In vivo effects of balanced, low molecular 6% and 10% hydroxyethyl starch compared with crystalloid volume replacement on the coagulation system in major pancreatic surgery-a sub-analysis of a prospective double-blinded, randomized controlled trial.

BACKGROUND: The outcome of patients undergoing major surgery treated with HES for hemodynamic optimization is unclear. This post-hoc analysis of a randomized clinical pilot trial investigated the impact of low-molecular balanced HES solutions on the coagulation system, blood loss and transfusion requirements. METHODS: The Trial was registered: EudraCT 2008-004175-22 and ethical approval was provided by the ethics committee of Berlin. Patients were randomized into three groups receiving either a 10% HES 130/0.42 solution, a 6% HES 130/0.42 solution or a crystalloid following a goal-directed hemodynamic algorithm. Endpoints were parameters of standard and viscoelastic coagulation laboratory, blood loss and transfusion requirements at baseline, at the end of surgery (EOS) and the first postoperative day (POD 1). RESULTS: Fifty-two patients were included in the analysis (HES 10% (n = 15), HES 6% (n = 17) and crystalloid (n = 20)). Fibrinogen decreased in all groups at EOS (HES 10% 338 [298;378] to 192 [163;234] mg dl-1, p<0.01, HES 6% 385 [302;442] to 174 [163;224] mg dl-1, p<0.01, crystalloids 408 [325;458] to 313 [248;370] mg dl-1, p = 0.01). MCF FIBTEM was decreased for both HES groups at EOS (HES 10%: 20.5 [16.0;24.8] to 6.5 [5.0;10.8] mm, p = <0.01; HES 6% 27.0 [18.8;35.2] to 7.0 [5.0;19.0] mm, p = <0.01). These changes did not persist on POD 1 for HES 10% (rise to 16.0 [13.0;24.0] mm, p = 0.88). Blood loss was not different in the groups nor transfusion requirements. CONCLUSION: Our data suggest a stronger but transient effect of balanced, low-molecular HES on the coagulation system. Despite the decline of the use of artificial colloids in clinical practice, these results may help to inform clinicians who use HES solutions.

Perioperative advanced haemodynamic monitoring of patients undergoing multivisceral debulking surgery: an observational pilot study.

BACKGROUND: Patients undergoing high-risk surgery show haemodynamic instability and an increased risk of morbidity. However, most of the available data concentrate on the intraoperative period. This study aims to characterise patients with advanced haemodynamic monitoring throughout the whole perioperative period using electrical cardiometry. METHODS: In a prospective, observational, monocentric pilot study, electrical cardiometry measurements were obtained using an Osypka ICON™ monitor before surgery, during surgery, and repeatedly throughout the hospital stay for 30 patients with primary ovarian cancer undergoing multivisceral cytoreductive surgery. Severe postoperative complications according to the Clavien-Dindo classification were used as a grouping criterion. RESULTS: The relative change from the baseline to the first intraoperative timepoint showed a reduced heart rate (HR, median - 19 [25-quartile - 26%; 75-quartile - 10%]%, p < 0.0001), stroke volume index (SVI, - 9.5 [- 15.3; 3.2]%, p = 0.0038), cardiac index (CI, - 24.5 [- 32; - 13]%, p < 0.0001) and index of contractility (- 17.5 [- 35.3; - 0.8]%, p < 0.0001). Throughout the perioperative course, patients had intraoperatively a reduced HR and CI (both p < 0.0001) and postoperatively an increased HR (p < 0.0001) and CI (p = 0.016), whereas SVI was unchanged. Thoracic fluid volume increased continuously versus preoperative values and did not normalise up to the day of discharge. Patients having postoperative complications showed a lower index of contractility (p = 0.0435) and a higher systolic time ratio (p = 0.0008) over the perioperative course in comparison to patients without complications, whereas the CI (p = 0.3337) was comparable between groups. One patient had to be excluded from data analysis for not receiving the planned surgery. CONCLUSIONS: Substantial decreases in HR, SVI, CI, and index of contractility occurred from the day before surgery to the first intraoperative timepoint. HR and CI were altered throughout the perioperative course. Patients with postoperative complications differed from patients without complications in the markers of cardiac function, a lower index of contractility and a lower SVI. The analyses of trends over the whole perioperative time course by using non-invasive technologies like EC seem to be useful to identify patients with altered haemodynamic parameters and therefore at an increased risk for postoperative complications after major surgery.

Impact of clinical factors and surgical outcome on long-term survival in high-grade serous ovarian cancer: a multicenter analysis.

INTRODUCTION: Long-term survivors of ovarian cancer are a unique group of patients in whom prognostic factors for long-term survival have been poorly described. Such factors may provide information for a more personalized therapeutic approach. The objective of this study is to determine further characteristics of long-term survivors with high-grade serous ovarian cancer. METHODS: Long-term survivors were defined as patients living longer than 8 years after first diagnosis and were recruited within seven high volume centers across Europe from November 1988 to November 2008. The control group included patients with high-grade serous ovarian cancer with less than 5 years' survival identified from the systematic 'Tumorbank ovarian cancer' database. A subanalysis of Charité patients only was performed separately for in-depth analysis of tumor dissemination. Propensity score matching with nearest-neighbor caliper width was used to match long-term survivors and the control group regarding age, FIGO stage, and residual tumor. RESULTS: A total of 276 patients with high-grade serous ovarian cancer were included, divided into 131 long-term survivors and 145 control group patients. After propensity score matching and multivariable adjustment, platinum sensitivity (p=0.002) was an independent favorable prognostic factor whereas recurrence (p<0.001) and ascites (p=0.021) were independent detrimental predictors for long-term survival. Significantly more long-term survivors tested positive for mutation in the BRCA1 gene than the BRCA2 gene (p=0.016). Intraoperatively, these patients had less tumor involvement of the upper abdomen at initial surgery (p=0.024). Complexity of surgery and surgical techniques were similar in both cohorts. CONCLUSION: Platinum sensitivity constitutes a favorable factor for long-term survival whereas tumor involvement of the upper abdomen, ascites, and recurrence have a negative impact. Based on clinical estimation, long-term survival is associated with combinations of clinical, surgical, and molecular factors.

Transfusion of red blood cells does not impact progression-free and overall survival after surgery for ovarian cancer.

BACKGROUND: Allogeneic red blood cells (RBCs) have the potential to impact the immunosurveillance of the recipient and may therefore increase the risk of recurrence after cancer surgery. In this article the relationship between perioperative RBC transfusion and the risk of recurrence after ovarian cancer surgery is examined. STUDY DESIGN AND METHODS: This is a retrospective cohort analysis of a prospective database of patients who underwent surgery due to primary ovarian cancer between 2006 and 2014 and who had no residual disease after surgery. Patients who did and did not receive perioperative RBC transfusion were compared. The primary endpoint was progression-free survival (PFS). Propensity score matching (PSM) and Cox proportional hazards regression (CPH) was used to control for between-group differences of prognostic determinants. RESULTS: A total of 529 patients with a median follow-up of 51.4 months (95% CI, 46.1-56.5) were eligible for analysis. Of those, 408 patients (77.1%) received allogeneic, leukoreduced RBCs with a median of 4 units (IQR, 2-6) per patient. There was a strong selection bias of prognostic determinants between patients with and without transfusion. In unadjusted analysis, transfusion of RBCs was associated with an increased risk of cancer recurrence (hazard ratio [HR] of PFS 2.71 [95% CI, 1.94-3.77], p < 0.001). After bias reduction, transfusion of RBCs was no longer associated with an increased risk of cancer recurrence, neither in PSM-adjusted (HR 1.03 [95% CI, 0.59-1.80], p = 0.91), nor in multivariable CPH-adjusted analysis (HR 1.26 [95% CI, 0.85-1.86], p = 0.23). CONCLUSION: Perioperative transfusion of RBCs did not increase the risk of recurrence after ovarian cancer surgery.

Duration of storage influences the hemoglobin rising effect of red blood cells in patients undergoing major abdominal surgery.

BACKGROUND: After transfusion of senescent red blood cells (RBCs) a considerable fraction is rapidly cleared from the recipients' circulation. Thus, transfusion of senescent RBCs may be less effective in terms of increasing hemoglobin concentration (cHb) after transfusion. STUDY DESIGN AND METHODS: Data were retrospectively obtained in patients who underwent major abdominal surgery between 2006 and 2012. Patients were eligible if they received RBCs during surgery and had at least two arterial blood gas analyses performed. The primary endpoint was the increase of recipients' cHb related to the transfusion of 1 unit of RBCs with respect to different storage periods. Four storage periods were defined according to the distribution of RBC storage of the study population. General estimating equation was used for calculation of the primary endpoint and to adjust for confounding variables. RESULTS: A total of 598 arterial blood gas samples from 120 patients, receiving 429 RBC units, were analyzed. Mean (±SD) RBC storage was 21 (±9) days. RBC storage duration and the increase in recipients' cHb were inversely and gradually related; that is, the older the RBCs, the lower the increase in the recipients' cHb after transfusion (storage < 12 days, ΔcHb per unit RBCs +0.82 [95% confidence interval, 0.42-1.21] g/dL, p < 0.01; storage 12-20 days, +0.66 [0.46-0.86] g/dL, p < 0.01; storage 21-29 days, +0.56 [0.33-0.79] g/dL, p < 0.01; storage ≥30 days, +0.39 [0.07 to 0.71] g/dL, p = 0.02). CONCLUSION: Transfusion of senescent RBCs increased cHb less effectively than transfusion of fresher RBCs.

Balanced 10% hydroxyethyl starch compared with balanced 6% hydroxyethyl starch and balanced crystalloid using a goal-directed hemodynamic algorithm in pancreatic surgery: A randomized clinical trial.

BACKGROUND: While hydroxyethyl starch (HES) solutions are not recommended any longer in critically ill patients, data on efficacy and safety during surgery are still limited. METHODS: In a randomized controlled trial 63 patients were assigned to receive 10% HES (130/0.42), 6% HES (130/0.42), or crystalloid within a goal-directed hemodynamic algorithm during pancreatic surgery. The primary endpoints were intraoperative volume of HES and time until fully on oral diet. RESULTS: The trial was terminated early upon recommendation of an independent data monitoring committee due to futility for efficacy at a planned interim analysis. The intraoperative volume of HES was not different between 10% and 6% HES group (2000 [1500; 2250] vs 2250 [1750; 3000] mL, P=.059). However, considering an inhomogeneity of patient's body weight between HES groups, there was a significant difference in intraoperative volume of HES between 10% and 6% group after adjusting for patient's body weight (24.0 [21.6; 28.3] vs 33.3 [28.2; 46.2] mL kg BW, P = .002). Patients in the HES groups required less additional fluid after dose limit than those in the crystalloid group, resulting in lower intraoperative net balances. The time until fully on oral diet was not different between all study groups. Applying KDIGO oliguria criterion, patients receiving 10% HES had more AKI compared to patients receiving crystalloids (86.7 vs 45.0%, P = .010), whereas those receiving 6% HES and crystalloids did not differ (58.8 vs 45.0%, P = .253). Further explorative analyses using a gray-zone approach indicated that patients receiving 6% HES below 18.8 mL kg will not experience AKI with near certainty. CONCLUSIONS: After adjusting for patient's body weight, patients receiving 6% HES required more volume of HES than patients receiving 10% HES. The relation of 140% represents very well the volume effect of a hyperoncotic 10% HES solution. Nonetheless, both HES solutions were similarly effective in reducing intraoperative fluid administration compared with crystalloid, but this did not result into differences in gastrointestinal outcomes. Patients receiving 10% HES showed an increased rate of AKI, whereas those receiving 6% HES and crystalloid did not differ. However, 6% HES should not be applied beyond 18 mL kg during surgery.

Diagnostic value of plasma NGAL and intraoperative diuresis for AKI after major gynecological surgery in patients treated within an intraoperative goal-directed hemodynamic algorithm: A substudy of a randomized controlled trial.

Data on early markers for acute kidney injury (AKI) after noncardiovascular surgery are still limited. This study aimed to determine the diagnostic value of plasma neutrophil-gelatinase-associated lipocalin (pNGAL) and intraoperative diuresis for AKI in patients undergoing major abdominal surgery treated within a goal-directed hemodynamic algorithm.This study is a post-hoc analysis of a randomized controlled pilot trial comparing intravenous solutions within a hemodynamic goal-directed algorithm based on the esophageal Doppler in patients undergoing epithelial ovarian cancer surgery. The diagnostic value of plasma NGAL obtained at ICU admission and intraoperative diuresis was determined with respect to patients already meeting AKI criteria 6 hours after surgery (AKI6h) and to all patients meeting AKI criteria at least once during the postoperative course (AKItotal). AKI was diagnosed by the definition of the Kidney Disease Improving Global Outcome (KDIGO) group creatinine criteria and was screened up to postoperative day 3. Receiver operating characteristic curves including a gray zone approach were performed.A total of 48 patients were analyzed. None of the patients had increased creatinine levels before surgery and 14 patients (29.2%) developed AKI after surgery. Plasma NGAL was predictive for AKI6h (AUCAKI6h 0.832 (95% confidence interval [CI], 0.629-0.976), P = .001) and AKItotal (AUCAKItotal 0.710 (CI 0.511-0.878), P = .023). The gray zones of pNGAL calculated for AKI6h and AKItotal were 210 to 245 and 207 to 274 ng mL, respectively. The lower cutoffs of the gray zone at 207 and 210 ng mL had a negative predictive value (NPV) (i.e., no AKI during the postoperative course) of 96.8% (CI 90-100) and 87.1% (CI 78-97), respectively. Intraoperative diuresis was also predictive for AKI6h (AUCAKI6h 0.742 (CI 0.581-0.871), P = .019) with a gray zone of 0.5 to 2.0 mL kg h. At the lower cutoff of the gray zone at 0.5 mL kg h, corresponding to the oliguric threshold, the NPV was 84.2% (78-92).This study indicates that pNGAL can be used as an early marker to rule out AKI occurring within 3 days after major abdominal surgery. Intraoperative diuresis can be used to rule out AKI occurring up to 6 hours after surgery. TRIAL REGISTRATION: ISRCTN 53154834.

Comparison of bedside assessed arm and leg fluid filtration determined by venous congestion plethysmography in perioperative cancer patients: An observational study investigating agreement.

In recent years, pathophysiology and clinical impact of microvascular fluid filtration has regained interest. As the latest data in surgical patients have been published almost 20 years ago, there is need for further research to better understand fluid filtration during the perioperative period. Venous congestion plethysmography (VCP) provides a rapid and noninvasive method, which has been shown suitable for the assessment of fluid filtration in limbs. Fluid filtration assessed by VCP can be obtained from forearm and calf measurement sites, while in many clinical situations a reduced access to the patient often restricts the measurements to patient's forearm. We aimed to investigate if fluid filtration obtained from forearm and calf measurement site is interchangeable in nonsedated perioperative patients.Fluid filtration by VCP was obtained simultaneously from forearm and calf in patients with ovarian cancer at 4 time points during the perioperative course and assessed by the difference of volume changes of the limb between third and sixth minutes (VC6-3min) during venous congestion. VC6-3min obtained from forearm and calf measurement sites was compared with respect to agreement and evaluated regarding the association with the presence of leg edema.A total of 74 paired measurements were analyzed in 29 patients. Forearm VC6-3min was significantly higher than calf VC6-3min (median [25th; 75th quartile], 0.6 (0.4; 0.9) vs 0.4 [0.3; 0.6] %, P = 0.008). Bland-Altman and Polar analysis revealed a poor agreement between forearm and calf VC6-3min at predefined time points and changes of VC6-3min during the perioperative course (bias +0.23%, limits of agreement [LOA] -1.1% to 1.6%; angular bias -2.5°, radial LOA -82° to +77°). Forearm VC6-3min was significantly increased in patients with presence of leg edema (0.7 (0.5; 1.0) vs 0.5 (0.4; 0.6) %, P < 0.001) while calf VC6-3min did not differ in patients with and without edema.This study indicates that forearm and calf measurement sites are not interchangeable when bedside assessing fluid filtration by VCP in nonsedated perioperative patients. Considering that only forearm fluid filtration was related to the presence of edema, forearm measurement site should be chosen as a primary site for assessing fluid filtration.

Hemodynamic Consequences of Malignant Ascites in Epithelial Ovarian Cancer Surgery*: A Prospective Substudy of a Randomized Controlled Trial.

Malignant ascites (MA) is most commonly observed in patients scheduled for epithelial ovarian cancer (EOC) surgery and is supposed as a major risk factor promoting perioperative hemodynamic deterioration. We aimed to assess the hemodynamic consequences of MA on systemic circulation in patients undergoing cytoreductive EOC surgery.This study is a predefined post-hoc analysis of a randomized controlled pilot trial comparing intravenous solutions within a goal-directed algorithm to optimize hemodynamic therapy in patients undergoing cytoreductive EOC surgery. Ascites was used to stratify the EOC patients prior to randomization in the main study. We analyzed 2 groups according to the amount of ascites (NLAS: none or low ascites [<500 mL] vs HAS: high ascites group [>500 mL]). Differences in hemodynamic variables with respect to time were analyzed using nonparametric analysis for longitudinal data and multivariate generalized estimating equation adjusting the analysis for the randomized study groups of the main study.A total of 31 patients in the NLAS and 16 patients in the HAS group were analyzed. Although cardiac output was not different between groups suggesting a similar circulatory blood flow, the HAS group revealed higher heart rates and lower stroke volumes during surgery. There were no differences in pressure-based hemodynamic variables. In the HAS group, fluid demands, reflected by the time to reindication of a fluid challenge after preload optimization, increased steadily, whereas stroke volume could not be maintained at baseline resulting in hemodynamic instability after 1.5 h of surgery. In contrast, in the NLAS group fluid demands were stable and stroke volume could be maintained during surgery. Clinically relevant associations of the type of fluid replacement with hemodynamic consequences were particularly observed in the HAS group, in which transfusion of fresh frozen plasma (FFP) was associated to an improved circulatory flow and reduced vasopressor and fluid demands, whereas the administration of artificial infusion solutions was related to opposite effects.Malignant ascites >500 mL implies increased fluid demands and substantial alterations in circulatory blood flow during cancer surgery. Fresh frozen plasma transfusion promotes recovering hemodynamic stability in patients with malignant ascites >500 mL, in whom artificial infusion solutions could not prevent from hemodynamic deterioration.

Haemodynamic Optimization by Oesophageal Doppler and Pulse Power Wave Analysis in Liver Surgery: A Randomised Controlled Trial.

UNLABELLED: Liver surgery is still associated with a high rate of morbidity and mortality. We aimed to compare different haemodynamic treatments in liver surgery. In a prospective, blinded, randomised, controlled pilot trial patients undergoing liver resection were randomised to receive haemodynamic management guided by conventional haemodynamic parameters or by oesophageal Doppler monitor (ODM, CardioQ-ODM) or by pulse power wave analysis (PPA, LiDCOrapid) within a goal-directed algorithm adapted for liver surgery. The primary endpoint was stroke volume index before intra-operative start of liver resection. Secondary endpoints were the haemodynamic course during surgery and postoperative pain levels. Due to an unbalance in the extension of the surgical procedures with a high rate of only minor procedures the conventional group was dropped from the analysis. Eleven patients in the ODM group and 10 patients in the PPA group were eligible for statistical analysis. Stroke volume index before start of liver resection was 49 (37; 53) ml/m2 and 48 (41; 56) ml/m2 in the ODM and PPA group, respectively (p=0.397). The ODM guided group was haemodynamically stable as shown by ODM and PPA measurements. However, the PPA guided group showed a significant increase of pulse-pressure-variability (p=0.002) that was not accompanied by a decline of stroke volume index displayed by the PPA (p=0.556) but indicated by a decline of stroke volume index by the ODM (p<0.001). The PPA group had significantly higher postoperative pain levels than the ODM group (p=0.036). In conclusion, goal-directed optimization by ODM and PPA showed differences in intraoperative cardiovascular parameters indicating that haemodynamic optimization is not consistent between the two monitors. TRIAL REGISTRATION: ISRCTN.com ISRCTN64578872.