Norepinephrine potentiates the efficacy of volume expansion on mean systemic pressure in septic shock.

BACKGROUND: Through venous contraction, norepinephrine (NE) increases stressed blood volume and mean systemic pressure (Pms) and exerts a "fluid-like" effect. When both fluid and NE are administered, Pms may not only result from the sum of the effects of both drugs. Indeed, norepinephrine may enhance the effects of volume expansion: because fluid dilutes into a more constricted, smaller, venous network, fluid may increase Pms to a larger extent at a higher than at a lower dose of NE. We tested this hypothesis, by mimicking the effects of fluid by passive leg raising (PLR). METHODS: In 30 septic shock patients, norepinephrine was decreased to reach a predefined target of mean arterial pressure (65-70 mmHg by default, 80-85 mmHg in previously hypertensive patients). We measured the PLR-induced increase in Pms (heart-lung interactions method) under high and low doses of norepinephrine. Preload responsiveness was defined by a PLR-induced increase in cardiac index ≥ 10%. RESULTS: Norepinephrine was decreased from 0.32 [0.18-0.62] to 0.26 [0.13-0.50] µg/kg/min (p < 0.0001). This significantly decreased the mean arterial pressure by 10 [7-20]% and Pms by 9 [4-19]%. The increase in Pms (∆Pms) induced by PLR was 13 [9-19]% at the higher dose of norepinephrine and 11 [6-16]% at the lower dose (p < 0.0001). Pms reached during PLR at the high dose of NE was higher than expected by the sum of Pms at baseline at low dose, ∆Pms induced by changing the norepinephrine dose and ∆Pms induced by PLR at low dose of NE (35.6 [11.2] mmHg vs. 33.6 [10.9] mmHg, respectively, p < 0.01). The number of preload responders was 8 (27%) at the high dose of NE and 15 (50%) at the low dose. CONCLUSIONS: Norepinephrine enhances the Pms increase induced by PLR. These results suggest that a bolus of fluid of the same volume has a greater haemodynamic effect at a high dose than at a low dose of norepinephrine during septic shock.

Fluid volume kinetics of 20% albumin.

AIMS: A population kinetic model was developed for the body fluid shifts occurring when 20% albumin is given by intravenous infusion. The aim was to study whether its efficacy to expand the plasma volume is impaired after major surgery. METHODS: An intravenous infusion of 3 mL/kg 20% albumin over 30 minutes was given to 15 volunteers and to 15 patients on the 1st day after major open abdominal surgery. Blood samples and urine were collected during 5 hours. Mixed-effect modelling software was used to develop a fluid volume kinetic model, using blood haemoglobin and urine excretion the estimate body fluid shifts, to which individual-specific covariates were added in sequence. RESULTS: The rise in plasma albumin expanded the plasma volume in excess of the infused volume by relocating noncirculating fluid (rate constant k21 ), but it also increased losses of fluid from the kinetic system (kb ). The balance between k21 and kb maintained the rise in plasma albumin and plasma volume at a virtual steady-state for almost 2 hours. The rate constant for urinary excretion (k10 ) was slightly reduced by the preceding surgery, by a marked rise in plasma albumin, and by a high preinfusion urinary concentration of creatinine. The arterial pressure, body weight, and plasma concentrations of C-reactive protein and shedding products of the endothelial glycocalyx layer (syndecan-1, heparan sulfate, and hyaluronic acid) did not serve as statistically significant covariates. CONCLUSIONS: There were no clinically relevant differences in the kinetics of 20% albumin between postoperative patients and volunteers.

Comparison of the pharmacokinetics of two formulations of hydroxyethyl starch in healthy horses.

A lower molecular weight and molar substitution formulation (130/0.4) of hydroxyethyl starch solution has been shown to have a more sustained effect on COP and similar hemodynamic effects as a higher molecular weight and molar substitution formulation (600/0.75) in healthy horses. In humans, these pharmacodynamic characteristics are coupled with more rapid clearance and decreased adverse coagulation effects and accumulation. The objective of this study was to determine and compare the pharmacokinetics of these two formulations in horses. Eight healthy horses were given a 10 mL/kg bolus of each formulation (600/0.75 and 130/0.4) of hydroxyethyl starch solution in a randomized crossover design. Blood was collected, and plasma was harvested for plasma levels over 24 h. Pharmacokinetic parameters for each horse were estimated from a noncompartmental analysis. Treatment with 600/0.75 resulted in a higher initial plasma concentration (C0 ), systemic half-life (t1/2 ), and overall drug exposure (AUC0-inf ) in addition to decreased elimination rate (ß), volume of distribution (Vd), and clearance (CL), compared to treatment with 130/0.4 (P < 0.001). The pharmacokinetic findings combined with previous pharmacodynamics findings suggest that 130/0.4 can provide similar benefits to 600/0.75 with a lower risk of accumulation in the circulation.

Hydroxyethyl starch and granulocyte transfusions: considerations of utility and toxicity profile for patients and donors.

Hydroxyethyl starch (hetastarch) is a synthetic glucose compound with extensive clinical use as a volume expander. Because of its red blood cell-sedimenting properties, hetastarch plays a major role in preparation of granulocyte products. Recent concerns have been raised about the use of hetastarch in critically ill patients for the development of renal injury and other severe adverse events. In contrast, granulocyte donors receive much less of this compound during collection procedures, and over many years, minimal toxicity has been documented in these individuals. Furthermore, granulocyte products contain very little hetastarch, and ill effects on renal function have not been associated with their administration. This review assesses available information about the toxicity profile of hetastarch in critically ill patients requiring a volume expander as well as granulocyte donors and recipients. Because of the lack of toxicity in these latter two groups, hetastarch should be available for preparation of granulocyte products and their administration.

Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use.

OBJECTIVE: To review and summarize the pharmacokinetics and pharmacodynamics of hydroxyethyl starch (HES), as well as reported risks and benefits of HES infusion, and to provide administration and monitoring recommendations for HES use in dogs and cats. DATA SOURCES: Veterinary and human peer-reviewed medical literature, including scientific reviews, clinical and laboratory research articles, and authors' clinical experience. SUMMARY: HES solutions are the most frequently used synthetic colloid plasma volume expanders in human and veterinary medicine. The majority of research in human medicine has focused on the adverse effects of HES infusion, with emphasis on acute kidney injury and coagulation derangements. The studies often differ in or fail to report factors, such as the type, amount, interval, and concentration of HES administered; the patient population studied; or concurrent fluids administered. Currently, there is no definitive clinical evidence that the reported adverse effects of HES use in human medicine occur in veterinary species. There is little information available on HES administration techniques or simultaneous administration of additional fluids in human and veterinary medicine. The rationale for HES use in small animals has been largely extrapolated from human medical studies and guidelines. A controlled approach to intravenous fluid resuscitation using crystalloid and HES volumes titrated to reach desired resuscitation end point parameters is outlined for small animal practitioners. CONCLUSION: The extrapolation of data from human studies directly to small animals should be done with the knowledge that there may be species variations and different pharmacokinetics with different HES solutions. Veterinary reports indicate that bolus and continuous rate infusions of 6% hetastarch solutions at moderate doses are well tolerated in feline and canine subjects. Further research in domesticated species is necessary to better define and expand the knowledge regarding use of HES solutions in small animal medicine.

Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review.

PURPOSE: To systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage. METHODS: MEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation. RESULTS: Forty-eight studies were included: 37 human studies with a total of 635 patients and 11 animal studies. The most frequent indication for fluid infusion was surgery accounting for 282 patients (45.9%). HES localization in skin was shown by 17 studies, in kidney by 12, in liver by 8, and in bone marrow by 5. Additional sites of HES deposition were lymph nodes, spleen, lung, pancreas, intestine, muscle, trophoblast, and placental stroma. Among major organs the highest measured tissue concentration of HES was in the kidney. HES uptake into intracellular vacuoles was observed by 30 min after infusion. Storage was cumulative, increasing in proportion to dose, although in 15% of patients storage and associated symptoms were demonstrated at the lowest cumulative doses (0.4 g kg(-1)). Some HES deposits were extremely long-lasting, persisting for 8 years or more in skin and 10 years in kidney. Pruritus associated with HES storage was described in 17 studies and renal dysfunction in ten studies. In one included randomized trial, HES infusion produced osmotic nephrosis-like lesions indicative of HES storage (p = 0.01) and also increased the need for renal replacement therapy (odds ratio, 9.50; 95% confidence interval, 1.09-82.7; p = 0.02). The tissue distribution of HES was generally similar in animals and humans. CONCLUSIONS: Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful.

Carbohydrate plasma expanders for passive tumor targeting: in vitro and in vivo studies.

The objective of this study was to investigate the suitability of carbohydrate plasma volume expanders as a novel polymer platform for tumor targeting. Many synthetic polymers have already been synthesized for targeted tumor therapy, but potential advantages of these carbohydrates include inexpensive synthesis, constant availability, a good safety profile, biodegradability and the long clinical use as plasma expanders. Three polymers have been tested for cytotoxicity and cytokine activation in cell cultures and conjugated with a near-infrared fluorescent dye: hydroxyethyl starches (HES 200 kDa and HES 450 kDa) and dextran (DEX 500 kDa). Particle size and molecular weight distribution were determined by asymmetric flow field-flow fractionation (AF4). The biodistribution was investigated non-invasively in nude mice using multispectral optical imaging. The most promising polymer conjugate was characterized in human colon carcinoma xenograft bearing nude mice. A tumor specific accumulation of HES 450 was observed, which proves it's potential as carrier for passive tumor targeting.

The impact of acepromazine on the efficacy of crystalloid, dextran or ephedrine treatment in hypotensive dogs under isoflurane anesthesia.

OBJECTIVE: To determine the impact of acepromazine on the cardiovascular responses to three treatments for hypotension in dogs during deep isoflurane anesthesia. STUDY DESIGN: Prospective blinded randomized cross-over experimental design. ANIMALS: Six adult (2.5 ± 0.5 year old) healthy mixed breed dogs (24.2 ± 7.6 kg). METHODS: Anesthesia was induced with propofol (4-6 mg kg(-1) , IV) and maintained with isoflurane. Each dog received six treatments separated by at least 5 days. Once instrumented, dogs randomly received acepromazine (0.05 mg kg(-1) ) (Ace) or saline (equal volume) (Sal) IV and end-tidal isoflurane (E'Iso) was adjusted to achieve hypotension, defined as a mean blood pressure between 45 and 50 mmHg. Dogs randomly received dextran (D) (7 mL kg(-1) ) or lactated Ringer's (LR) (20 mL kg(-1) ) over 14 minutes, or ephedrine (Eph) (0.1 mg kg(-1) followed by 10 µg kg(-1) minute(-1) ) throughout the study. Measurements were taken at baseline, 5, 10, 15, 20, 30, and 40 minutes. Data were analyzed with a Latin Square in two factors (Ace/Sal and treatment) for repeated measures, with further comparisons if appropriate (p < 0.05). RESULTS: E'Iso producing hypotension was significantly less following Ace (2.07 ± 0.23%) than Sal (2.43 ± 0.23%). No improvement in cardiac output (CO) was observed with D or LR. LR initially intensified hypotension with a significant reduction in SVR, while D caused a minor improvement in ABP. Eph produced a significant increase in ABP, CO, hemoglobin, oxygen content and delivery. Pre-treatment with Ace minimized ABP improvements with all treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Acepromazine (0.05 mg kg(-1) IV) enhanced the hypotensive effect of isoflurane, although it maintained CO. Administration of LR significantly worsens ABP initially by further vasodilation. D caused minimal improvement in ABP. At the infusion studied, Eph effectively countered the cardiovascular depression produced by deep isoflurane anesthesia, but extremes in ABP associated with initial vasoconstriction prevent our recommendation at this dose.

Pharmacokinetics and safety of 6 % hydroxyethyl starch 130/0.4 in healthy male volunteers of Japanese ethnicity after single infusion of 500 ml solution.

PURPOSE: This phase I study was performed in volunteers of Japanese ethnicity to compare pharmacokinetic data after infusion of 6 % hydroxyethyl starch (HES) 130/0.4 with historical data of Caucasians. METHODS: In an open-label, uncontrolled, single-center study, 12 healthy male Japanese volunteers received single intravenous infusions of 500 ml 6 % HES 130/0.4 (Voluven 6 %; Fresenius Kabi Deutschland, Bad Homburg, Germany) over 30 min. RESULTS: Plasma concentration of 6 % HES 130/0.4 was highest at end of infusion (5.53 ± 0.55 mg/ml) and decreased following a biphasic manner. Total plasma clearance and rapid and slow elimination half-lives obtained by a two-compartment model were 1.14 ± 0.16 l/h, 1.12 ± 0.26 h, and 9.98 ± 2.38 h, respectively, and the volume of distribution was 4.76 ± 0.64 l. Mean area under the concentration-time curve was 26.7 ± 3.75 mg/ml h. The total amount of HES excreted into urine was 59.4 % of the applied dose. Hemodilution was observed in all 12 subjects as indicated by a decrease of hemoglobin from 15.5 ± 0.4 g/dl at baseline to 13.8 ± 0.4 g/dl after the end of infusion. Adverse events in this study refer to changes of laboratory parameters and were assessed as not clinically relevant. CONCLUSION: Single administration of a 500 ml solution of 6 % HES 130/0.4 was confirmed to be safe and tolerable in healthy male Japanese subjects. A rapid renal excretion was observed within 24 h after drug administration, accounting for 96 % of the total amount excreted. A comparison with pharmacokinetic data derived from Caucasians did not reveal significant differences to Japanese and confirmed the good tolerability in both ethnic groups.

Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies.

BACKGROUND: Intravenously infused hydroxyethyl starch (HES) can be found in urine, plasma and tissues. HES remaining in plasma and tissues is thought to increase the risk of clinical complications. HES solutions of lower molecular weight and substitution have been developed to increase urinary excretion and reduce plasma persistence. However, their effect on tissue uptake of HES has not been investigated in human subjects. OBJECTIVE: Our objective was to test the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES. DATA SOURCES: Computer searches were performed of MEDLINE; EMBASE; the Cochrane Library; meeting abstract databases in surgery, anaesthesiology and intensive care; ClinicalTrials.gov; and Google. Supplementary sources were reference lists and electronic tables of journal contents. No time period or language restrictions were imposed. STUDY SELECTION: Clinical studies were eligible for inclusion in the meta-analysis, if data were reported both for cumulative urinary excretion of HES over 24 hours after infusion and for plasma HES concentration at 24 hours. DATA EXTRACTION: Data were extracted on 24-hour urinary excretion of HES, 24-hour HES plasma concentration, plasma volume, HES molecular weight and substitution, study design, type and demographics of subjects, indication for fluid infusion, and HES infusion regimen. Tissue uptake of HES was computed as the difference between the infused dose and the sum of urinary excretion and residual plasma HES at 24 hours. DATA SYNTHESIS: Twenty-five clinical studies totalling 287 subjects were included. Tissue uptake of low-molecular-weight HES (≤200 kD) was 42.3% (95% confidence interval [CI] 39.6, 45.0) compared with 24.6% (CI 17.8, 31.4) for high-molecular-weight HES (p < 0.001). Similarly, tissue uptake of lower-substitution HES (≤0.5) was 42.4% (CI 39.5, 45.3) versus 26.6% (CI 19.6, 33.6) for higher-substitution HES (p < 0.001). Among the three most often investigated single HES solutions, tissue uptake of 130/0.4 (42.6%; CI 35.0, 50.2) and HES 200/0.5 (43.3%; CI 39.4, 47.2) closely coincided, whereas uptake of HES 450/0.7 (22.2%; CI 14.8, 29.6) was lower (p = 0.001 and p < 0.001, respectively). CONCLUSIONS: This meta-analysis did not support the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES. Further clinical studies of HES tissue uptake are needed.

Site-specific chemical modification of human serum albumin with polyethylene glycol prolongs half-life and improves intravascular retention in mice.

Human serum albumin (HSA) is used as an important plasma volume expander in clinical practice. However, the infused HSA may extravasate into the interstitial space and induce peripheral edema in treating the critical illness related to marked increase in capillary permeability. Such poor intravascular retention also demands a frequent administration of HSA. We hypothesize that increasing the molecular weight of HSA by PEGylation may be a potential approach to decrease capillary permeability of HSA. In the present study, HSA was PEGylated in a site-specific manner and the PEGylated HSA carrying one chain of polyethylene glycol (PEG) (20 kDa) per HSA molecule was obtained. The purity, PEGylated site and secondary structure of the modified protein were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), thiol group blockage method and circular dichroism (CD) measurement, respectively. In addition, the pharmacokinetics in normal mice was investigated, vascular permeability of the PEGylated HSA was evaluated in lipopolysaccharide (LPS)-induced lung injury mouse model and the pharmacodynamics was investigated in LPS-induced sepsis model with systemic capillary leakage. The results showed that the biological half-life of the modified HSA was approximately 2.3 times of that of the native HSA, PEG-HSA had a lower vascular permeability and better recovery in blood pressure and haemodilution was observed in rats treated with PEG-HSA. From the results it can be inferred that the chemically well-defined and molecularly homogeneous PEGylated HSA is superior to HSA in treating capillary permeability increase related illness because of its longer biological half-life and lower vascular permeability.

Analysis of gelatin plasma substitutes in blood based on detection of hydroxyproline derivatives.

The gelatin plasma substitute is often polydisperse and heterogenous, making it difficult to determine the elimination rate and half-life in the body. In this study, one method was developed based on quantitative determination of hydroxyproline derivatives. Two plasma substitutes were prepared by succinylation and genipin-crosslinking, respectively. After transfusion, the blood samples were hydrolyzed and derivatized, and then analyzed by HPLC. A two-phase exponential association equation was used for fitting the time-concentration curves. The results indicated that this method could be used for quantitative determination of gelatin in blood, and the pharmacokinetic parameters such as elimination rate and half-life.

Superior plasma retention of a cross-linked human serum albumin dimer in nephrotic rats as a new type of plasma expander.

Human serum albumin (HSA) is used clinically as a plasma expander in patients with hypoalbuminemia and can also function as a drug carrier. However, the administered HSA is readily eliminated from the blood circulation under pathological conditions, especially the nephrotic syndrome. In this study, we present data on the pharmacokinetics of a structurally defined HSA dimer [two HSA molecules that are cross-linked by reaction with 1,6-bis(maleimido)hexane via Cys34] in nephrotic rats and its superior circulation persistence, owing to the molecular size effect. The half-time (t(1/2)) of the HSA dimer persisted in the circulation 1.3 times longer than that of monomeric HSA in normal rats, primarily because of the suppression of the accumulation of the HSA dimer in the skin and muscle. In nephrotic rats, the t(1/2) of the HSA monomer decreased considerably, whereas the HSA dimer remained unaltered in the blood stream, similar to that for normal rats. As a result, the t(1/2) of the HSA dimer was 2-fold longer than that of the HSA monomer. This longer t(1/2) can be attributed to the fact that accumulation in the kidney and urinary excretion of the HSA dimer were significantly suppressed. The cross-linked HSA dimer shows a longer blood circulation than native HSA monomer in nephrotic rats, which can be attributed to the suppression of renal filtration and leakage into the extravascular space. This HSA dimer has the potential for use as a drug carrier, new plasma expander, and an artificial albumin-based oxygen carrier under a high glomerular permeability condition such as nephrosis.

[Hydroxyethylstarch-induced pruritus: an understimated side effect of its application also in ENT diseases]. / Hydroxyethylstärke-induzierter Pruritus: Eine unterschätzte und hartnäckige medikamentöse Nebenwirkung auch bei HNO-ärztlichen Erkrankungen.

Chronic pruritus may be caused by drugs such as colloid infusions with hydroxyethylstarch (HES). HES-induced pruritus can be diagnosed by typical patient's history, clinical characteristics, confirmed application of HES and its cutaneous tissue storage obtained by electron microscopy. Pruritus occurs on the whole body and significantly impairs patient's quality of life. It persists daily in high and constant intensity. After several to 15 months in average pruritus decreases gradually and finally ceases when the HES deposits are degraded. Topical and systemic treatments are only of symptomatic value. HES-induced pruritus is severe, protracted and mostly therapy-refractory. Limiting the dose and the duration of HES application may help reducing this intractable side effect.

Modern rapidly degradable hydroxyethyl starches: current concepts.

Hydroxyethyl starch (HES) is a widely used plasma substitute for correcting perioperative hypovolemia. HES preparations are defined by concentration, molar substitution (MS), mean molecular weight (M(w)), the C(2)/C(6) ratio of substitution, the solvent, and the origin. The possible unwanted side effects of HES are anaphylactic reactions, alterations of hemostasis resulting in increased bleeding, kidney dysfunction, accumulation, and pruritus. In view of the potential side effects, it is crucial to distinguish among the different HES preparations; all HES preparations are not the same. The first generation of HES preparation showing a high M(w) (>450 kD) and a high MS (>0.7) was associated with negative effects with regard to coagulation, organ function, and accumulation. This review is focused on whether modern (third generation), more rapidly degradable HES preparations with a lower M(w) (130 kD) and a lower MS (<0.5) are safer and have fewer side effects. Several studies demonstrated that such modern HES preparations appear to be safe with regard to hemostasis, kidney function, itching, and accumulation. Modern HES preparations are dissolved in balanced, plasma-adapted solutions that no longer contain unphysiological amounts of sodium and chloride and are thus suitable for correcting hypovolemia.

A randomized, single-blind, increasing dose safety trial of an oxygen-carrying plasma expander (Hemospan) administered to orthopaedic surgery patients with spinal anaesthesia.

The objective of this study was to further explore the safety of Hemospan (Sangart Inc., San Diego, CA, USA), an oxygen-carrying plasma expander. The aim of this study was to determine if Hemospan is well tolerated in orthopaedic surgery patients with spinal anaesthesia in doses up to 1 L. Hemospan was previously found to be well tolerated in normal volunteers and orthopaedic surgery patients with spinal anaesthesia in doses up to 500 mL. Five cohorts of six orthopaedic surgery patients, American Society of Anesthesiologists (ASA) I and II, were studied. In each cohort, four patients received Hemospan in doses ranging from 200 to 1000 mL, and two received Ringer's lactate immediately prior to induction of spinal anaesthesia. There were no serious adverse events (SAEs). Iohexol clearance measured before and 24 h after dosing was unaffected. There were 14 adverse events (AEs) in the 10 control patients (1.4 per patient) and 30 in the 20 patients receiving Hemospan (1.5 per patient). One patient in the group receiving 200 mL Hemospan had elevated mean arterial pressure after dosing, but there were no elevations in any of the other patients. The peak plasma Hemospan concentration in the 1000 mL group was 1.3 g dL(-1), with a dose-dependent clearance (T(1/2)) ranging from 14.1 to 23.0 h. Plasma methaemoglobin levels were independent of dose, reaching a maximum at 40 h after dosing and never exceeded 0.125 g dL(-1). Troponin T was transiently elevated in two patients receiving Hemospan without symptoms or electrocardiographic abnormalities or elevation of myocardial creatinine kinase isoenzyme. Hemospan was well tolerated in this group of patients at doses up to 1000 mL.