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Background: Hydroxyethyl starch (HES) 130 is a frequently used fluid to replace intravascular losses during surgery or trauma. In the past years, several trials performed in critically ill patients have raised questions regarding the safety of this product. Our aim in this meta-analysis was to evaluate the safety and efficacy of 6% HES during surgery and in trauma., Methods: This systematic review and meta-analysis was registered at PROSPERO (CRD42018100379). We included 85 fully published articles from 1980 to June 2018 according to the protocol and three additional recent articles up to June 2020 in English, French, German, and Spanish reporting on prospective, randomised, and controlled clinical trials applying volume therapy with HES 130/0.4 or HES 130/0.42, including combinations with crystalloids, to patients undergoing surgery. Comparators were albumin, gelatin, and crystalloids only. A meta-analysis could not be performed for the two trauma studies as there was only one study that reported data on endpoints of interest., Results: Surgical patients treated with HES had lower postoperative serum creatinine (P<0.001) and showed no differences in renal dysfunction, renal failure, or renal replacement therapy. Although there was practically no further difference in the colloids albumin or gelatin, the use of HES improved haemodynamic stability, reduced need for vasopressors (P<0.001), and decreased length of hospital stay (P<0.001) compared with the use of crystalloids alone., Conclusions: HES was shown to be safe and efficacious in the perioperative setting. Results of the present meta-analysis suggest that when used with adequate indication, a combination of intravenous fluid therapy with crystalloids and volume replacement with HES as colloid has clinically beneficial effects over using crystalloids only., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Sufficient tissue oxygen tension may reduce the risk of postoperative wound infections. Supplemental administration of crystalloids increases subcutaneous oxygen tension (P sq o 2 ). Colloids remain longer in the intravascular system and might therefore increase P sq o 2 even more than crystalloids. Therefore, we tested the hypothesis that goal-directed colloid administration increases the perioperative P sq o 2 more compared with crystalloid administration., Methods: We randomly assigned 80 patients undergoing elective open abdominal surgery to receive fluid boluses of hydroxyethyl starch (HES) or lactated Ringer's (LR) solution guided by oesophageal Doppler. Intraoperative P sq o 2 was measured in the upper arm. After operation, we measured the P sq o 2 in the upper arm and in the surgical wound., Results: Forty patients were enrolled in each group. Patients in the colloid group received HES solution 750 ml (500; 1000) and LR solution 1500 ml (1000; 2000). Patients in the crystalloid group received LR solution 2825 ml (2000; 3960). The goal-directed administration of colloids did not improve intraoperative P sq o 2 in the arm compared with crystalloid administration (11.4 kPa [9.0; 16.6] vs 11.2 kPa [8.6; 15.1], respectively; P=0.58). Postoperative arm P sq o 2 was 8.1 kPa (6.5; 9.6) in the colloid group and 7.3 kPa (5.7; 9.1) in the crystalloid group (P=0.11). Postoperative surgical wound P sq o 2 was 10.7 kPa (8.6; 13.4) in the colloid group and 10.1 kPa (8.1; 12.7) in the crystalloid group (P=0.68)., Conclusions: Goal-directed colloid administration did not increase P sq o 2 compared with goal-directed crystalloid administration in patients undergoing open abdominal surgery., Clinical Trial Registration: NCT00517127., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The approach to i.v. fluid therapy for hypovolaemia may significantly influence outcomes for patients who experience a systemic inflammatory response after sepsis, trauma, or major surgery. Currently, there is no single i.v. fluid agent that meets all the criteria for the ideal treatment for hypovolaemia. The physician must choose the best available agent(s) for each patient, and then decide when and how much to administer. Findings from large randomized trials suggest that some colloid-based fluids, particularly starch-based colloids, may be harmful in some situations, but it is unclear whether they should be withdrawn from use completely. Meanwhile, crystalloid fluids, such as saline 0.9% and Ringer's lactate, are more frequently used, but debate continues over which preparation is preferable. Perhaps most importantly, it remains unclear how to select the optimal dose of fluid in different patients and different clinical scenarios. There is good reason to believe that both inadequate and excessive i.v. fluid administration may lead to poor outcomes, including increased risk of infection and organ dysfunction, for hypovolaemic patients. In this review, we summarize the current knowledge on this topic and identify some key pitfalls and some areas of agreed best practice., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Vasopressor administration is recommended to prevent hypotension during spinal anaesthesia (SA) for elective Caesarean delivery. We aimed to test the superior efficacy and ensure safety of a hydroxyethyl starch (HES) vs a Ringer's lactate (RL) preloading, when combined with a phenylephrine-based prophylaxis., Methods: A total of 167 healthy parturients undergoing elective Caesarean delivery under SA were included in this multicentre, randomized, double-blind study. Patients received 500 ml of 6% HES (130/0.4)+500 ml of RL (HES group) or 1000 ml of RL (RL group) i.v. before SA. After SA, i.v. phenylephrine boluses were titrated when systolic arterial pressure (SAP) was below 95% of baseline. The primary outcome was the incidence of maternal hypotension (SAP <80% of baseline)., Results: The incidence of both hypotension and symptomatic hypotension (i.e. with dizziness, nausea/vomiting, or both) was significantly lower in the HES group vs the RL group: 36.6% vs 55.3% (one-sided P=0.025) and 3.7% vs 14.1%. There was no significant difference in total phenylephrine requirements [median (range): 350 (50-1800) vs 350 (50-1250) µg]. The decrease in maternal haemoglobin value the day after surgery was similar in the two groups [1.2 (1.0) vs 1.0 (0.9) g dl(-1)]. There was no detectable placental transfer of HES in six umbilical cord blood samples analysed in the HES group. Neonatal outcomes were comparable between the groups., Conclusions: Compared with a pure RL preloading, a mixed HES-RL preloading significantly improved prevention of both hypotension and symptomatic hypotension based on early phenylephrine bolus administration and did not induce adverse effects., Clinical Trial Registration: NCT00694343 (http://clinicaltrials.gov)., (© The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Trials suggest that the use of i.v. hydroxyethyl starch (HES) solutions is associ-ated with increased risk of death and acute kidney injury (AKI) in critically ill patients. It is uncertain whether similar adverse effects occur in surgical patients., Methods: Systematic review and meta-analysis of trials in which patients were randomly allocated to 6% HES solutions or alternative i.v. fluids in patients undergoing surgery. Ovid Medline, Embase, Cinhal, and Cochrane Database of Systematic Reviews were searched for trials comparing 6% HES with clinically relevant non-starch comparator. The primary end-point was hospital mortality. Secondary endpoints were requirement for renal replacement therapy (RRT) and author-defined AKI. Pre-defined subgroups were cardiac and non-cardiac surgery., Results: Four hundred and fifty-six papers were identified; of which 19 met the inclusion criteria. In total, 1567 patients were included in the analysis. Dichotomous outcomes were expressed as a difference of proportions [risk difference (RD)]. There was no difference in hospital mortality [RD 0.00, 95% confidence interval (CI) -0.02, 0.02], requirement for RRT (RD -0.01, 95% CI -0.04, 0.02), or AKI (RD 0.02, 95% CI -0.02 to 0.06) between compared arms overall or in predefined subgroups., Conclusions: We did not identify any differences in the incidence of death or AKI in surgical patients receiving 6% HES. Included studies were small with low event rates and low risk of heterogeneity. Narrow CIs suggest that these findings are valid. Given the absence of demonstrable benefit, we are unable to recommend the use of 6% HES solution in surgical patients.

Background: Hydroxyethyl starch (HES) solutions alter blood coagulation, mainly platelet function and fibrinogen polymerization. Haemostasis can also be impaired by dilutional-hyperchloraemic acidosis induced by the HES carrier solution. We hypothesized that a saline-based tetrastarch carrier solution impairs parameters of blood coagulation more than a balanced carrier solution., Methods: The study was designed as a prospective, double-blinded, randomized, cross-over trial in healthy male volunteers. At intervals of at least 10 days, 13 subjects received 20 ml kg(-1) of balanced or saline-based tetrastarch over 2 h. Blood was subjected to blood gas analysis, assessment of platelet function [with multiple electrode aggregometry (MEA)], and clot formation (with rotational thrombelastometry)., Results: Maximum aggregation in response to adenosine diphosphate (ADP) decreased after saline-based HES infusion, but not after balanced solution-based HES infusion. ADP-induced platelet aggregation was significantly lower after saline-based HES compared with baseline (21%; P<0.025) and compared with balanced solution-based HES (17%; P<0.025). There were no significant changes in platelet aggregation induced by thrombin receptor-activating peptide and in any parameter of rotational thrombelastometry. Chloride concentrations were significantly higher after saline-based HES compared with balanced solution-based HES., Conclusions: The carrier solution for HES up to 20 ml kg(-1) had little impact on platelet aggregation or clot formation as assessed by MEA and rotational thrombelastometry, respectively. Further clinical studies are required to verify this finding in patients and to correlate results of whole blood aggregometry and rotational thrombelastometry with perioperative bleeding and transfusion requirements.

Background: This study aims to study changes in blood volume after 1 litre infusions of Gelofusine(®) [4% succinylated gelatine in 0.7% saline, weight-average molecular weight (MWw) 30 kDa] and Voluven(®) (6% hydroxyethyl starch in 0.9% saline, MWw 130 kDa) in the presence of increased capillary permeability., Methods: In this randomized double-blind study, adults undergoing laparoscopic cholecystectomy received 1 litre of Gelofusine(®) (n=12) or Voluven(®) (n=13) over 1 h at the induction of anaesthesia. No other fluids were given. Haematocrit, serum electrolytes, and osmolality were measured before infusion and hourly thereafter for 4 h. Changes in blood volume were calculated from changes in haematocrit. The urinary albumin:creatinine ratio (ACR) was measured before and after operation., Results: Baseline parameters before the two infusions were similar (P>0.050). The urinary ACR increased significantly after operation after Gelofusine(®) (P=0.011) and Voluven(®) (P=0.002), indicating increased capillary permeability. Voluven(®) produced a greater increase in serum chloride concentration (P=0.028) and a larger decrease in strong ion difference (P=0.009) than Gelofusine(®). There were no significant differences in changes in haematocrit (P=0.523) and blood volume (P=0.404) over the study period when the two infusions were compared, nor were there any differences in serum sodium, potassium, bicarbonate, and albumin concentrations (P>0.050). Urine output, sodium concentration, and osmolality were similar after the two infusions (P>0.050)., Conclusions: The blood volume-expanding effects of the two colloids were not significantly different, despite the increase in postoperative urinary ACR and the 100 kDa difference in MWw.

Background: Recombinant activated factor VII (rFVIIa) is indicated in bleeding patients when a life-threatening haemorrhage occurs. Prothrombin complex concentrates (PCCs) are also used for this indication in several countries, without any evidence-based rationale. Our objective was to compare the efficacy and safety of PCC and rFVIIa in a model of bleeding and thrombosis in haemodiluted rabbits., Methods: Forty-eight rabbits were randomly allocated into four groups: a control group and three treatment groups, in which animals were haemodiluted with hydroxyethyl starch 130/0.4 then administered either placebo, 160 µg kg(-1) rFVIIa, or 25 IU FIX kg(-1) PCC. The primary endpoint was hepatosplenic (HS) blood loss. Secondary endpoints were: (i) ear immersion bleeding time (IBT); (ii) thrombosis risk assessed by cyclic flow reductions (CFRs) of the carotid artery; and (iii) activated partial thromboplastin time (aPTT), and progress of thrombin activity., Results: Haemodilution increased HS blood loss by 80% from 8 g (5-16) (control group) to 14 g (8-45) (placebo group) (P<0.01). HS blood loss was not different in animals receiving either rFVIIa [10 g (7-22)] or PCC [15 g (4-33)] (P<0.05) compared with the placebo group. Ear IBT was reduced with both rFVIIa and PCC. CFRs disappeared after haemodilution and were not restored with any treatment. Although PCC nearly doubled the total amount of thrombin generated, no significant change in the total amount of thrombin was seen in animals treated with rFVIIa., Conclusions: Neither rVIIa nor PCC reduced HS blood loss, whereas they both controlled the bleeding time, without increasing the thrombosis risk.

Background: Colloids are often used after cardiac surgery as intravascular volume replacement therapy. Cardiac surgical patients have an increased risk of bleeding. Both hydroxyethylstarch (HES) and gelatin solutions impair haemostasis. We examined the impact and dose effect on coagulation of HES 130/0.4, gelatin, or Ringer's acetate solutions after cardiac surgery., Methods: Forty-five patients received three boluses (each 7 ml kg(-1)) of either 6% HES 130/0.4, 4% gelatin, or Ringer's acetate solution after elective cardiac surgery. The infusion of study solution was continued in the dose 7 ml kg(-1) over the following 12 h. The total dose of study solution was 28 ml kg(-1). Hypovolaemia was treated with Ringer's acetate. Modified thromboelastometry was performed to detect coagulation disorders., Results: Clot formation time was prolonged and clot strength decreased after infusion of 7, 14, and 21 ml kg(-1) of either colloid compared with the Ringer's acetate group. After infusion of 14 and 21 ml kg(-1) of Ringer's acetate, clot strength was slightly, but significantly, increased. On the first postoperative morning, clot strength was still decreased in the gelatin group in comparison with the Ringer's acetate group. Neither HES nor gelatin induced fibrinolysis. Chest tube drainage was comparable between all groups., Conclusions: Even a small dose of HES 130/0.4 or gelatin impaired clot strength after cardiac surgery in a dose-dependent fashion, but neither colloid increased blood loss.

Background: The effects of hydroxyethylstarch (HES) 130/0.4 6% and gelatin 4% on inflammation, endothelial integrity, and renal function after cardiac surgery were compared., Methods: Sixty patients aged >80 yr undergoing cardiac surgery were randomized to receive gelatin (n=30) or HES 130/0.4 (n=30). The colloid was used in the priming of the cardiopulmonary bypass circuit (500 ml) and for volume replacement until the second postoperative day (POD). Serum creatinine, creatinine clearance, IL-6, IL-10, intercellular adhesion molecule-1 (sICAM-1), urinary glutathione transferase-alpha, and neutrophil gelatinase-associated lipocalin (NGAL) were measured perioperatively. Serum creatinine was also reported approximately 60 days after discharge., Results: The mean(sd) volume of gelatin infused was 4180(440) ml, which was greater than the volume of HES infused 2910(330) ml (P=0.002). The mean(sd) volume of serum creatinine on the first POD was 151(24) micromol litre(-1) in the gelatin group and 126(13) micromol litre(-1) in the HES group (P=0.004). Values for the second POD were 161(0.26) and 133(16) micromol litre(-1), respectively (P=0.004). Creatinine clearance was lower in the gelatin group on the first POD [37(7) vs 46(8) ml min(-1) 1.73 m2 (P=0.004)] and the second POD [32(8) vs 45(10) ml min(-1) 1.73 m2 (P=0.002)]. Kidney function approximately 60 days after discharge did not differ between the groups. IL-6, IL-10, and sICAM-1 were significantly lower in the HES group than in the gelatin group on the first and second PODs. Urinary alpha-GST increased in both groups to a comparable extent. Urinary NGAL concentrations were higher in the gelatin than in the HES patients 5 h after surgery and on the first and second PODs., Conclusions: In cardiac surgery patients aged >80 years, volume therapy with HES 130/0.4 6% was associated with less marked changes in kidney function and a less marked endothelial inflammatory response than gelatin 4%.

Background: This study investigated whether haemodilution-enhanced coagulation can be demonstrated under regional anaesthesia, whether this occurs before surgery, and whether the fluid used influences the effect., Methods: Patients were randomly allocated to receive either crystalloid or colloid intravenous fluid. An epidural was administered. Samples of venous blood were taken before fluid administration, after completion of the epidural and initial fluid load, during surgery before heparin, and after 24 h. Thrombelastograph analysis was performed, and full blood count, international normalised ratio, activated partial thromboplastin time, D-dimers and thrombin-antithrombin complex were measured., Results: In the crystalloid group, enhanced coagulation compared with baseline was demonstrated after initial fluid load (mean (SD) r-time 10.1 (4.9) min; P < 0.033; k-time 3.5 (1.7) min; P < 0.01; alpha-angle 54.9 (13.9) degrees; P < 0.01) and before heparin administration (r-time 8.8 (3.9) min; P < 0.01; alpha-angle 54.9 (12.6) degrees; P < 0.02). There was no enhancement of coagulation in the colloid group. There were no changes from baseline after 24 h., Conclusions: This study confirms that the enhanced perioperative coagulation mechanism is related to dilution, rather than surgery, and is triggered by rapid crystalloid haemodilution. Consideration should be given to the use of colloid rather than crystalloid solutions for rapid fluid loading in vasculopathic patients undergoing surgery.

Tissue deposits occur after administration of plasma substitutes. After hydroxyethyl starch (HES), deposits may last for months, causing pruritus and impairment of function. Because elimination of HES deposits has not been demonstrated in humans, we studied 26 patients, for up to 7 yr after HES administration, to assess HES storage. HES dose ranged from 0.34 to 15.00 g kg-1 body weight, and administration intervals from 1 day to 7 yr. Biopsies of the liver, muscle, spleen, intestine or skin were studied using light and electron microscopy and immunohistochemistry. HES storage was dose-dependent, decreased in all organs with time and was greater in patients suffering from pruritus. We conclude that tissue deposition of HES is transitory and dose-dependent, with differences between subjects in severity and duration.

We have studied the effects of two types of volume replacement on the microcirculation in an open, controlled study in 45 patients undergoing aorto-coronary bypass grafting whose pulmonary capillary wedge pressure (PCWP) was less than 5 mm Hg. Hypertonic saline prepared in hydroxyethylstarch solution (HS-HES, n = 15) and 6% HES 200/0.5 solution (6% HES; n = 15) were infused randomly before operation in order to double the PCWP. Patients not given an infusion served as controls (n = 15). Skin microcirculatory blood flow was investigated by laser Doppler flow (LDF) measured simultaneously at the forearm and forehead before and after cardiopulmonary bypass (CPB). Less HS-HES (3.8 (SD 0.3) ml kg-1) than 6% HES-solution (9.7 (1.5) ml kg-1) was necessary to double baseline PCWP. There were no differences in heart rate and mean arterial pressure (MAP) between the groups. Cardiac index (CI) increased significantly in both volume groups (HS-HES max. +54%; 6% HES max. +30%). Systemic vascular resistance (SVR) decreased after infusion of HS-HES (-30%) and after 6% HES(-19%) and remained almost unchanged in the control group. Plasma viscosity decreased after infusion of HS-HES and increased slightly in control patients (+4%). In comparison with the 6% HES and particularly with the control group, LDF was significantly greater after infusion of HS-HES (forearm +80%; forehead +28%). LDF during CPB and thereafter was always greater than baseline values in the HS-HES group, whereas after bypass LDF was reduced in the 6% HES (-5%) and particularly in the control patients (-30%).(ABSTRACT TRUNCATED AT 250 WORDS)