The Effect Of Hydroxyethyl Starch 130/0.4 On Vascular Leakage In Children With Congenital Heart Diseases And Related Pharmacological Investigation On Hydroxyethyl Starch 130/0.4

BackgroundHydroxyethyl starch (HES) is one of volume expansion when administered into intravenously, and mainly is used for clinical liquid treatment. It HSA been reported that HES had a greater risk for kidney injury, and it was the source of German medical authorities JoachimBoldt’s thesis fraud. The international top medical journal BMJ published an article named "Boldt, the great pretender", and more than 90 pieces of HES clinical papers of Boldt’s were products of behind closed doors. Now HES is on controversial because of its’efficacy and safety problems, and it significantly increases the risk of kidney damage especially the risks of infants and young children.Voluven as the third generation of HES is the trade name for 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection and is with optimizing molecular daltons and molar substitution. It is clear that the higher molar substitution of Voluven the less amount of enzyme degradation, so Voluven is smaller influence on blood coagulation and liver function. Voluven HSA a good effect on blood dilution effect. Colloid osmotic pressure (COP) which determined by proteins especially human serum albumin (HSA) is about from 25 to 28 mmHg. But the COP of Voluven is about from 38 to 42 mmHg, when Voluven is inputted into blood, and it can increase the body’s blood plasma colloid osmotic pressure (PCOP) in a certain period of time. Congenital heart disease (CHD) is a frequent occurrence of pediatric disease, and the surgical repairs of ventricular septal defect and atrial septal defect patients need cardiopulmonary bypass. Voluven HSA been widely used in patients undergoing open heart surgeries in association with cardiopulmonary bypass. Voluven as a kind of macromolecule material also can treat blood capillary leakage in adult patient, and the mechanisms may be related to mechanical blockage and anti-inflammatory effects, but a small amount of Voluven can escape out of blood vessels at the same time. If Voluven may escaping out of blood vessels in children is not clear, so the vascular leakage research of Voluven in children is needed to do.This topic mainly studies the blood vascular leakage of Voluven in low age children. By comparing the changes of blood expansion ratio, PCOP and the plasma Voluven concentration in different aged children after acute hemodilution (AHD), the vascular leakage research of Voluven in low age group children is needed to research. While the indexes of hemodynamic and pressure-volume during mechanical ventilation in patients after AHD with Voluven are observed. The combing state of drugs with HSA into the blood system shows its activity and metabolism. In order to improve clinical research, using modern instruments in the laboratory studies the interaction mechanism about pharmacokinetic and toxicology interaction mechanism of Voluven combining HSA. The binding affinity of Voluven and HSA under physiological condition should be investigated needly. To futher guiding the safety of cilincal application, and these parameters of Voluven-protein interaction, quenching mechanism with thermodynamic parameters, binding sites and effect of common ions are also important for understanding pharmacokinetic and toxicological properties of Voluven.Part 1 The effect of hydroxyethyl starch 130/0.4 on vascular leakage in children with congenital heart diseases.ObjectonsIt HSA not been clear that Voluven may be administered in lower age children patients safely although Voluven HSA been widely used in the liquid treatment of children. The purpose of this article was to study Voluven doing AHD at a certain speed in children with CHD. By comparing the changes of blood expansion ratio, PCOP and the plasma Voluven concentration in different age children groups after AHD, and studied the difference of distribution and metabolism of Voluven in the children, then the vascular leakage research of Voluven in low age children needed to research. Meanwhile the indexes of hemodynamics and pressure-volume curve were observed during mechanical ventilation in children after AHD with Voluven.MethodsForty children with CHD were divided into two groups according to the ages. A group was the preschool children (2≤age≤6 years old, n=20) and B group was the school children (6< age≤12 years old, n=20). After the endotracheal intubation of anesthesia, invasive measurement of radial artery pressure and center venipuncture were done. Then 10% blood volume of Voluven according to blood volume formula were target controlled infused into the patients at the speed of 0.5 mL·Kg-1·min-1 through central venous. Vitro model was set up in a test tube before infusing Voluven in which the proportion of the blood and volume was 10:1 as the same proportion as Voluven inputting huaman body. The indexes of heart rate(HR), mean arterial pressure (MAP), central venous pressure(CVP), peak inspiratory pressure(Ppeak), plateau inspiratory pressures (Pplat), positive end-expiratory pressure(Ppeep), compliance (Cdyn), pulse oxygen saturation (SpO2) and pressure of end-tidal carbon di-oxide (PETCO2) were measured in the following time points, prior to the Voluven infusion(T1), the infusion of half volume of Voluven(T2), the finish of Voluven infusion (T3),3min (T4),5min (T5) and 10min (T6) after infusion.The indexes of PCOP, plasma Voluven concentration,hemoglobin(HGB), potential of hydrogen(pH), serum kalium (K+) and serum calcium (Ca2+) were measured in the following time points, prior to the Voluven infusion(T1), infusion 15min (T7) and 30min (T8) after infusion.Results1. The basic situation of children.Forty chidren with CHD were enrolled in the study. A group was the preschool children (2≤age≤6 years old, n=20), male 12 cases, female 8 cases, ASD9 example, VSD11 example, average age (4.4 ± 1.3)y, average height (1.11±0.10) m, average weight (18.7 ±3.1)kg. B group was the school children (6< age≤12 years old, n=20), male 12 cases, female 8 cases, ASD8 example, VSD12 example, the average age (10.6 ±1.5)y, average height (1.48± 0.11) m, average weight (38.7 ±7.1) kg. The amount of inputting Voluven in group A was (7.82±0.3)/kg and in group B was (7.72±0.2 mm)/kg, mesnwhile the infusion time of group A was(15.6 ±0.7) min and group B was (15.4 ±0.5) min.2. The hemodynamic indexes of all the children before and after infusion. Compared with the baseline value at T1, HR was significantly decreased atT3～T6, and CVP was significantly increased at T2～T6, but all the indexes of HR and CVP were in the normal ranges. There was no significantly difference of MAP.The hemodynamic indexes of children in two groups before and after infusion. Compared with the baseline value at T1, HR were significantly decreased at T2～T6 in group Aand significantly decreased at T5 in group B. Compared with group A, HR of group B was significantly decreased at T1～T6. Compared with the baseline value at T1, CVP were significantly increased at T3～T5 in group A and significantly increased at T2～T6 in group B. There were no significantly differences of the MAP between the two groups.3. The respitatory indexes of all the children before and after infusion. Compared with the baseline value at T1, there were no significantly differences of AP, Ppeak, Pplat, Ppeep, Cdy, SpO2 and PETCO2.The respirator indexes of children in two groups before and after infusion. Compared with group A, the AP, Ppeak and Ppeep were significantly lower at T1～T6 in group B, and the Cdyn was significantly higher at T1～T6 in group B. There were no significantly differences of Pplat, SpO2 and PEtCO2 between the two groups.4. The indexes of PCOP and blood gas indexes in all the children before and after infusion. Compared with the baseline value at T1, HGB and in vitro model of HGB were significantly decreased at T7, and PCOP was significantly increased at T7 while significantly increased at T7 and Tg in viro model of PCOP, and K+ were significantly decreased at T7. The relative dilution degree after influsing Volven was10.4% nearly to 10% blood volume according to volume formula.The indexes of PCOP and blood gas in two groups of children before and after infusion. Compared with the baseline value at T1, PCOP were significantly increased at T7 and T8 in group B but there were no significantly difference in group A. There were no significant differences of the PH and Ca2+ between the two groups.5. The plasma Voluven concentrations of children in two groups before and after infusion. Compared with the point of T7, plasma Voluven concentrations in two groups were significantly decreased at T8.The plasma Voluven concentrations in group B and the vitro models of group B were significantly higher than that of group A in T7 and T8. Within 30min after ifusion, Voluven concentratons of urine were (0.40±0.05)mg/ml in group A and (0.40±0.05)mg/ml in group B. There were no significantly differences of urine Voluven concentraton between the two groups.ConclusionsIt can effectively maintain hemodynamic and respiratory stable and good blood expansion effect in CHD children after AHD with 10% blood volume of Voluven at the speed of 0.5 ml·kg-1·min-1. By comparing the changes of blood expansion ratio, PCOP and the plasma Voluven concentration and urine Voluven concentration in different age groups children after AHD with Voluven, and we find that blood expansion ratio with Voluwen is the same in two groups but the PCOP and plasma Voluven concentration in low age group children are lower. That is to say, the vascular leakage of Voluven in low age group children is more obvious. It should be more careful to use Voluven less than six years old children.Part Two Related pharmacological investigation on hydroxyethyl starch 130/0.4 (Voluven). Investigation on the interaction of hydroxyethyl starch 130/0.4 (Voluven) and serum albumin for pharmacokinetic and toxicological implications.BackgroundBinding of drugs to the proteins in blood stream is a significant process to determine their eventual activities and the fate of the drugs entering into the circulatory system. When Voluven comes into veins, the first step would be association with HSA. These parameters of Voluven-HSA interaction, quenching mechanism with thermodynamic parameters, binding sites and effect of common ions are important for understanding pharmacokinetic and toxicological properties of Voluven, and that are also import for studing the moleculer biological basis on vascular leakage of Voluven in infantile. The degree of Voluven combined with HSA affect its concentration in plasma. Voluven combined with HSA caughing some ions will improve the blood concentration of free Voluven, thus studing the role of certain ions with Voluven in plasma is of great significance. So the investigations on the interaction of Voluven and HSA for pharmacokinetic and toxicological implications are more importance for drug development and improvement.ObjectivesVoluven was infusioned in different age groups children at the same proportion of Voluven, and we fond the same of expansion ratio but the differences of PCOP and Voluven plasma concentrations in the first part of the clinical research. Voluven in low age group children was more vascular leakage. This research mainly in the laboratory using modern instrumentals from molecular biology analysis study the Volven-HSA interaction combination of state and the factors affect the concentration of plasma Voluven, and also study some metal ions such as K+and Ca2+ affecting Voluven- HAS combination.MethodsUnder the condition in vitro, using modern instrumental of Fluorescence, Fourier transform infrared spectroscopy and Circular dichroism in the laboratory, studied the interaction mechanism about pharmacokinetics and toxicology interaction mechanism of Voluven -HSA combination.Results1. This observation suggested that 1:1 complexation occurred between Voluven and HSA, and the probable reason of fluorescence quenching was a static mechanism.2. The thermodynamic parameters and the energy transfer principle indicated that Voluven -HSA combination was exothermic reaction, and electrostatic force was the main binding force. Because Voluven -HSA combination was the weak forces, thus in electrolytes environment in the blood the Voluven -HSA combination was easy to be separated into free Voluven.3. Forster radiation energy transfer theory indicating the binding distance was calculated to be 2.85nm, which indicated that efficient energy transfer can occur between the trytophan residue of HSA and Voluven. The distance of the Voluven-HSA system was 2.8nm, which again elucidated a static quenching mode of the system.4. Circular dichroism and Fourierinfrared spectroscopy measurements showed that voluven influenced from the skeleton amino acid residues on the chain, and destroyed the hydrogen bonding network caused part of the protein restructure.5. Some metal ions such as K+ and Ca2+ combinated Voluven -HSA combination with ion bridges, and increased the free Voluven concentration in plasma meanwhile those ions concentrations decreased.ConclusionsThis observation suggests that 1:1 complexation occurred between the Voluven and HSA, and Voluven -HSA combination can easily become free Voluven due to the weak combining force. Some metal ions such as K+and Ca2+ combinate Voluven-HSA combination with ion bridges, and increases the free Voluven concentration in plasma meanwhile thouse ions concentrations decrease.