Hydroxyethyl Starch Solution Research Articles

Anaphylaxis induced by hydroxyethyl starch during general anesthesia -A case report-

Hydroxyethyl starch (HES) solutions are synthetic non-protein colloid solutions used to treat hypovolemia. However, their use is not free from the risk of allergic reactions. A 42-year-old male was scheduled to undergo aortic-iliac-femoral bypass surgery for the treatment of arteriosclerosis obliterans. He had no history of allergy. Two hours after the start of surgery, and within minutes after HES administration, facial erythema, hypotension and bronchospasm developed. HES infusion was discontinued under the estimation of anaphylaxis. The patient received phenylephrine, ephedrine, diphenhydramine and hydrocortisone with hydration. After restoration of vital signs, surgery was performed without complications.

Use of hydroxyethyl starch for inducing red blood cell aggregation

Aggregation of human red blood cells (RBC) remains of biological and clinical interest. Replacement of plasma proteins by polymers to induce RBC aggregation may help to unravel the fundamentals of the aggregation process. Two theories exist to explain RBC aggregation mechanisms: a depletion and a bridging theory. RBC aggregation induced by hydroxyethyl starch (HES) increases with polymer size, which suggests that aggregation is induced via the bridging theory. In this study, the electrophoretic mobility (EPM) was measured to investigate RBC aggregation induced by 200 kDa HES polymers. Also, we evaluated if these polymers were useful for demonstrating aggregation differences between RBCs from healthy and type-1 diabetes mellitus (T1DM) subjects. Our results demonstrate that EPM values of RBCs in 200 kDa HES solutions were less negative than could be predicted by the viscosity of the suspension, supporting the bridging theory. Furthermore, aggregation analysis using the LORCA demonstrated that 200 kDa HES solution enhanced RBC aggregation of healthy and diabetic subjects similarly as standard 500 kDa dextran solutions. our data supports the bridging mechanism underlying 200 kDa HES induced RBC aggregation. In addition, both polymers are useful for demonstrating cellular induced aggregation differences between RBCs from healthy and T1DM subjects.

Neuromuscular Blockade with Rocuronium Bromide Increases the Tolerance of Acute Normovolemic Anemia in Anesthetized Pigs

Background: The patient’s individual anemia tolerance is pivotal when blood transfusions become necessary, but are not feasible for some reason. To date, the effects of neuromuscular blockade (NMB) on anemia tolerance have not been investigated. Methods: 14 anesthetized and mechanically ventilated pigs were randomly assigned to the Roc group (3.78 mg/kg rocuronium bromide followed by continuous infusion of 1 mg/kg/min, n = 7) or to the Sal group (administration of the corresponding volume of normal saline, n = 7). Subsequently, acute normovolemic anemia was induced by simultaneous exchange of whole blood for a 6% hydroxyethyl starch solution (130/0.4) until a sudden decrease of total body O₂ consumption (VO₂) indicated a critical limitation of O₂ transport capacity. The Hb concentration quantified at this time point (Hb_crit) was the primary endpoint of the protocol. Secondary endpoints were parameters of hemodynamics, O₂ transport and tissue oxygenation. Results: Hb_crit was significantly lower in the Roc group (2.4 ± 0.5 vs. 3.2 ± 0.7 g/dl) reflecting increased anemia tolerance. NMB with rocuronium bromide reduced skeletal muscular VO₂ and total body O₂ extraction rate. As the cardiac index increased simultaneously, total body VO₂ only decreased marginally in the Roc group (change of VO₂ relative to baseline –1.7 ± 0.8 vs. 3.2 ± 1.9% in the Sal group, p < 0.05). Conclusion: Deep NMB with rocuronium bromide increases the tolerance of acute normovolemic anemia. The underlying mechanism most likely involves a reduction of skeletal muscular VO₂. During acellular treatment of an acute blood loss, NMB might play an adjuvant role in situations where profound stages of normovolemic anemia have to be tolerated (e.g. bridging an unexpected blood loss until blood products become available for transfusion).

The viscous behaviour of HES 130/0.4 (Voluven®) and HES 260/0.45 (Pentaspan®)

Several fluids are available for volume therapy to address hypovolemia. We focus on two hydroxyethyl starches (HES) available for volume expansion in Canada, HES 130/0.4 (Voluven®) and HES 260/0.45 (Pentaspan®). Although information is available regarding their pharmacokinetic and risk/benefit profiles, this paper examines their viscous properties. Dynamic viscosities of HES 130/0.4 and HES 260/0.45 were measured through capillary viscometry at 21°C and 37°C. The viscosities of the solutions were then measured through a closed flow loop at room temperature across physiologically relevant flow rates that maintained a laminar flow regime. Measured dynamic viscosity through capillary viscometry for HES 130/0.4 and HES 260/0.45 was 2.76 centipoises (cP) and 7.62 cP, respectively, at 21°C decreasing to 1.74 cP and 4.25 cP, respectively, at 37°C. Pipe flow analysis found that HES 130/0.4 (expiry 02/13) and HES 260/0.45 (expiry 10/10) displayed marginal variation in viscosity suggesting Newtonian behaviour. However, a sample of HES 130/0.4 (expiry 10/10) displayed an appreciable increase in viscosity (13%) at higher flow rates suggesting shear thickening behaviour. This study represents an innovative characterization of not only the viscosity of two commonly utilized HES solutions but also their viscous behaviour across physiologically relevant flow rates. The shear thickening behaviour of a sample of HES 130/0.40 (expiry 10/10) at high flow rates was not expected, and the effect this result may have on endothelial cell function is unknown.

Retractions Lead to Revision of Review Article “Contemporary Fluid Management in Cardiac Anesthesia”

Numerous articles authored by Dr Joachim Boldt were retracted from international journals on anesthesia and intensive care medicine because of missing institutional review board approvals. Therefore, we believe our recent publication1Habicher M. Perrino Jr, A. Spies C.D. et al.Contemporary fluid management in cardiac anesthesia.J Cardiothorac Vasc Anesth. 2011; 25: 1141-1153Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar needed to be updated to re-evaluate conclusions that might have been influenced by the retracted data. Our review cited 5 articles by Dr Boldt.2Boldt J. Lenz M. Kumle B. et al.Volume replacement strategies on intensive care units: Results from a postal survey.Intensive Care Med. 1998; 24: 147-151Crossref PubMed Scopus (118) Google Scholar, 3Boldt J. Haisch G. Suttner S. et al.Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation.Br J Anaesth. 2002; 89: 722-728Crossref PubMed Scopus (99) Google Scholar, 4Boldt J. PRO: Hydroxyethyl starch can be safely used in the intensive care patient—The renal debate.Intensive Care Med. 2009; 35: 1331-1336Crossref PubMed Scopus (27) Google Scholar, 5Boldt J. Brenner T. Lehmann A. et al.Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: Comparison of a new starch preparation with gelatin.Intensive Care Med. 2003; 29: 763-769Crossref PubMed Scopus (91) Google Scholar, 6Boldt J. Brosch Ch. Röhm K. et al.Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients.Br J Anaesth. 2008; 100: 457-464Crossref PubMed Scopus (76) Google Scholar Three of these 5 publications are among the articles that were retracted.3Boldt J. Haisch G. Suttner S. et al.Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation.Br J Anaesth. 2002; 89: 722-728Crossref PubMed Scopus (99) Google Scholar, 5Boldt J. Brenner T. Lehmann A. et al.Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: Comparison of a new starch preparation with gelatin.Intensive Care Med. 2003; 29: 763-769Crossref PubMed Scopus (91) Google Scholar, 6Boldt J. Brosch Ch. Röhm K. et al.Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients.Br J Anaesth. 2008; 100: 457-464Crossref PubMed Scopus (76) Google Scholar After discussion within our group, we decided to remove all sentences and paragraphs discussing these publications by Dr Boldt to counter the argument that any conclusion drawn in this review article could have been influenced by possibly fraudulent data. In particular, the section “Colloids and Renal Function in Cardiac Surgery” is a concern because the 2 prospective randomized trials addressing this issue were authored by Dr Boldt and are among the retracted articles. We removed the discussion of the articles by Dr Boldt and discussed data from related surgical specialties because, to the best of our knowledge, no other studies investigating the effect of colloids on renal function in cardiac surgery are available. The conclusions drawn are different from the original article because no recommendations on the safe use of starch solutions regarding renal function in cardiac surgical patients, regardless of the generation of starches used, can be made. The entire discussion of the issue concerning Dr Boldt emphasizes that the gap of knowledge regarding the safety of colloid solutions and especially the impact on renal function in cardiac surgery needs to be addressed by sufficiently powered, prospective, randomized trials. Contemporary Fluid Management in Cardiac AnesthesiaJournal of Cardiothoracic and Vascular AnesthesiaVol. 25Issue 6PreviewTHE PRESCRIPTION OF perioperative fluids has been a persistent controversy among anesthesiologists, surgeons, and intensivists. Interestingly, disagreements within each specialty as to the appropriate types and amounts of fluids required are just as intense as that seen among the specialties. The challenge in navigating these waters is demanding because the safe harbor of optimal fluid administration is bounded by hypovolemia and end-organ hypoperfusion (resulting from inadequate fluids) and congestive heart failure and the negative effects of edema formation on respiration and wound healing (resulting from excessive fluids). Full-Text PDF

Pulse Pressure Variation Predicts Fluid Responsiveness in Elderly Patients After Coronary Artery Bypass Graft Surgery

To assess the ability of pulse pressure variation to predict fluid responsiveness in mechanically ventilated elderly patients after coronary artery bypass graft surgery. A prospective, interventional study. An academic, tertiary referral hospital. Sixty patients >70 years old and mechanically ventilated after coronary artery bypass graft surgery. Intravascular volume expansion using 6% hydroxyethyl starch solution, 7 mL/kg over 20 minutes. Heart rate, arterial blood pressure, pulse pressure variation, central venous pressure, pulmonary artery occlusion pressure, and stroke volume index were measured immediately before and after volume expansion. Fluid responsiveness was defined as an increase in stroke volume index ≥ 15% after volume expansion. Forty-one patients were fluid responders and 19 patients were nonresponders. In contrast to central venous pressure or pulmonary artery occlusion pressure, pulse pressure variation was higher in the responders than in the nonresponders (22 ± 6% v 9.3 ± 3%, p = 0.001) and correlated with the percent changes in the stroke volume index after volume expansion (r = 0.47, p = 0.001). The area under the receiver operating characteristic curve for pulse pressure variation was 0.85 (95% confidence interval 0.75-0.94). The threshold value of 11.5% allowed the discrimination between responders and nonresponders with a sensitivity of 80% and a specificity of 74%. Pulse pressure variation is a reliable predictor of fluid responsiveness in mechanically ventilated elderly patients after coronary artery bypass graft surgery.

Application of the Multisolute Osmotic Virial Equation to Solutions Containing Electrolytes

The prediction of multisolute solution behavior of solutions containing electrolytes is important in many areas of research, including cryopreservation. In this study, the use of a novel form of the osmotic virial equation for multisolute solutions containing an electrolyte is investigated and compared to a rigorous electrolyte solution theory, the Pitzer-Debye-Huckel equation. For aqueous solutions containing a small molecule (either dimethyl sulfoxide or glycerol) and sodium chloride, the multisolute osmotic virial equation, which utilizes only two parameters to capture the electrolyte solution behavior, is shown to be as accurate as the Pitzer-Debye-Huckel equation, which utilizes six empirical parameters and multiple functions to capture the electrolyte solution behavior. In addition, an approach based on the multisolute osmotic virial equation to investigate the effect of electrolyte concentration on macromolecule solution behavior is presented and applied to aqueous solutions of hydroxyethyl starch and sodium chloride. The multisolute osmotic virial equation is shown to be an accurate, straightforward predictive solution theory for important multisolute solutions containing electrolytes.

Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review

Hydroxyethyl starch solutions (HES) are plasma volume expanders which affect hemostasis. Newer HES 130/0.4 is said to be safer. Reevaluation of published evidence is necessary after the recent retraction of studies. Systematic review of studies assessing HES 130/0.4 effects on hemostasis by thrombelastography (TEG, ROTEM) or Sonoclot (SCR) in comparison with crystalloid or albumin control fluids was performed. Only studies which provided statistical comparisons between study fluids were analyzed. Studies were divided into in vitro or in vivo hemodilution studies. We assessed study quality, HES effects which differed significantly from controls, values outside normal range, degree of hemodilution, and cumulative HES dose. Seventeen in vitro and seven in vivo hemodilution studies were analyzed. Four studies reported quality control measures. Nineteen studies (all 15 ROTEM studies, 3 of 5 in vitro TEG, and 1 of 2 SCR studies) showed a significant hypocoagulatory effect of HES 130/0.4 on clot formation, while clotting time was not uniformly affected. Three in vivo TEG studies with low HES doses or cancer patients found mixed or nonsignificant results. In studies which provided normal ranges (n = 9), more values were outside normal ranges in the HES than in the control groups (87/122 vs. 58/122, p < 0.001). Dose effects were apparent in the in vitro studies, which investigated higher dilutions up to 80%. In vivo studies were fewer and did not investigate doses >40 ml/kg. HES 130/0.4 administration results in a weaker and smaller clot. Until results from well-designed clinical trials are available, safer fluids should be chosen for patients with impaired coagulation.

Feasibility and safety of acute hypervolemic hemodilution in neurosurgical patients

To evaluate the preoperative effects of acute hypervolemic hemodilution (AHH) on intracranial pressure, cerebral oxygen supply-demand balance and cardiovascular functions of neurosurgical patients. Approved by hospital ethics committee, a total of 80 ASA grade I/II patients at our hospital during 2009, of either gender aged 18-60 yrs, undergoing elective craniotomy were recruited. The subjects were randomly divided equally into 2 groups: group H (hemodilution) and group C (control) (n = 40 each). After induction, 6% hydroxyethyl starch solution was infused at the rate of 24 ml×kg(-1)×h(-1) in group H, while patients in group C received compound electrolyte solution at the rate of 6 ml×kg(-1)×h(-1). Central venous pressure (CVP), cardiac output index (CI), stroke volume variation (SVV) and cerebral spinal fluid pressure (CSFP) were recorded at the following time points: T(Base) (before induction), T(0) (after induction and hemodynamic stabilization), T(30) (after infusion for 30 min) and T(60) (after infusion for 60 min). Blood samples from radial artery and jugular bulb were collected and calculated for systemic vascular resistance index (SVRI) and cerebral oxygen uptake rate (CERO(2)). The dosing frequency of vasoactive drugs was also recorded. CI in group H was significantly higher than that in group C (P < 0.01). No significant difference was found in both SjvO(2) and CERO(2) between groups and among different points of time (P > 0.05). At the end of AHH, CVP and CSFP were (12 ± 2.2) mm Hg and (20.0 ± 2.1) mm Hg respectively. They were significantly higher than that in group C (P < 0.01). Preoperative AHH in craniotomy will increase CI and maintain the balance of cerebral oxygen supply. But its clinical application is limited in the patient with high intracranial pressure due to the simultaneous increases in CVP and CSFP.

281 Rapidly Degradable Hydroxyethyl Starch Solutions Increase the Risk of Massive Transfusion in Blunt Trauma Patients

281 Rapidly Degradable Hydroxyethyl Starch Solutions Increase the Risk of Massive Transfusion in Blunt Trauma Patients

Maternal Cardiac Output Changes After Crystalloid or Colloid Coload Following Spinal Anesthesia for Elective Cesarean Delivery

Minimizing hypotension associated with spinal anesthesia for cesarean delivery by administration of IV fluids and vasopressors reduces fetal and maternal morbidity. Most studies have concentrated on noninvasive systolic blood pressure (SBP) measurements to evaluate the effect of such regimens. We used a suprasternal Doppler flow technique to measure maternal cardiac output (CO) variables in parturients receiving a phenylephrine infusion combined with the rapid administration of crystalloid or colloid solution at the time of initiation of anesthesia (coload). We hypothesized that a colloid coload compared with a crystalloid coload would produce a larger sustained increase in CO and therefore reduce vasopressor requirements. We recruited 60 healthy term women scheduled for elective cesarean delivery under spinal anesthesia for this randomized double-blind study. Baseline heart rate, baseline SBP, and CO variables including stroke volume, corrected flow time, and contractility were recorded in the left lateral tilt position. At the time of spinal injection, subjects were allocated to receive a rapid 1-L coload of either 6% w/v hydroxyethyl starch solution (HES) or Hartmann (crystalloid) solution (HS). A phenylephrine infusion was titrated to maintain maternal baseline SBP. CO was measured at 5-minute intervals for 20 minutes after initiation of spinal anesthesia. The primary outcome, CO, was compared between groups, as were secondary outcomes: phenylephrine dose and maternal hemodynamic and fetal outcome data. Maternal demographics, surgical times, and fetal outcome data were similar between groups. There were no significant differences between groups in any measured CO variable at any time point. CO was transiently higher than baseline at 5 minutes in the HS group and at 5 and 10 minutes in the HES group (range, 0.13-1.74 L/min); the overall mean difference in CO between crystalloid and colloid over the study period was 0.06 L/min (95% confidence interval: -0.46 to 0.58). Stroke volume was higher than baseline in both groups throughout; peak velocity was consistently higher than baseline only in the HES group; and corrected flow time increased in both groups; the effect was transient in the HS but sustained in the HES group. Heart rate was not different at any time point within or between groups but did decrease over time. The total phenylephrine dose from time of spinal anesthesia to delivery was similar between groups. We found no difference in CO in women randomized to colloid or crystalloid coload. In addition, there were no differences in vasopressor requirements or hemodynamic stability. We conclude that there is no advantage in using colloid over crystalloid when used in combination with a phenylephrine infusion during spinal anesthesia for elective cesarean delivery.

Hypertonic Saline Hydroxyethylstarch Restores Right Ventricular-Arterial Coupling after Normovolemic Hemodilution in Piglets

Normovolemic hemodilution is known to inhibit hypoxic pulmonary vasoconstriction. How the coupling between the pulmonary arterial (PA) circulation and the right ventricle (RV) is affected by normovolemic hemodilution and by the composition of replacement solutions remains unknown. Therefore, the effects of isotonic and hypertonic saline hydroxyethylstarch solutions on the pulmonary circulation and RV, in control and hypoxic conditions, were compared. Anesthetized piglets (n = 14) were equipped with manometer-tipped catheters in the RV and main PA and an ultrasonic flow probe around the main PA. The pulmonary circulation was assessed by pressure-flow relations and vascular impedance, RV afterload by effective arterial elastance (Ea), RV contractility by end-systolic elastance (Ees), and RV-PA coupling by the Ees/Ea ratio. Measurements were done in control (Fio2 0.40) and hypoxic (Fio2 0.12) conditions before and after acute normovolemic hemodilution with either 20 ml/kg isotonic saline hydroxyethylstarch (hydroxyethylstarch 130/0.4 6% in NaCl 0.9%, Voluven, Fresenius-Kabi, Sevres, France) or 5 ml/kg hypertonic saline hydroxyethylstarch (hydroxyethylstarch 200/0.5 6% in NaCl 7.2%, HyperHES, Fresenius-Kabi) solutions. Hypoxic pulmonary vasoconstriction was associated with proportional increases in Ea and Ees and did not affect RV-PA coupling. Hemodilution attenuated the hypoxic response. Hemodilution with isotonic saline hydroxyethylstarch did not affect the RV-PA coupling, whereas hemodilution with hypertonic saline hydroxyethylstarch increased Ees and the Ees/Ea ratio. In experimental normovolemic hemodilution, both in control and in hypoxic conditions, RV-PA coupling is unaffected by isotonic saline hydroxyethylstarch but improved by hypertonic saline hydroxyethylstarch, mainly because of an increase in RV contractility.

P47. The application of the electrolyte balanced hydroxyethylstarch solution – Tetraspan in complex infusion therapy of preeclampsia in perioperative care

P47. The application of the electrolyte balanced hydroxyethylstarch solution – Tetraspan in complex infusion therapy of preeclampsia in perioperative care

Stroke volume variation obtained with Vigileo/FloTrac™ system during bleeding and fluid overload in dogs

Stroke volume variation (SVV) is a parameter for estimating fluid responsiveness. Recently, the Vigileo™ and the Flo-Trac™ sensor (Edwards Lifesciences, Irvine, CA, USA) were made available for clinical use to estimate SVV. The aim of this study was to investigate the relationship between the circulating blood volume and SVV, measured by the Vigileo-FloTrac™ system (SVV-FloTrac) or by central venous pressure (CVP), during a dynamic change in circulating blood transfusion volume, using a continuous constant bleeding and fluid-overload model in dogs. Ten anesthetized and mechanically ventilated beagles were used. SVV-FloTrac and CVP were measured during a bleeding period (2ml/kg/min, 15min), a stabilization period (15min), a blood transfusion period (2ml/kg/min, 15min), and a 6% hydroxyethyl starch solution overload period (2ml/kg/min, 15min). SVV-FloTrac changed significantly when more than 8ml/kg blood was withdrawn or when more than 8ml/kg blood was transfused. The change in SVV-FloTrac directly reflected the circulating blood volume change during continuous bleeding and blood transfusion. CVP decreased significantly when more than 4ml/kg blood was withdrawn or when more than 10ml/kg was infused, and this indicated that the CVP change did not directly reflect the level of the circulating blood volume change. During the stable circulating blood volume period after blood withdrawal, SVV-FloTrac changed significantly but CVP remained constant. During the fluid overload period, CVP, but not SVV-FloTrac, changed significantly. SVV-FloTrac is a sensitive indicator of the dynamic circulating blood volume change during both bleeding and transfusion, but not during either the stable circulating blood volume period after blood withdrawal or the fluid-overload period, in mechanically ventilated dogs.

In Response

We appreciate Drs. Rice and Gravenstein's1 concern regarding the number of questionably valid Boldt papers included in our recent systematic analysis of randomized controlled trials (RCTs) with hydroxyethyl starch (HES) 130/0.4.2 The disclosure of a fraudulent RCT of Dr. Boldt coincided with the publication of the systematic review which included a total of 18 RCTs published by Boldt. In an accompanying editorial3 we explained that if all the Boldt studies were withdrawn from the systematic analysis the conclusion would still remain the same: “The remaining 28 surgical RCTs still have low power (median patient n=27 in HES vs. n=33 in control groups), a median study period of 18 hours, two-thirds use other starches or gelatins as control fluids and a median HES dose well below the daily dose limit…published clinical data is insufficient to allow conclusion about whether HES 130/0.4 is safer than other HES solutions in surgical and critically ill patients.” We would also strongly encourage authors who want to keep up with science that is “without a shadow of doubt” to turn to summaries from independent groups such as the Cochrane Collaboration (www.cochrane.org/cochrane-reviews). In this case, three Cochrane Reviews on HES4–6 concluded that HES is not superior to crystalloids or other colloids, may be harmful to the kidneys in patients at increased risk for renal failure, and that there are insufficient clinical data to support suggestions that HES 130/0.4 may be safer. Christiane S. Hartog Konrad Reinhart Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich-Schiller-University, Jena Germany [email protected]

O-74 A word of caution for using hypertonic hydroxyethyl starch solution in valvular heart surgery

O-74 A word of caution for using hypertonic hydroxyethyl starch solution in valvular heart surgery

Long-term Urokinase Therapy and Isovolemic Hemodilution: A Clinical and Hemodynamic Comparison in Patients with Refractory Angina Pectoris.

Antiischemic effectiveness of long-term urokinase therapy and isovolemic hemodilution therapy has been reported in patients with symptomatic coronary artery disease, but both interventions have never been compared. In patients with refractory angina pectoris and end-stage coronary artery disease (clinical functional class III), isovolemic hemodilution (n = 9) (hydroxyethyl starch solution 6%, 1-2 times/week), and urokinase therapy (n = 11) (500,000 U urokinase per i.v. injection, 3 times a week) were performed over a period of 12 weeks, each additionally to maximal conventional treatment. Apart from the assessment of clinical symptoms and rheologic parameters, invasive hemodynamic measurements were carried out at rest and during exercise testing before and after treatment. After treatment with urokinase, patients showed a significant reduction of clinical symptoms (from 19.8 +/- 6.5 to 5.0 +/- 4.3 anginal events/week, p < 0.001), fibrinogen (from 410 +/- 88 to 238 +/- 40 mg/dl, p < 0.001), plasma viscosity (from 1.45 +/- 0.10 to 1.33 +/- 0.03 mPa x s-1, p < 0.01), and no changes of hematocrit (from 0.45 +/- 0.02 to 0.45 +/- 0.02) and whole blood viscosity (from 4.7 +/- 0.5 to 4.4 +/- 0.7 mPa x s-1); however, hemodilution resulted in a decrease of hematocrit (from 0.46 +/- 0.01 to 0.39 +/- 0.01, p < 0.001) and whole blood viscosity (from 4.7 +/- 0.5 to 4.0 +/- 0.3 mPa x s-1, p < 0.001) and no changes of initially comparable levels of clinical symptoms, fibrinogen, and plasma viscosity. Hemodynamic parameters at rest improved after urokinase therapy with a reduction of pulmonary capillary wedge pressure (from 9.1 +/- 5.1 to 5.5 +/- 2.8 mmHg, p < 0.05) at comparable levels of systemic vascular resistance (from 1510 +/- 340 to 1420 +/- 510 dyn x s x cm-5). Hemodilution did not result in any significant hemodynamic changes. Apart from clinical symptoms, long-term intermittent urokinase therapy reduces pulmonary capillary wedge pressure at rest. This may reflect an improved diastolic function due to a rheological enhancement of myocardial perfusion at the level of the coronary microcirculation. Isovolemic hemodilution seems to be of no benefit.

Advances of balanced hydroxyethyl starch

Background Hydroxyethylstarch (HES) is a widely used plasma substitute for correcting intravascular volume deficit and improving systemic hemodynamics as well as microcirculation. HES dissolved in isotonic saline may result in acid-base have been available. Purpose To review the chemical properties and the developing process of different generations of HES. The advantages of new balanced solutions over the unbalanced in acid -base status, coagulation and renal function are also discussed.Content Several studies demonstrated that such modern balanced HES preparations appeared to be safer with regard to acid-base balance, hemostasis, kidney function. Besides, the preliminary results in assessing the value of a total balanced volume replacement strategy including plasma-adapted HES solutions are quite promising. Trend The use of this new balanced HES will be widely Accepted in the future,and total balanced volume replacement strategy might be a pronising approach to further improves the safety of HES. Key words: Hydroxyethylstarch; Balanced; Plasma substitutes; Total balanced volume replacement

Effects of balanced crystalloid vs. 0.9% saline-based vs. balanced 6% tetrastarch infusion on renal function and tubular integrity in ovine endotoxemic shock*

Conflicting data exist on the renal effects of hydroxyethyl starch preparations. The aim of the present study was to evaluate the impact of balanced crystalloids, as well as 0.9% saline-based and balanced 6% tetrastarch solutions, on renal function and ultrastructural morphologic correlates of acute kidney injury in an established model of ovine endotoxemic shock. Randomized, controlled, experimental study. Animal research facility of a university hospital. A total of 31 awake instrumented sheep. The animals were subjected to continuous endotoxin infusion (Salmonella typhosa) at incremental doses until the mean arterial pressure was <65 mm Hg and arterial lactate was ≥ 2 mmol·L⁻¹ or (if arterial hypotension was absent) arterial lactate was ≥ 4 mmol·L⁻¹. The subjects were then randomized to receive no fluid resuscitation (control group, n = 5) or blinded infusion of a balanced crystalloid (n = 9), 0.9% saline-based (n = 8), or balanced 6% hydroxyethyl starch 130/0.4 (n = 9) up to a maximum dose of 50 mL·kg⁻¹, followed by open-label infusion of balanced crystalloid. Animals surviving the 12-hr intervention period were deeply anesthetized and killed. Kidney samples were taken immediately for transmission electron microscopic analyses. Additional specific experiments were performed to take kidney samples ex vivo. Endotoxemia was associated with arterial hypotension and capillary leakage. Fluid resuscitation established a hypotensive-hyperdynamic circulation in all resuscitated animals without significant hemodynamic differences among groups. Plasma creatinine and urea concentrations were higher in both hydroxyethyl starch groups as compared to the crystalloid group (creatinine, 1.2 ± 0.1 and 1.4 ± 0.3 vs. 0.8 ± 0.1 mg·dL⁻¹; urea, 21 ± 1 and 21 ± 2 vs. 17 ± 2 mg·dL⁻¹; p < .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids at 8 hrs). In contrast, kidney function, as measured by creatinine clearance and cumulative creatinine excretion, was similar between the colloid and crystalloid treatment groups (creatinine clearance at 8 hrs, 122 ± 18 and 108 ± 31 vs. 107 ± 13 mL·min⁻¹·m⁻²; creatinine excretion per hour alive, 283 ± 29 and 264 ± 19 vs. 291 ± 24 mg·hr⁻¹; p > .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids), whereas kidney function deteriorated markedly in control animals. The electron microscopic tubular injury score was lower in hydroxyethyl starch-treated animals as compared to the crystalloid group. Vacuolar tubular cell alterations were present in all groups. The percentage of intact microvilli brush borders was significantly higher in sheep treated with either hydroxyethyl starch solution as compared to the other groups. The present study provides evidence that renal function, as measured by creatinine clearance and cumulative creatinine excretion as well as ultrastructural tubular integrity, is preserved with the use of 6% tetrastarch solutions despite increases in plasma levels of renal retention variables in ovine endotoxemic shock.

Hydroxyethyl Starch (130 kD) Inhibits Toll-Like Receptor 4 Signaling Pathways in Rat Lungs Challenged with Lipopolysaccharide

A number of studies have shown that hydroxyethyl starch (HES) solutions are able to down-regulate the expression of inflammatory mediators and inhibit neutrophil-mediated tissue injuries when they are used in patients with sepsis or other diseases with severe inflammatory responses. However, our knowledge about the underlying mechanisms is limited. Toll-like receptor 4 (TLR4) signaling has a pivotal role in inflammatory processes. In this study, we examined the possible involvement of TLR4 signaling in the antiinflammatory effects of HES. Male Sprague-Dawley rats were exposed to lipopolysaccharide (LPS) (10 mg/kg, IV) and received IV saline (30 mL/kg) or HES 130/0.4 (15 or 30 mL/kg). Six hours after LPS challenge, rats were killed and their lungs harvested. Lung injury was examined by hematoxylin and eosin staining. TLR4 mRNA expression, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1/2 MAPK activation, and activator protein 1 (AP-1) activity in the lungs were detected with quantitative polymerase chain reaction, Western blotting, and electrophoretic mobility shift assay, respectively. Compared with saline, HES profoundly attenuated the histological changes induced by LPS in the lungs at both dose levels. Molecular analysis showed that both 15 and 30 mL/kg HES significantly decreased TLR4 mRNA levels and inhibited activation of p38 MAPK and AP-1 in rats challenged with LPS, whereas activation of extracellular signal-regulated kinases 1/2 MAPK was not affected by either dose of HES. These findings indicate that the beneficial effects of HES 130/0.4 on inflammation are mediated at least in part by inhibiting the TLR4/p38 MAPK/AP-1 pathway in lungs from rats challenged with LPS.