Molecular Weight Hydroxyethyl Starch Research Articles

Efficient granulocyte collection method using high concentrations of medium molecular weight hydroxyethyl starch.

Granulocyte transfusion therapy is a rational therapeutic option for patients with prolonged, severe neutropenia. Although high molecular weight hydroxyethyl starch (hHES) facilitates the separation of red blood cells during granulocyte collection, renal dysfunction has been noted as a potential side effect. HES130/0.4 (Voluven®) is a medium molecular weight HES (mHES) with superior safety profiles compared to hHES. Although HES130/0.4 is reportedly effective in the collection of granulocytes, we lack studies comparing the efficiency of granulocyte collection using HES130/0.4 and hHES. We retrospectively collected the data from 60 consecutive apheresis procedures performed on 40 healthy donors at the Okayama University Hospital between July 2013 and December 2021. All procedures were performed using the Spectra Optia system. Based on the HES130/0.4 concentration in the separation chamber, granulocyte collection methods using HES130/0.4 were classified into m0.46, m0.44, m0.37, and m0.8 groups. We used HES130/0.4 and hHES groups to compare the various sample collection methods. The median granulocyte collection efficiency (CE) was approximately 24.0% and 28.1% in the m0.8 and hHES groups, respectively, which were significantly higher than those in the m0.46, m0.44, and m0.37 groups. One month following granulocyte collection with HES130/0.4, no significant changes were observed in serum creatinine levels compared to those before the donation. Therefore, we propose a granulocyte collection approach employing HES130/0.4, which is comparable to the use of hHES in terms of the granulocyte CE. A high concentration of HES130/0.4 in the separation chamber was considered crucial for granulocyte collection.

A pilot study on impact of use of medium molecular weight hydroxyethyl starch in granulocyte apheresis using Spectra Optia

IntroductionGranulocyte transfusion (GT) is a therapeutic option for prolonged neutropenic patients with severe bacterial or fungal infections. Efficient apheresis based granulocyte collection may be better achieved by infusion of high-molecular-weight (HMW) hydroxyethyl starch (HES). But multiple adverse incidents have been reported with HMW-HES. Due to availability issues and adverse incidents related to it, use of HMW-HES has become limited. Few studies have mentioned about medium molecular weight HES (MMW-HES) (130 kDa) as efficient for this purpose with minimal adverse incidents. So, the aim was to assess the impact of the use of MMW-HES in granulocyte apheresis when using Spectra Optia. MethodologyIn this observational study, donors who received MMW-HES during granulocyte harvest were included in HES group and another group who did not receive HES were grouped as non-HES. Injection G-CSF 10 microgram/kg and tablet dexamethasone 8 mg given 12 h before for non-HES group and 6 – 8 h in case of HES group blood donors. Number of adverse incidents observed were noted. Donor/procedure parameters were compared using Mann–Whitney U test / unpaired t test. ResultsGranulocyte yield was significantly higher in the HES group (2.5 × 1010 vs. 1.75 × 1010, p < 0.01) and was attributed to the difference in collection efficiency (22.61% vs. 10.15%, p < 0.01). There were no significant differences in occurrence of adverse events between HES and non-HES groups. ConclusionOur results clearly indicate that sufficient number of granulocytes can be harvested by using MMW-HES in Spectra Optia apheresis system even after short interval between mobilization to harvest.

Спосіб інтенсивної терапії загального переохолодження

Актуальність. Загальне переохолодження є однією з найбільш складних проблем сучасної інтенсивної терапії критичних станів. Метою роботи були вивчення ефективності розробленого способу інтенсивної терапії загального переохолодження, оцінка його впливу на швидкість корекції патофізіологічних зрушень і рівень летальності пацієнтів у критичному або термінальному стані. Матеріали та методи. Обстежено 50 пацієнтів (середній вік — 43,00 ± 3,62 року), стан яких був оцінений відповідно до класифікації стадій загального переохолодження Швейцарського товариства гірської медицини. Пацієнти були розподілені на 2 групи: I група (n = 25) — з активним зігріванням системою конвекційного обігріву Warm Air 135 (CSZ, США) та інфузією 37 °С кристалоїдних розчинів у таких дозах: при легкому ступені — 20–30 мл/кг; помірного та тяжкого ступеня — 50–70 мл/кг, із включенням колоїдних розчинів. II група (n = 25) — із пасивним зігріванням і стандартним комплексом інтенсивної терапії, що включав інфузію кристалоїдних і колоїдних розчинів кімнатної температури в дозі 20–30 мл/кг. Вивчалися езофагальна і тімпанітна температури, показники гемодинаміки (артеріальний тиск, частота серцевих скорочень, середній артеріальний тиск), ступінь неврологічного дефіциту за шкалою коми Глазго, швидкість зігрівання. Результати. Вихідна температура ядра тіла у I групі становила 29,03 ± 2,76 °С, у II групі — 31,50 ± 1,97 °С. Мінімальне та максимальне значення температури ядра тіла в I групі становили 24,3 і 33,6 °С; у II — 27,2 і 34,5 °С відповідно. Початковий рівень середнього артеріального тиску становив у I групі 49,86 ± 20,71 мм рт.ст., у II — 70,45 ± 11,72 мм рт.ст.; через 48 годин — 76,65 ± 12,27 мм рт.ст. та 60,82 ± 36,39 мм рт.ст. відповідно. Швидкість досягнення нормотермії (36,0 °С) у I і II групах становила 6,48 ± 3,47 години та 9,20 ± 6,52 години відповідно. Рівень летальності в I групі — 12 %, у II — 48 %, указані відмінності були вірогідними. Висновки. Використання вказаного вище способу інтенсивної терапії загального переохолодження дозволяє знизити летальність на 25 %.

Resuscitation fluid types in sepsis, surgical, and trauma patients: a systematic review and sequential network meta-analyses

BackgroundCrystalloids and different component colloids, used for volume resuscitation, are sometimes associated with various adverse effects. Clinical trial findings for such fluid types in different patients’ conditions are conflicting. Whether the mortality benefit of balanced crystalloid than saline can be inferred from sepsis to other patient group is uncertain, and adverse effect profile is not comprehensive. This study aims to compare the survival benefits and adverse effects of seven fluid types with network meta-analysis in sepsis, surgical, trauma, and traumatic brain injury patients.MethodsSearched databases (PubMed, EMBASE, and Cochrane CENTRAL) and reference lists of relevant articles occurred from inception until January 2020. Studies on critically ill adults requiring fluid resuscitation were included. Intervention studies reported on balanced crystalloid, saline, iso-oncotic albumin, hyperoncotic albumin, low molecular weight hydroxyethyl starch (L-HES), high molecular weight HES, and gelatin. Network meta-analyses were conducted using random-effects model to calculate odds ratio (OR) and mean difference. Risk of Bias tool 2.0 was used to assess bias. Confidence in Network Meta-Analysis (CINeMA) web application was used to rate confidence in synthetic evidence.ResultsFifty-eight trials (n = 26,351 patients) were identified. Seven fluid types were evaluated. Among patients with sepsis and surgery, balanced crystalloids and albumin achieved better survival, fewer acute kidney injury, and smaller blood transfusion volumes than saline and L-HES. In those with sepsis, balanced crystalloids significantly reduced mortality more than saline (OR 0.84; 95% CI 0.74–0.95) and L-HES (OR 0.81; 95% CI 0.69–0.95) and reduced acute kidney injury more than L-HES (OR 0.80; 95% CI 0.65–0.99). However, they required the greatest resuscitation volume among all fluid types, especially in trauma patients. In patients with traumatic brain injury, saline and L-HES achieved lower mortality than albumin and balanced crystalloids; especially saline was significantly superior to iso-oncotic albumin (OR 0.55; 95% CI 0.35–0.87).ConclusionsOur network meta-analysis found that balanced crystalloids and albumin decreased mortality more than L-HES and saline in sepsis patients; however, saline or L-HES was better than iso-oncotic albumin or balanced crystalloids in traumatic brain injury patients.Trial registrationPROSPERO website, registration number: CRD42018115641).

Successful granulocyte apheresis using medium molecular weight hydroxyethyl starch.

Granulocyte transfusion (GTX) is a therapeutic option for severe bacterial or fungal infection in patients with sustained neutropenia after chemotherapy or stem cell transplantation. However, high molecular weight hydroxyethyl starch (HES), which has been used for selective sedimentation of red blood cells during apheresis, is not easily available in many countries including Japan. In this study, we evaluated the efficiency of granulocyte collection using medium molecular weight HES (130kDa) in combination with the Spectra Optia apheresis system. Apheresis was performed for 2 consecutive days from seven donors and the mean total neutrophil yield from the first and second apheresis was 5.27 ± 3.10 × 1010 and 2.91 ± 2.92 × 1010, respectively. Infusion of concentrates from the first apheresis resulted in a significant neutrophil count increase and concentrates from the second apheresis were enough for maintenance of the neutrophil counts in all the recipients. Although the number of cases is limited, our results clearly show that sufficient number of granulocytes can be harvested by using medium molecular weight HES and this strategy is a safe and effective clinical practice in countries where high molecular weight HES is not available.

Modern opportunities for the burn shock resuscitation

Burn shock is characterized by significant disturbances of central hemodynamic, the presence of microcirculatory disorders due to primary hypovolemia, stress reaction, mass release of inflammatory response mediators, the development of all types of hypoxia, sharp changes in the acid-base state, blood coagulation, dysproteinaemic changes, electrolyte imbalance and quickly leads to the organ dysfunction and multiple organ failure. In this regard, infusion therapy is important in the treatment of burn patients, aimed at blood rheology improving, tissues microcirculation, acidosis correction. Significant homeostatic disturbances during the burn shock acutely determine the infusion solutions choice problem for the hemodynamic disturbance’s correction. The infusion solutions characteristics of for the correction of hemodynamic disturbances during burn shock have been given. Volume deficit recovery for tissue perfusion support and metabolic acidosis correction can be achieved with crystalloid and colloid solutions. Among plasma substitutes, these are low molecular weight hydroxyethyl starch which replaced dextran and native proteins (albumin, plasma). But crystalloids cause swelling. Dextran are not applied now. Albumin transfusion is indicated only for hypoproteinaemia, and plasma for the coagulation factors deficiency. The role of Rheosorbilact in the correction of hypovolemia and metabolic acidosis in patients with burn disease is shown. The presence in clinical practice of domestic polyionic multifunctional solutions of Rheosorbilact gives a positive impetus to the development of new infusion therapy methods.

Intra-operative hydroxyethyl starch is not associated with post-craniotomy hemorrhage.

BackgroundIntraoperative intravascular volume expansion with hydroxyethyl starch-based colloids is thought to be associated with an increased risk of post-craniotomy hemorrhage. Evidence for this association is limited. Associations between resuscitation with hydroxyethyl starch and risk of repeat craniotomy for hematoma evacuation were examined.MethodsUsing a retrospective cohort of neurosurgical patients at Duke University Medical Center between March 2005 and March 2012, patient characteristics were compared between those who developed post-craniotomy hemorrhage and those who did not.ResultsA total of 4,109 craniotomy procedures were analyzed with 61 patients having repeat craniotomy for post-operative hemorrhage (1.5%). The rate of reoperation in the group receiving 6% High Molecular Weight Hydroxyethyl Starch (Hextend®) was 2.6 vs. 1.3% for patients that did not receive hetastarch (P = 0.13). The reoperation rate for those receiving 6% hydroxyethyl Starch 130/0.4 (Voluven®) was 1.4 vs. 1.6% in patients not receiving Voluven (P = 0.85).ConclusionsIn this retrospective cohort, intra-operative hydroxyethyl starch was not associated with an increased risk of post-craniotomy hemorrhage.

Perioperative clinical and economic outcomes associated with replacing first-generation high molecular weight hydroxyethyl starch (Hextend®) with low molecular weight hydroxyethyl starch (Voluven®) at a large medical center

BackgroundSeveral plasma volume expander alternatives exist to enhance intravascular volume status in patients undergoing surgery. The optimal intravascular volume expander in the perioperative setting is currently unknown. Low molecular weight hetastarch, Voluven® (130/0.4), may have a better safety profile than high molecular weight hetastarch, Hextend® (450/0.7). We examined the clinical and cost outcomes of converting from Hextend® to Voluven® in a large tertiary medical center.MethodsUsing a large electronic database, we retrospectively compared two different time periods (2009 and 2010) where the availability of semisynthetic colloids changed. Perioperative and postoperative outcomes including the use of red blood cells (RBC), platelets and coagulation factors, length of stay in the postoperative acute care unit (PACU), intensive care unit and hospital, as well as 30-day and 1-year mortality were compared. In addition, direct acquisition costs of all intraoperative and PACU colloids and crystalloid use were determined.ResultsA total of 4,888 adult subjects were compared of which 1,878 received Hextend® (pre-conversion) and 2,759 received Voluven® (post-conversion) during two separate 7-month periods within 1 year apart, with the remainder receiving Plasmanate. The patients were similar in terms of patient demographics, preoperative comorbidities, ASA status, emergency surgery, types of surgery, intraoperative, and PACU times. In unadjusted outcomes, patients in the Hextend® group received more lactated Ringer’s than in the Voluven® group (2,220 + 1,312 vs. 1,946 ± 1,097 ml; P < 0.0001). The use of albumin (Plasmanate) was reduced from 10.5% of patients to 1.1% when Voluven® was substituted for Hextend®. Unadjusted outcomes were similar in each group including hospital LOS, percent change from baseline creatinine and receipt of intraoperative and PACU blood product administration. However, overall unadjusted total fluid costs were greater in the Voluven® compared to Hextend® group ($116.7 compared to $59.3; P < 0.001).ConclusionsConversion from Hextend® to Voluven® in the perioperative period resulted in decreased albumin use and was not associated with changes in clinical outcomes and short- and long-term mortality. The conversion was associated with decreases in crystalloid use and an increase in colloid use and hence IV fluid acquisition costs in the Voluven® group.

Incidence of acute kidney injury in critically burned patients resuscitated with crystalloid and colloid according to parameters of transpulmonary thermodilution, diuresis and lactic acid

The purpose was to study the incidence of acute kidney injury (AKI) according to RIFLE and AKIN criteria in critically ill burn patients resuscitated with Ringer's solution and supplements of lower molecular weight hydroxyethyl starch (HES)130/0.4/6%, and to determine the relationship between RRT indication and mortality.

This Month In: Anesthesiology

This Month In: Anesthesiology

The effect of colloid formulation on colloid osmotic pressure in horses with naturally occurring gastrointestinal disease.

BackgroundNaturally occurring gastrointestinal disease is an important cause of acute hypoproteinemia in adult horses and hydroxyethyl starch colloid fluid treatment is a component of supportive care in these cases to improve plasma volume and maintain colloid osmotic pressure (COP). The objectives of the present study were to compare 2 formulations of high molecular weight hydroxyethyl starch and their relative effect on COP, acid-base status, and survival of horses with acute hypoproteinemia secondary to gastrointestinal disease.MethodsTwenty adult horses, ≥ 1 year of age, were prospectively enrolled, with informed client consent, if they developed acute hypoproteinemia, defined as a plasma total protein <5.0 g/dL or albumin <2.2 g/dL during hospitalization while undergoing treatment for gastrointestinal disease. Horses were randomly assigned to receive a rapid infusion of either 6% hydroxyethyl starch in 0.9% saline or 6% hydroxyethyl starch in lactated ringers solution at a dose of 10ml/kg. Venous blood gas analysis, COP, and PCV were evaluated before and after colloid administration.ResultsFor both groups, average COP prior to treatment was 11.0 mmHg (9.7 – 12.2 mmHg) and post colloid treatment was 13.2 mmHg (12.0 -14.7 mmHg) [Normal range 18 – 22 mmHg]. COP was significantly increased with colloid treatment (p<0.001) but this increase was not significantly different between treatment groups. Venous pH did not change significantly with treatment. Twelve horses survived to hospital discharge and survival did not differ significantly between treatment groups.ConclusionsPost-treatment COP improved approximately 20% regardless of the formulation used, however, values did not reach the normal range of COP observed in healthy horses. Acid-base parameters were not significantly impacted by either treatment. Further study is needed to determine how these two products compare with regards to other outcome measures. Evaluation of the relative effects of colloid formulation in horses with clinical disease is a future area of interest.

Comparison of low molecular weight hydroxyethyl starch and human albumin as priming solutions in children undergoing cardiac surgery

Human albumin is the conventional cardiopulmonary bypass circuit primer. However, it has high manufacturing costs. Crystalloid and colloid solutions have been developed as alternatives, including a new generation of non-ionic hydroxyethyl starch (HES). The efficacy of hydroxyethyl starch with a 130 molecular weight and substitution degree of 0.4 (hydroxyethyl starch 130/0.4) was compared with human albumin for use in cardiopulmonary bypass surgery in American Society of Anesthesiologists' grade I-II pediatric congenital heart disease patients. Efficacy was evaluated by comparing perioperative hemodynamic parameters, including plasma colloid osmotic pressure, renal function, blood loss, allogeneic blood volumes and plasma volume substitution. The hydroxyethyl starch group exhibited significantly higher preoperative colloid osmotic pressure (p<0.01) and significantly lower operative renal function and postoperative allogeneic blood volumes than the human albumin group. No significant differences were observed in serum creatinine, glucose, hematocrit or lactic acid levels (p>0.05). Our results indicate that hydroxyethyl starch may be a viable alternative to human albumin in pediatric patients undergoing relatively simple cardiopulmonary bypass surgeries.

In vitro evaluation of canine hemostasis following dilution with hydroxyethyl starch (130/0.4) via thromboelastometry

To assess the effects of in vitro hemodilution of canine blood with a low molecular weight hy-droxyethyl starch (HES 130/0.4) by means of thromboelastometry (TEM). In vitro experimental study. University Teaching Hospital. Ten healthy adult staff-owned dogs were sampled for the purposes of the study. Samples were also collected from 45 clinically normal dogs to establish thromboelastometric reference intervals. For each dog whole blood was collected by jugular venipuncture and placed into tubes containing 3.8% trisodium citrate and stored at 37°C. Two standard dilutions (1:4 and 1:10) from canine blood specimens were prepared with HES 130/0.4 and saline 0.9%. The effects of dilution were studied by TEM. No statistically significant differences were observed between the TEM values of the control samples and the samples diluted with saline solution (ratio 1:10 and 1:4). In contrast, hypocoagulability was observed in the samples treated with HES 130/0.4, with more severe effects at 1:4 dilution than at 1:10 dilution. The 1:4 dilution with HES 130/0.4 produced marked alterations: CT (P = 0.035) and CFT (P = 0.0007) on the ex-TEM profile, CT (P = 0.0005) and ML (P = 0.0017) on the fib-TEM profile and CFT (P = 0.0043) on the in-TEM, were all significantly increased (P < 0.05), whereas MCF (P = 0.0042) and alpha angle (P = 0.002) on the in-TEM and MCF (P = 0.011) and alpha angle (P = 0.001) ex-TEM profiles and MCF (P = 0.0001) on the fib-TEM profile were significantly decreased (P < 0.05). Dilution of canine blood with HES 130/0.4 results in a thromboelastometric pattern consistent with hypocoagulation and this effect appears to result from a dose-dependent alteration in fibrinogen concentration and inhibition of platelet function. As this is an in vitro study, further in vivo investigations are necessary to confirm the results.

Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis

To assess shock reversal and required fluid volumes in patients with septic shock. Prospective before and after study comparing three different treatment periods. Fifty-bed single-center surgical intensive care unit. Consecutive patients with severe sepsis. Fluid therapy directed at preset hemodynamic goals with hydroxyethyl starch (predominantly 6% hydroxyethyl starch 130/0.4) in the first period, 4% gelatin in the second period, and only crystalloids in the third period. Main outcome was time to shock reversal (serum lactate <2.2 mmol/L and discontinuation of vasopressor use). Hemodynamic goals were mean arterial pressure >70 mm Hg; ScvO2 <70%; central venous pressure >8 mm Hg. Safety outcomes were acute kidney injury defined by Risk, Injury, Failure, Loss, and End-stage kidney disease criteria and new need for renal replacement therapy. Hemodynamic measures, serum lactate, and creatinine were comparable at baseline in all study periods (hydroxyethyl starch n = 360, gelatin n = 352, only crystalloids n = 334). Severity scores, hospital length of stay, and intensive care unit or hospital mortality did not differ significantly among groups. All groups showed similar time to shock reversal. More fluid was needed over the first 4 days in the crystalloid group (fluid ratios 1.4:1 [crystalloids to hydroxyethyl starch] and 1.1:1 [crystalloids to gelatin]). After day 5, fluid balance was more negative in the crystalloid group. Hydroxyethyl starch and gelatin were independent risk factors for acute kidney injury (odds ratio, 95% confidence interval 2.55, 1.76-3.69 and 1.85, 1.31-2.62, respectively). Patients receiving synthetic colloids received significantly more allogeneic blood products. Shock reversal was achieved equally fast with synthetic colloids or crystalloids. Use of colloids resulted in only marginally lower required volumes of resuscitation fluid. Both low molecular weight hydroxyethyl starch and gelatin may impair renal function.

Retrospective analysis of treatment for severe ovary hyperstimulation syndrome complicated by pleural effusion and ascites

To investigate the effectiveness of treatment for severe ovary hyperstimulation syndrome (OHSS) complicated by pleural effusion and ascites after in vitro fertilization preembryo transfer (IVF-ET). One hundred and thirty-two patients with severe OHSS in our hospital (from January 2007 to December 2010) were retrospectively analyzed and the efficacy of three therapeutic methods was compared. Twenty-five patients in group I were treated with low-molecular dextran and albumin, 67 patients in group II were treated with 6% medium molecular-weight hydroxyethyl starch, and 40 patients in group III were treated with active aspiration of pleural effusion and ascites. All three therapies improved the symptoms of OHSS and various blood biochemical parameters. The duration of hospitalization of group III [(7.4±4.5) d] was significantly less than those of group I [(21.4±9.2) d] or II [(15.6±6.7) d], and the cost of group III [(2656.2±1882.8) Yuan] was also significantly lower than that of group I or II [(11937.6±7989.8) and (5182.7±2991.7) Yuan, respectively]. Abdominal B ultrasonography-guided trans-abdominal wall aspiration of pleural effusion and ascites combined with blood volume maintenance is an effective and economical way to treat OHSS.

Is perioperative low molecular weight hydroxyethyl starch infusion a risk factor for delayed graft function in renal transplant recipients?

Crystalloid or colloid fluids may be utilized during kidney transplantation. Histopathological and clinical data indicate that hydroxyethyl starch (HES) may have nephrotoxic potential. This retrospective single-centre cohort study screened 192 and included 113 patients who underwent renal transplantation between 2003 and 2007 at University of Leipzig Medical Faculty, Germany. The primary outcome parameter was delayed graft function (DGF). Patients were divided into two groups. Patients in group CRYS (N = 73) received crystalloid solution (acetated Ringer's or normal saline) only. Patients in the group HES (N = 40) received a minimum of 500 mL 6% HES 130/0.4 and additional crystalloid solution by discretion of the transplant team. Patients in both groups did not differ with respect to demographic data and American Society of Anesthesiologists Physical Status Classification System scores, except for the donor age, which was significantly lower in the group HES. The rate of DGF was not found to be different in group CRYS (31.5%) when compared to group HES (32.5%) (P = 1.00, n.s.). In this single-centre retrospective cohort study, infusion of low molecular weight 6% HES 130/0.4 during and after renal transplantation was found to have no significant negative effect upon the rate of DGF.

Preparation of granulocyte concentrates by apheresis: collection modalities in the USA

Preparation of granulocyte concentrates by apheresis: collection modalities in the USA

Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S - Scandinavian Starch for Severe Sepsis/Septic Shock trial): Study protocol, design and rationale for a double-blinded, randomised clinical trial

BackgroundBy tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis.Methods/DesignThe 6S trial will randomise 800 patients with severe sepsis in 30 Scandinavian ICUs to masked fluid resuscitation using either 6% HES 130/0.4 in Ringer's acetate or Ringer's acetate alone. The composite endpoint of 90-day mortality or end-stage kidney failure is the primary outcome measure. The secondary outcome measures are severe bleeding or allergic reactions, organ failure, acute kidney failure, days alive without renal replacement therapy or ventilator support and 28-day and 1/2- and one-year mortality. The sample size will allow the detection of a 10% absolute difference between the two groups in the composite endpoint with a power of 80%.DiscussionThe 6S trial will provide important safety and efficacy data on the use of HES 130/0.4 in patients with severe sepsis. The effects on mortality, dialysis-dependency, time on ventilator, bleeding and markers of resuscitation, metabolism, kidney failure, and coagulation will be assessed.Trial RegistrationClinicalTrials.gov: NCT00962156

Carbon monoxide releasing molecule-2 enhances coagulation and attenuates fibrinolysis by two mechanisms: insights gained with colloid dilution

Carbon monoxide releasing molecule-2 (CORM-2, tricarbonyldichlororuthenium (II) dimer) enhances coagulation and attenuates vulnerability to fibrinolysis. Our goal was to further define the CORM-2-mediated mechanisms using colloids with known effects on coagulation/fibrinolytic proteins. Plasma diluted 0 or 30% with 0.9% NaCl, 5% human albumin, low molecular weight hydroxyethyl starch (130 kDa) or high molecular weight hydroxyethyl starch (450 kDa) was exposed to 0 or 100 μmol/l CORM-2 before activation with tissue factor (n = 8 per condition). A second identically diluted series of experiments were performed with the addition of tissue-type plasminogen activator. Thrombelastographic data were collected until clot strength stabilized or clot lysis occurred. Dilution resulted in fluid-specific decreases in velocity of clot growth, strength and clot growth time with progressive increases in macromolecule size. CORM-2 exposure significantly increased the velocity of clot formation and strength (thin fibrin fiber promoting), but not clot growth time, under all conditions. Fibrinolysis was enhanced to the greatest extent by hydroxyethyl starch (antiα2-antiplasmin effect), and CORM-2 addition attenuated fibrinolysis in all conditions (α2-antiplasmin enhancement). CORM-2 exposure attenuated the decrease in coagulation kinetics mediated by hemodilution by two different mechanisms based on kinetic profile differences between the diluents tested. Further laboratory-based investigation is warranted to further define the molecular mechanisms responsible for CORM-2-mediated effects on coagulation and fibrinolysis.

Increased viscosity of hemoglobin-based oxygen carriers retards NO-binding when perfused through narrow gas-permeable tubes

Increased fluid viscosity of a solution of hemoglobin-based oxygen carriers (HBOCs) reduces vasoconstrictive effects because increased shear stress on the vascular wall enhances the production of vasorelaxation factors such as NO. Nevertheless, on a microcirculatory level, it remains unclear how viscosity affects the reaction of HBOCs and NO. In this study, different HBOCs were perfused through narrow gas-permeable tubes (25 μm inner diameter at 1 mm/s centerline velocity; hemoglobin concentration [Hb] = 5 g/dL). The reaction was examined microscopically based on the Hb visible-light absorption spectrum. When immersed in a NO atmosphere, the NO-binding of deoxygenated Hb solution (viscosity, 1.1 cP at 1000 s − 1 ) in the tube occurred about twice as rapidly as that of red blood cells (RBCs): 1.6 cP. Binding was reduced by PEGylation (PEG-Hb, 7.7 cP), by addition of a high molecular weight hydroxyethyl starch (HES) (2.8 cP), and by encapsulation to form Hb-vesicles (HbVs, 1.5 cP; particle size 279 nm). However, the reduction was not as great as that shown for RBCs. A mixture of HbVs and HES (6.2 cP) showed almost identical NO-binding to that of RBCs. Higher viscosity and particle size might reduce lateral diffusion when particles are flowing. The HbVs with HES showed the slowest NO-binding. Furthermore, Hb encapsulation and PEGylation, but not HES-addition, tended to retard CO-binding. Increased viscosity reportedly enhances production of endothelium NO. In addition, our results show that the increased viscosity also inhibits the reaction with NO. Each effect might mitigate vasoconstriction.