Short-term morbidities in moderate and late preterm infants.

OBJECTIVE: To determine (1) the association between neonatal morbidity and gestational age and (2) the impact of pre-existing maternal medical conditions, pregnancy and birth complications on neonatal outcome in moderate and late preterm infants (32-36 completed weeks). METHODS: Retrospective single-centre cohort study including all moderate and late preterm infants without congenital anomalies born at the Children's and Maternity Hospital Linz, Austria, between January 2007 and June 2010. Stepwise regression analysis was used to determine significant associations between morbidities, maternal and perinatal complications and the gestational age. RESULTS: Of 870 infants included the incidence of neonatal morbidities increased from 24% at 36 weeks to 43% at 35 weeks', 55% at 34 weeks', 75% at 33 weeks' and 93% at 32 weeks' gestation. Infants at 32 weeks had a 4-fold (RR: 3.88; 95% CI: 1.87-8.06) increased risk compared with those at 36 weeks, and infants of 32 weeks were 16 times (RR: 16.01; 95% CI: 9.82-26.09) more likely to be admitted to the NICU than infants of 36 weeks'. Hyperbilirubinemia (29%) and respiratory morbidity (14.3%) were the most common neonatal diagnoses. Intrauterine growth restriction, preeclampsia, preterm premature rupture of the membranes, lack of antenatal steroid administration, antepartum hemorrhage, multiple pregnancy and male gender were all associated with any kind of neonatal morbidity, admission rate to the NICU and length of hospital stay (p<0.05). CONCLUSION: Nearly half of all infants suffered from any morbidity, and several risk factors were identified being significantly associated with NICU admission rate and length of hospitalization.

Intestinal elimination of hydroxyethyl starch?

OBJECTIVE: Hydroxyethyl starch (HES) is mainly eliminated via the kidneys. Any information about extrarenal elimination obtained so far has been either incomplete or contradictory. The objective of this study was to quantify the intestinal excretion of infused HES with a mean molecular weight of 200,000 and a molar substitution of 0.5 (HES 200/0.5) and to compare the reappearance/recovery rate in urine and plasma. DESIGN: Prospective clinical study without control group. SETTING: The study was conducted at the Institute of Hypertension of the Society of Clinical Pharmacology, Vienna, Austria, which is an establishment for research in volunteers. PARTICIPANTS: The results of six out of seven healthy male volunteers were appropriate for analysis. One trial subject had to be excluded from the study because of severe protocol violation (mixing of stool and urine samples). INTERVENTIONS AND METHODS: Each volunteer was administered 500 ml of 10% HES 200/0.5 in a 0.9% NaCl solution intravenously within 1 h. A gut lavage with 6 l of a polysaccharide free solution was continuously administered from 3 h prior to until 2 h after the HES infusion to facilitate the collection of the samples and to exclude any source of error at analysis. HES was quantified with the hexokinase method. MEASUREMENTS AND RESULTS: Right from the beginning of the infusion until 10 h after its completion, the cumulative HES excretion with feces (principle parameter) and urine as well as selective plasma volume and HES plasma level were measured. Six and 14 h after the infusion had been completed, the recovery rates of HES in urine were about 30% and 40%, respectively, and in plasma about 23% and 8%, respectively. By contrast, not more than a kind of "background noise amount" of HES (about 0.2 %) could be recovered in feces ( mean value in % of the infused amount of the substance). Six and 14 h after the infusion had been completed, the total recovery rates of HES were 53% and 49%, respectively. CONCLUSION: In a physiologically unimpaired gut HES 200/0.5 is not, or only to an infinitesimal extent, eliminated via the intestine. The question if there is any alternative path to renal excretion for HES still remains to be answered. As the calculated reappearance/recovery rate of HES is only about 50 % of the administered dose, further investigations as to the final fate of HES appear necessary.

Hypervolumetric hemodilution with HES 100/0.5 10% in patients with peripheral arterial occlusive disease (Fontaine, stage II): an open clinical and pharmacological phase IV study.

The efficacy of three weekly interventions with hypervolumetric hemodilution of a new preparation of hydroxyethyl starch (HES 100/0.5, 10%, C2/C6 substitution ratio of 6.5) on pain-free walking distance of patients with peripheral arterial occlusive disease (PAOD) stage IIb on the Fontaine classification was investigated. In addition quantitative data on the pharmacokinetic properties of this HES preparation, and it's impact on hemorheology, hemostasis and homeostasis were shown. Ten patients were included according to a predefined protocol, and treated openly with 500 ml HES 100/0.5 10% on nine occasions over 18 days. Pain-free walking distance, the main outcome measure, showed a mean increase of 82 m (+60%). Hematocrit decreased 4 percentage points on average (5.5 percentage points one hour after interventions). Plasma viscosity dropped 5% on average with significant changes immediately after interventions only in patients whose baseline values had been equal to or above the 2 s reference area. Erythrocyte aggregation decreased by 16% in the course of treatment (8% immediately after interventions), systolic blood pressure by 13%, and total protein by 7%. Complement showed a trend towards lower values (-20%), and creatinine, pH and urine viscosity remained unchanged. Apart from complement changes, all reductions mirrored the dilution effects. As to pharmacokinetics, serum mean molecular weight distribution was very similar to that of the infusion. A minor adverse drug reaction (light, spontaneously disappearing pruritus) was observed in one case.

Hydroxyethyl starch antibodies in humans: incidence and clinical relevance.

UNLABELLED: Hydroxyethyl starch (HES) is a plasma expander used for perioperative i.v. fluid management, as well as for resuscitation from trauma and shock. HES is very well tolerated, and the incidence of anaphylactic reactions is lower than with dextran or gelatin. Dextran anaphylaxis is caused by circulating dextran-reactive antibodies (ABs) of the immunoglobin G (IgG) class found in most adults. Histamine release from mast cells induces adverse reactions after gelatin infusion. The cause of adverse reactions due to HES is not yet clear. To investigate AB formation due to HES, we collected sera of 1004 patients at least 14 days after starch administration. Using a highly sensitive enzyme-linked immunoabsorbent assay technique, we found one patient with a low 1:10 titer of HES-reactive ABs (immunoglobin M [IgM] class). Despite repeated HES infusions, no clinical reaction could be detected in this patient. On the basis of a binomial distribution, a one-tailed confidence interval (99%) was used to calculate the percentage of the occurrence of ABs in general with maximum of 33 in 10,000 persons (IgM) and 23 in 10,000 persons (IgG). We suggest that HES-reactive ABs are extremely rare and that they do not necessarily induce anaphylaxis. Other mechanisms may be responsible for adverse reactions due to HES. IMPLICATIONS: The frequency of antibody formation due to hydroxyethyl starch, a commonly used plasma expander, was prospectively investigated in 1004 patients. Only one patient showed transient antibody formation, which was not harmful to the patient. This low antigenicity could explain the excellent tolerance of hydroxyethyl starch compared with other plasma expanders.

[Intestinal lavage solution for orthograde intestinal irrigation]. / Darmspüllösung zur orthograden Darmspülung.

Gut lavage by ingestion of large volumes of electrolyte solutions has been shown to be an effective method of cleansing the colon before colonoscopy, barium enema or surgery. Absorption of water and electrolytes, which might be hazardous to patients who are unable to readily excrete an additional sodium and/or water load, is prevented by addition of non-absorbable substances to the solutions, but systematic studies are lacking. We have evaluated the influence of three solutions for gut lavage with different electrolyte composition (sodium concentration 67 mmol/l and 125 mmol/l) and addition of different non-absorbable substances (mannitol and polyethylene glycol [PEG]) on water and electrolyte homeostasis and subjective tolerance, both in healthy volunteers and in patients before endoscopy of the colon. In a randomized, blind study 6 liters of the three solutions were administered via a nasogastric tube to 6 healthy volunteers during 4 hours (i.e. 1.5 l/h). Body weight, serum concentrations of sodium, potassium and of phosphate were measured before infusion of the solution and after the last rhythmic rectal effluent. No significant changes were observed in any of the studied parameters and the incidence of side effects (nausea, abdominal cramps) was comparable. In an additional clinical double blind study, 26 patients before diagnostic colonoscopy were asked to drink 4 liters of the gut lavage solutions as quickly as possible in order to clean out the colon. The time for drinking was significantly shorter in patients using the mannitol and low sodium solution (204 +/- 70 minutes) than in patients drinking the solution with polyethylene glycol and a high sodium concentration (387 +/- 137 minutes). There was a tendency to a longer drinking period in patients ingesting the solution with polyethylene glycol and low sodium (306 +/- 106 minutes). Thus, the acceptance for solutions containing polyethylenglycol and high sodium concentration is reduced because of low palatibility. Again no influence on serum electrolyte concentrations or body weight could be observed in any patient, the spectrum of side effects was similar and the cleansing effect of all three solutions was adequate. In conclusion solutions for gut lavage containing a balanced electrolyte concentration and nonresorbable substances such as mannitol or polythylenglycol are equivalent. However, solutions containing mannitol and a low sodium concentration are better tolerated by the patients but the use of mannitol is limited because of the risk of releasing explosive gases during interventional endoscopy. To enhance the acceptance and palatibility of solutions for gut lavage containing polethylenglycol the addition of flavoured substances is recommended.

[Comparison of postoperative volume therapy in heart surgery patients]. / Vergleichende Untersuchungen zur postoperativen Volumentherapie bei kardiochirurgischen Patienten.

UNLABELLED: Patients who have undergone cardiac surgery with use of extracorporeal circulation frequently reveal marked hypovolaemia in spite of a highly positive fluid balance. This is thought to be due to transient microvascular damage and extravascular fluid shift. Further volume replacement to achieve haemodynamic stability in the postoperative period may cause fluid overload and congestive heart failure. The present study was designed to investigate whether this fluid overload could be avoided by using a hypertonic-hyperoncotic solution (group I: HHL, 10% hydroxyethylstarch 200/0.5 in 7.2% saline) instead of two different standard colloid solutions (group II: HA, 5% albumin; group III: HES, 6% hydroxyethylstarch in 0.9% saline). METHODS: Twenty-one patients meeting our criteria for hypovolaemia immediately after cardiac surgery were randomly assigned to three groups. Patients in group I received HHL in increments of 150 ml, while patients in group II and group III were given HA and HES respectively in increments of 500 ml until hypovolemia was corrected. Haemodynamic assessment was done using a pulmonary artery thermodilution catheter. Intra- and extravascular volumes, including extravascular lung water (EVLW), intrathoracic blood volume (ITBV), and total blood volume (TBV) were measured by the double indicator technique using lung water software (COLD-System, Pulsion, Munich, Germany). RESULTS: Correction of hypovolaemia-related haemodynamic parameters and restoration of normal TBV were achieved by 236 +/- 80 ml of HHL (group I), 857 +/- 244 ml of HA (group II) and 1000 +/- 0 ml of HES (group III) respectively. TBV increased significantly in each group, compared to baseline values. EVLW did not change significantly in any group. We found that the volume-augmenting effect of HHL per millilitre infused solution was more than four times that of HA and HES, primarily as a result of increasing plasma osmolality due to an increase of plasma sodium levels. This pronounced effect on intravascular volume of HHL lasted for only 2 h following infusion, however, and did not lead to any unwanted side effects. In the period between 2 and 20 h after primary volume replacement, further fluid therapy with colloids and crystalloids, guided by clinical signs of hypovolaemia, was necessary in each group of patients. The overall fluid requirements for the first 20 h after operation did not differ among the three resuscitation regimens. CONCLUSION: We found that HHL is a safe and effective solution for acute correction of hypovolaemia after cardiac surgery. The advantages of a smaller initial volume load by HHL cannot be maintained for longer than 2 h.

[Comparison of 2 6% middle-molecular hydroxyethyl starch solutions on elimination kinetics and flow characteristics of blood in volunteers]. / Vergleich von zwei 6%igen mittelmolekularen Hydroxyäthylstärkelösungen auf die Eliminationskinetik und die Fliessfähigkeit des Blutes bei freiwilligen Probanden.

OBJECTIVE: Investigation of the influence of C2/C6 occupation ratio of 2 different 6% hydroxyethyl starch (HES) solutions on elimination kinetics and blood fluidity. DESIGN: A single-blinded, prospective randomised cross-over study. SETTING: Haemostasiological-angiologic outpatient department of the university of Homburg. SUBJECTS: 6 voluntary apparently healthy subjects. INTERVENTIONS: A 500 ml infusion of 2 different HES solutions (6% HES 200/0.5 or 6% HES 200/0.62, respectively) was given intravenously within 1 h. A wash-out phase of 3 months was kept between both infusions. The concentration and distribution of the molecular weight of the intravasal HES molecules up until 24 h after the infusion as well as the blood fluidity before and after the infusion were measured. RESULTS: Besides the molecular substitution (MS), which is different for the 2 employed HES solutions, the occupation ratio of the C2 respectively C6 (C2/C6 occupation ratio) of the glucose ring influences the breakdown of the HES molecules. This influences the blood fluidity. While the decrease in haematocrit 1 h after the end of the infusion is comparable, the decrease in the haematocrit in the case of high C2/C6 occupation ratio and a high MS is maintained for a longer period of time. The increase in plasma viscosity in the case of high C2/C6 occupation ratio and high MS is more marked. CONCLUSIONS: The infusion of HES 200/0.62 leads to a significantly longer prevalence in comparison to HES 200/0.5, in combination with clearly larger degradation products in the plasma; this fact causes a more marked dilutional effect, but also a more marked increase in the plasma viscosity up to 24 h after the end of infusion. In the discussion on haemodilution therapy in patients with arterial occlusive disease the employment of HES which induces an increase in plasma viscosity is thought to be a disadvantage.

["Small volume resuscitation"--does it open new possibilities in the treatment of hypovolemic shock?]. / "Small volume resuscitation"--Eröffnen sich damit neue Möglichkeiten in der Behandlung des hypovolämischen Schocks?

Hypertonic-hyperoncotic solutions are a supplementation to conventional fluid regimens in the management of hypovolemia due to trauma, hemorrhage and shock. In this review the possible modes of action of these solutions are discussed and their efficacy both in experimental and clinical settings is presented. Possible side effects, such as hypernatremia and possible problems in the presence of increased intracranial pressure, following administration of hypertonic-hyperoncotic solutions are discussed, as well as the reaction of normovolemic patients to such infusions.

[The effect of molecular structure of hydroxyethyl starch on the elimination kinetics and fluidity of blood in human volunteers]. / Einfluss der Molekülstruktur von Hydroxyäthylstärke auf die Eliminationskinetik und die Fliessfähigkeit des Blutes bei Probanden.

Influence of the Molecular Structure of Hydroxyethyl Starch on Elimination Kinetics and Blood Fluidity in Voluntary Subjects In a cross-over study 6 volunteers received an infusion of 500 ml hydroxyethyl starch of a batch with a high C2/C6-substitution ratio (10.8), or after a washout period of 3 months they received a batch with a low C2/C6-substitution ratio (5.8). The infusion solution was administered at random. The batches were identical as regards their physicochemical characteristics (HES 200/0.5 10%). The concentration and molecular weight distribution of the intravascular hydroxyethyl starch molecules were determined after infusion up to 24 h, the blood fluidity before and after infusion. The substitution ratio of the C2- or C6-atoms in the glucose ring has an effect on the degradation of the hydroxyethyl starch molecule: the molecules with a high C2/C6-substitution ratio appear to be degraded within the same period of time, the resulting degradation products, however, have a higher molecular weight. This influences the blood fluidity. While the haematocrit decrease occurring 1 h after end of infusion is comparable, it keeps up for a longer time in case of a higher C2/C6-substitution ratio. The increase of plasma viscosity is more pronounced in case of a high C2/C6-substitution ratio. Clinical consequences are discussed.

Hydroxyethylstarch deposits in human skin--a model for pruritus?

Severe itching for unknown reasons has been reported after administration of hydroxyethylstarch (HES) in haemodilution therapy of humans. After HES treatment, vacuoles in cells of various organs in humans have been shown, predominantly affecting the mononuclear phagocyte system. These vacuoles present indirect evidence for phagocytosis of HES particles. Since phagocytosis is also known to occur in the skin, this organ might represent a target for HES deposition, resulting in subsequent release of mediators responsible for the observed itching. The aim of the present investigation was to study skin biopsies of patients, who had received HES and suffered subsequently from itch. Skin sections were investigated for morphological impairment by means of light and electron microscopy, immunohistochemistry and immunoelectron microscopy using a polyclonal anti-HES antiserum. Storage of HES was demonstrated in the skin of all patients, mainly in dermal macrophages, endothelial cells of blood and lymph vessels, some perineural cells and endoneural macrophages of larger nerve fascicles, some keratinocytes and Langerhans cells. Treatment with antihistaminic agents proved ineffective in these patients; this fits with the observation that morphological signs of histamine release from mast cells were absent. These findings indicate that other mediators from HES-affected cells must be responsible for the development of the itching. Thus, investigation of HES storage may be a useful contribution to the elucidation of release of itch mediators and induction of pruritus.

Histological and immunohistochemical investigations of hydroxyethyl-starch deposits in rat tissues.

Tissue storage of hydroxyethyl starch (HES), a widely used artificial colloid, has been reported. In order to clarify whether storage of HES can be detected in tissues by immunohistochemical methods, use was made of a polyclonal rabbit anti-HES antiserum. Thirteen days after a single intravenous injection of HES rats were sacrificed and liver, spleen, lymph node, lung, kidney and skin were removed. On paraffin sections in all organs the anti-HES antiserum stained mainly cells which could be attributed to the mononuclear phagocyte system, as confirmed by the use of the antimacrophage monoclonal antibody ED1. The use of a polyclonal anti-HES antiserum may allow analysis of long-term storage and possible side effects in various tissues of man.