Uterine defects and estradiol-dependent development of oviductal diverticula in mice lacking the SMAD4 C-terminal Mad homology 2 domain.

In female mammals, the oviduct and uterus are essential sites for female and male gamete transport, fertilization, implantation, and maintenance of a successful pregnancy. To delineate the reproductive function of Mothers against decapentaplegic homolog 4 (Smad4), we specifically inactivated Smad4 in ovarian granulosa cells and, oviduct and uterine mesenchymal cells using the Amhr2-cre mouse line. Deletion of exon 8 of Smad4 results in the production of an MH2-truncated SMAD4 protein. These mutant mice are infertile due to the development of oviductal diverticula and defects during the implantation process. The ovaries are fully functional as demonstrated in an ovary transfer experiment. The development of oviductal diverticula occurs shortly after puberty and is dependent on estradiol. The diverticula interfere with sperm migration and embryo transit to the uterus, reducing the number of implantation sites. Analysis of the uterus shows that, even if implantation occurs, decidualization and vascularization are defective resulting in embryo resorption as early as the seventh day of pregnancy. Thus, Smad4 plays an important function in female reproduction by controlling the structural and functional integrity of the oviduct and uterus.

PCO2 gap, its ratio to arteriovenous oxygen content, ScvO2 and lactate in high-risk abdominal surgery patients: An observational study.

BACKGROUND: The difference between arterial and central venous carbon dioxide partial pressure (PCO2 gap), a marker of oxygen delivery (DO2) and oxygen consumption (VO2) adequacy, has been evaluated as a promising prognostic tool in intensive care unit (ICU) patients. We therefore sought to study the association between intraoperative PCO2 gap and postoperative complications (POC) in the perioperative setting of elective major abdominal surgery. METHODS: We conducted a single-centre prospective observational study. All adult patients who underwent major planned abdominal surgery were eligible. PCO2 gap was measured every 2 h during surgery, at ICU admission and repeated 12 h and 24 h later. Severe POC within 28 days after surgery were defined as complications graded 3 or more according to Clavien-Dindo classification. Following a univariate analysis, a multivariable analysis using a logistic regression model was performed. RESULTS: Ninety patients were included and divided into two groups according to the occurrence of POC. No significant difference was found between groups regarding baseline characteristics at inclusion. Thirty-nine (43%) patients developed postoperative complications. The median [IQR] intraoperative PCO2 gap was significantly higher in patients who had complications (6.5 [5.5-7.3] mmHg) compared to those who did not (5.0 [3.9-5.8] mmHg; p < 0.001). The area under the receiver operating characteristic curve for occurrence of POC was 0.78 for the PCO2 gap. After multivariable analysis, PCO2 gap was found independently associated with POC (OR: 14.9, 95% CI [4.68-60.1], p < 0.001) with a threshold value of 6.2 mmHg. The duration of surgery (OR: 1.01, 95% CI [1.00; 1.01], p = 0.04) and the need for vasoactive support during surgery (OR: 5.76, 95% CI [1.72; 24.1], p = 0.006) were also independently associated with POC. CONCLUSION: Intraoperative PCO2 gap is a relevant predictive factor of severe postoperative complications in high-risk elective surgery patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03914976.

Impact of 2016 Enhanced Recovery After Surgery (ERAS) Recommendations on Outcomes after Hepatectomy in Cirrhotic and Non-Cirrhotic Patients.

BACKGROUND: The Enhanced Recovery After Surgery (ERAS) society published new recommendations for hepatectomy in 2016. Few studies have assessed their clinical impact. The aim of this monocentric study was to assess the impact of those guidelines on outcomes after liver surgery with a special focus on cirrhotic patients. METHOD: Postoperative outcomes of patients undergoing hepatectomy 30 months before and after ERAS implementation according to the 2016 ERAS guidelines were compared after inverse probability of treatment weighting (IPTW). Primary endpoint was 90-day morbidity. RESULTS: From 2015 to 2020, 430 patients underwent hepatectomy including 226 procedures performed before and 204 after ERAS implementation. After IPTW, overall morbidity (42.5% vs. 64.7%, p < 0.001), Comprehensive Complication Index (CCI) score (14.3 vs. 20.8, p = 0.004), length of stay (10.4 vs. 13.7 days, p = 0.001) and textbook outcome (50% vs. 40.2%, p = 0.022) were significantly improved in the ERAS group, while mortality and severe complications were similar in both groups. In the non-cirrhosis subgroup (n = 321), these results were confirmed. However, in the cirrhosis subgroup (n = 105), no difference appeared on outcomes after hepatectomy with an overall morbidity (47.5% vs. 65.2%, p = 0.069) and a length of stay (8 vs. 9 days, p = 0.310) which were not significantly different. The compliance rate to ERAS guidelines was 60% in both cirrhotic and non-cirrhotic subgroups. CONCLUSION: Perioperative ERAS program for hepatectomy results in improved outcomes with decreased rate of non-severe morbidity. Although those guidelines are not deleterious for cirrhotic patients, they probably require revisions to be more effective in this patient population.

The use of a thromboelastometry-based algorithm reduces the need for blood product transfusion during orthotopic liver transplantation: A randomised controlled study.

BACKGROUND: Orthotopic liver transplantation is associated with a risk of bleeding. Coagulation in cirrhotic patients is difficult to assess with standard coagulation tests because of rebalanced coagulation. This can be better assessed by thromboelastometry which can detect coagulation impairments more specifically in such patients. OBJECTIVES: Our first objective was to compare the number of units of blood products transfused during liver transplantation when using an algorithm based on standard coagulation tests or a thromboelastometry-guided transfusion algorithm. DESIGN: Randomised controlled trial. SETTING: Single-centre tertiary care hospital in France, from December 2014 to August 2016. PARTICIPANTS: A total of 81 adult patients undergoing orthotopic liver transplantation were studied. Patients were excluded if they had congenital coagulopathies. INTERVENTION: Transfusion management during liver transplantation was guided either by a standard coagulation test algorithm or by a thromboelastometry-guided algorithm. Transfusion, treatments and postoperative outcomes were compared between groups. MAIN OUTCOME MEASURES: Total number of transfused blood product units during the operative period (1 U is one pack of red blood cells (RBCs), fresh frozen plasma (FFP) or platelets). RESULTS: Median [interquartile range] intra-operative transfusion requirement was reduced in the thromboelastometry group (3 [2 to 4] vs. 7 [4 to 10] U, P = 0.005). FFP and tranexamic acid were administered less frequently in the thromboelastometry group (respectively 15 vs. 46.3%, P = 0.002 and 27.5 vs. 58.5%, P = 0.005), whereas fibrinogen was more often infused in the thromboelastometry group (72.5 vs. 29.3%, P < 0.001). Median transfusions of FFP (3 [2 to 6] vs. 4 [2 to 7] U, P = 0.448), RBCs (3 [2 to 5] vs. 4 [2 to 6] U, P = 0.330) and platelets (1 [1 to 2] vs. 1 [1 to 2] U, P = 0.910) were not different between groups. In the postoperative period, RBC or platelet transfusion, the need for revision surgery or occurrence of haemorrhage were not different between groups. CONCLUSION: A transfusion algorithm based on thromboelastometry assessment of coagulation reduced the total number of blood product units transfused during liver transplantation, particularly FFP administration. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02352181.

Fluid and pain management in liver surgery (MILESTONE): A worldwide study among surgeons and anesthesiologists.

BACKGROUND: Fluid and pain management during liver surgery (eg, low central venous pressure) is a classic topic of controversy between anesthesiologists and surgeons. Little is known about practices worldwide. The aim of this study was to assess perioperative practices in liver surgery among and between surgeons and anesthesiologists worldwide that could guide the design of future international studies. METHODS: An online questionnaire was sent to 22 societies, including 4 international hepatopancreatobiliary societies, the American Society of Anesthesiologists, and 17 other (inter-)national societies. RESULTS: A total of 913 participants (495 surgeons and 418 anesthesiologists) from 66 countries were surveyed. A large heterogeneity in fluid management practices was identified, with 66% using low central venous pressure, 22% goal-directed fluid therapy, and 6% normovolemia. In addition, large heterogeneity was found regarding pain management practices, with 49% using epidural analgesia, 25% patient-controlled analgesia with opioids, and 12% regional techniques. Most participants assume that there is a relation between perioperative pain management and morbidity and mortality (78% of surgeons vs 89% of anesthesiologists; P < .001). Both surgeons and anesthesiologists have the highest expectations for minimally invasive surgery and enhanced recovery pathways for improving outcomes in liver surgery. No clear differences between continents were found. CONCLUSION: Worldwide there is a large heterogeneity in fluid and pain management practices in liver surgery. This survey identified several areas of interest for future international studies aiming to improve outcomes in liver surgery.

The evolution of diastolic function during liver transplantation.

INTRODUCTION: The peroperative management of liver transplantation is still associated with many cardiocirculatory complications in which diastolic dysfunction may play a contributive role. Transoesophageal echocardiography is a monitoring device commonly used in liver transplantation allowing diastolic function assessment. METHODS: We prospectively analysed the peroperative transoesophageal echocardiography recordings of 40 patients undergoing liver transplantation in order to describe changes in diastolic function at different steps of the surgery. The diastolic function marker we used was the lateral mitral annulus motion (E' wave velocity) obtained by tissue-Doppler imaging. In addition, we also studied the left ventricular filling pressure indices and systolic function. RESULTS: As a whole, there was no global change in E' wave velocity throughout the surgery. However, 11 patients (27.5%) presented a decrease in E' wave velocity up to 15% that identified an occurrence of diastolic function alteration. In this group, other peroperative data were not different from other patients (amount of bleeding, fluid administration or vasopressive support). Conversely, this group experienced lower preoperative E' wave velocity values (9cm·s-1 versus 12cm·s-1, P=0.05) and an increased incidence of postoperative cardiorespiratory complications (OR=6 [1-56], P=0.02). Considering all patients, 18 patients had an E' wave velocity under 10cm·s-1 at unclamping, characterizing a diastolic dysfunction according to the usual criteria. This dysfunction was not associated with cardiorespiratory complications. CONCLUSION: This work investigated peroperative systematic echocardiographic evaluation of diastolic function during liver transplantation. Diastolic dysfunction occurs frequently during liver transplantation and could lead to postoperative cardiorespiratory complications.

Comparison between respiratory variations in pulse oximetry plethysmographic waveform amplitude and arterial pulse pressure during major abdominal surgery.

BACKGROUND: To assess preload dependence, the variation of the plethysmographic waveform of pulse oximetry (ΔPOP) has been proposed as a surrogate of the pulse pressure variation (ΔPP). The aim of the study was to assess the ability of the pulse oximeter-derived plethysmographic analysis to accurately trend ΔPP in patients undergoing major abdominal surgery by using standard monitors. METHODS: A continuous recording of arterial and plethysmographic waveform was performed in 43 patients undergoing abdominal surgery. ΔPP and ΔPOP were calculated on validated respiratory cycles. RESULTS: For analysis, 92,467 respiratory cycles were kept (73.5% of cycles recorded in 40 patients). The mean of intrapatient coefficients of correlation was low (r = 0.22). The Bland and Altman analysis showed a systematic bias of 5.21; the ΔPOP being greater than the ΔPP, this bias increased with the mean value of the two indices and the limits of agreement were wide (upper 21.7% and lower -11.3%). Considering a ΔPP threshold at 12% to classify respiratory cycles as responders and nonresponders, the corresponding best cutoff value of ΔPOP was 13.6 ± 4.3%. Using these threshold values, the observed classification agreement was moderate (κ = 0.50 ± 0.09). CONCLUSIONS: The wide limits of agreement between ΔPP and ΔPOP and the weak correlation between both values cast doubt regarding the ability of ΔPOP to substitute ΔPP to follow trend in preload dependence and classify respiratory cycles as responders or nonresponders using standard monitor during anesthesia for major abdominal surgery.