ΔHVPG could be measured in 21 patients with 12 patients HVPG showing increases in HVPG (∆HVPG≥1mmHg) while 9 patients remained stable. AKI developed in 7/12 of patients with increasing HVPG, but only in 2/9 of patients with stable DHVPG (p=0.302). Noradrenalin levels were significantly higher in patients with increasing DHVPG than in patients with stable DHVPG. (p=0.009). Biomarkers reflecting RAAS and SNS activity remained similar in patients with increasing vs. stable DHVPG. Conclusions: Patients with increasing HVPG were more likely to develop postoperative AKI as compared those with stable HVPG values.

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Background: Pulmonary function is impaired after major abdominal surgery and might be improved by restrictive fluid administration. Under the assumption of a fluid sparing effect of colloids we tested the hypothesis that an intraoperative colloid-based goal-directed fluid management strategy improves postoperative pulmonary function parameters compared to goal-directed crystalloid administration. Methods: We performed a preplanned, single-center substudy within a recently published trial evaluating the effect of goal-directed crystalloids versus colloids on a composite of major complications. 60 patients undergoing major open abdominal surgery were randomized to Doppler-guided intraoperative fluid replacement therapy with lactated Ringer’s solution (n = 31) or 6% hydroxyethyl starch 130/0.4 (n = 29). A blinded investigator performed bedside spirometry (Spirobank-G, Medical International Research; Rome, Italy) preoperatively as well as 6-, 24-, and 48 hours postoperatively. Results: Median total intraoperative fluid requirements were significantly higher during crystalloid administration compared to patients receiving colloids (4567 ml vs. 3044 ml, p = 0.01). 6 hours after surgery pulmonary function parameters did not differ significantly between the crystalloid - and the colloid group: forced vital capacity (FVC): 1.6 l (1.2 - 2 l) vs.1.9 l (1.5 - 2.4 l), p = 0.15; forced expiratory volume in 1 second (FEV1): 1.1 l (0.9 - 1.6 l) vs. 1.4 l (1.2 - 1.7 l), p = 0.18; peak expiratory flow (PEF): 2 l.sec -1 (1.5 - 3.6 l.sec -1) vs. 2.3 l.sec -1 (1.8 - 3.4 l.sec -1 ), p = 0.23. Similarly, postoperative time weighted averages of FVC (p = 0.50), FEV1 (p = 0.96) and PEF (p = 0.39) did not differ significantly. Conclusion: Intraoperative goal-directed colloid administration did not significantly improve postoperative pulmonary function parameters in patients undergoing open abdominal surgery compared to goal-directed crystalloid administration.Trial Registration: ClinicalTrials.gov (NCT00517127, registered on August 16th, 2007, https://clinicaltrials.gov/ct2/show/NCT00517127) and EudraCT (2005-004602-86)