[Hyperoxia-induced liberation of big-endothelin into jugular venous blood of electric neurosurgical patients]. / Hyperoxie-induzierte Freisetzung von BIG-Endothelin in das jugularvenöse Blut elektiver neurochirurgischer Patienten.

The use of hyperoxia in emergency situations is generally accepted, but the routine and uncritical application of higher oxygen concentrations is criticized. The influence of short-term application of hyperoxia on cerebral oxygenation, cerebral lactate and BIG-endothelin (BIG-ET) was studied. After approval by the Ethics Committee of the University of Leipzig, 22 patients (hyperoxia group n = 16, normoxia, control group n = 6) undergoing an elective craniotomy were included in the study. After induction of a total intravenous anaesthesia (sufentanil and propofol), a fibre-optic catheter was inserted into the bulb of the jugular vein. The inspiratory concentration of oxygen was raised from 0.4 to 1.0 for 15 minutes. Before, during and after hyperoxia, a blood gas analysis and analysis of lactate and BIG-ET were performed from arterial and jugularvenous blood. Hyperoxia caused a significant increase in jugularvenous oxygen saturation (sjO2) from 60.4 +/- 8.8% to 68.6 +/- 10.4% and jugularvenous oxygen content (cjvO2) from 10.27 +/- 2.06 vol% to 11.76 +/- 2.16 vol%. These changes were reversible after the end of hyperoxia. The jugularvenous lactate decreased significantly (9%) from 1.20 +/- 0.48 mmol/l to 1.10 +/- 0.45 mmol/l after the end of hyperoxia. Hyperoxia led to a significant increase in jugularvenous BIG-ET from 3.35 +/- 0.61 pg/ml to a maximum of 3.82 +/- 0.95 pg/ml and a decrease in the arterio-jugularvenous difference of BIG-ET from 0.19 +/- 0.53 pg/ml to a minimum -0.11 +/- 0.32 pg/ml. The changes in lactate and BIG-ET were also seen after the end of the hyperoxia. In the control group (normoxia, FiO2 0.4), no significant changes in sjO2, oxygen content, lactate and BIG-ET were observed. The increase in jugularvenous BIG-ET and the decrease in the arterio-jugularvenous difference of BIG-ET following hyperoxia indicate a higher cerebral release of BIG-ET.

Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta-thalassemia.

The butyrate derivative isobutyramide (IBT) increases fetal hemoglobin (HbF) in patients with beta-hemoglobinopathies, but little is known about its usefulness for prolonged therapeutic use. We treated 8 patients with transfusion-dependent beta-thalassemia with 350 mg/kg of body weight per day of oral IBT for 126 to 384 days. During the trial period, the hemoglobin level was maintained between 85 g/L (range 82-87 g/L) (pretransfusion) and 115 g/L (range 110-119 g/L) (post-transfusion) (median, interquartile range), corresponding to 4-week transfusion intervals in all patients during the pretreatment phase. Adverse effects (bitter taste, epigastric discomfort) did not cause discontinuation of IBT. HbF increased in all patients from 3.1% (range 1.9%-4.8%) to 6.0% (range 3.3%-8.7) (P =.0017), while free Hb dropped from 0.48 g/L (range 0.39-0.81 g/L) to 0.19 g/L (range 0.16-0.24 g/L) (P <.0001). Transfusion intervals were consistently extended to 8 or 9 weeks in 1 patient, resulting in a decrease of daily iron load from 455 microgram/kg per day (range 451-459 microgram/kg per day) before therapy to 211 microgram/kg per day (range 203-286 microgram/kg per day) during the 12-month treatment period. Prolongation of transfusion intervals achieved by IBT was less consistent in another patient, whose parenteral iron load nevertheless decreased from 683 microgram/kg per day (range 618-748 microgram/kg per day) to 542 microgram/kg per day (340-596 microgram/kg per day). In the other 6 patients, no prolongation of transfusion intervals was achieved. Response to treatment was associated with high pretreatment HbF (> 4.5%), high parental HbF, and increased erythropoietin levels (> 150 IU/L). We conclude that IBT prolongs transfusion intervals and reduces parenteral iron burden in some patients with transfusion-dependent beta-thalassemia.

[The effects of perioperative continuous administration of mivazerol on early postoperative hemodynamics and plasma catecholamines after major surgery]. / Die Auswirkungen der perioperativen Gabe des alpha 2-Adrenorezeptor-Agonisten Mivazerol auf frühpostoperative Hämodynamik und Plasmakatecholaminspiegel nach grossen chirurgischen Eingriffen.

OBJECTIVE: During and after surgical procedures a strong activation of the sympatho-adrenergic system is common with correlation to adverse cardiac outcome. Several drugs (alpha 2-adrenoceptor-agonists, beta blockers) are discussed to prevent this reaction. The new alpha 2-adrenoceptor-agonist mivazerol with marked specificity for alpha 2-adrenergic receptors may be suitable for this indication. The aim of the present study was to investigate the effects of perioperative continuous administration of mivazerol on plasma catecholamines, body temperature and calculated haemodynamic parameters in the early postoperative period in cardiac risk patients undergoing non-cardiac surgery. METHODS: 36 patients with known coronary heart disease or risk factors for coronary heart disease scheduled for elective abdominal or vascular surgery were included in the study. Patients received either mivazerol (n = 18) or placebo (n = 18) [initial dose 4 micrograms kg-1 for 10 minutes before induction of anaesthesia, followed by a continuous infusion of 1.5 micrograms kg-1 h-1 intraoperatively and for as long as 72 h after surgery] in a double-blinded, randomized manner. Blood pressure, heart rate and body temperature were measured every 10 minutes until 240 minutes after arrival at the ICU. During 240 minutes after arrival at the ICU measured parameters (CVP, PAP, PCWP, SaO2, SvO2, CO), calculated parameters (CI, SVR, PVR, VO2) and plasma catecholamines were measured at defined time intervalls. RESULTS: The plasma concentrations of epinephrine and norepinephrine and the heart rate were significantly lower in the mivazerol group in the study period. Regarding blood pressure and body temperature there were no differences between the groups. At some measuring points preload was higher in the mivazerol group, but there were no differences between the groups for measured (SaO2, SvO2, CO) and calculated (CI, SVR, PVR, VO2) cardiorespiratory parameters. The incidence of shivering, nausea and vomiting were similar in both groups. CONCLUSION: Continuous, perioperative administration of mivazerol decreased the heart rate and the plasma catecholamines in the early postoperative period, but did not affect blood pressure, body temperature and the incidence of shivering. There were also no effects of mivazerol on calculated haemodynamic parameters (CO, SVR, PVR, VO2). These findings show a selective decrease in heart rate by Mivazerol without markedly cardiorespiratory side effects.

A challenge to the concept of tubal reflux to explain the rise and fall of CA125 in serum during the first trimester.

Although amniotic fluid concentrations of cancer antigen (CA) 125 rise during the first two trimesters of pregnancy, the serum concentrations of CA125 peak during the first trimester and drop to non-pregnant values in the second and third trimester. A previous hypothesis to explain this phenomenon was that in the early first trimester decidual CA125 gains access to the maternal compartment via 'tubal reflux' and subsequent absorption by peritoneal lymphatics. However, as pregnancy advances, the decidua capsularis fuses with the decidua parietalis, thus obliterating the endometrial cavity at 10-12 weeks; the Fallopian tubes thus become functionally obstructed. To test this hypothesis, we evaluated early first trimester CA125 concentrations in women conceiving by in-vitro fertilization (IVF) and embryo transfer with patent tubes (group 1) and in those conceiving by IVF and embryo transfer with bilateral tubal occlusion (group 2). We also compared those conceiving with human menopausal gonadotrophin therapy for ovulation induction without assisted reproduction (group 3) and those conceiving without fertility drugs in assisted reproduction (group 4). Mean CA125 concentrations were similar in groups 1-3; the mean CA125 concentration in group 4 was lower but this difference was not statistically significant, probably due to the small sample size. These data do not support the concept that tubal reflux explains the rise and fall of serum concentrations of CA125, since these were equal in IVF conceptions with or without tubal patency.

[Comparison of various methods of anesthesia by plasma catecholamine determination]. / Vergleich verschiedener Anästhesiemethoden mittels Plasma-Katecholamin-Bestimmungen.

Three different methods of anaesthesia (propofol or isoflurane with fentanyl/alfentanil, atracurium and O2/air or neurolept-anaesthesia with fentanyl, dehydrobenzperidol, pancuronium and N2O/O2) were compared in 64 patients undergoing cardiac surgery before the start of extracorporeal circulation. Plasma catecholamine contents were determined and haemodynamic changes were recorded for the detection and quantification of sympathoadrenal responses to the typical points of stimulation (intubation, skin incision, sternotomy). The level of anaesthesia was held comparable by EEG monitoring (spectral edge frequencies between 8 and 12 Hz). Noradrenaline and adrenaline showed significantly lower values in the propofol group in comparison to the groups with isoflurane and neuroleptanaesthesia. The clearest increases in catecholamines were found in all groups before starting the extracorporeal circulation. There is no evident congruity between catecholamine levels and haemodynamic changes because of various interindividual differences. Derived values of haemodynamic parameters (integrals of blood pressure, rate pressure product and triple index) are more useful than single measurements for the description of circulatory reactions.

Comparison of hCG versus GnRH analog for releasing oocytes following ultra low-dose gonadotropin stimulation.

Previous data have suggested there is a higher incidence of luteinized unruptured follicle (LUF) syndrome (defined as failure to release any oocyte as determined by sonography) in gonadotropin-treated patients following human chorionic gonadotropin (hCG) versus the gonadotropin releasing hormone agonist (GnRH-a) leuprolide acetate. The present study was designed to determine if an ultra low-dose gonadotropin regimen, designed not to raise the serum estradiol level much above normal for non-stimulated cycles, might result in a decrease in LUF following hCG treatment, and even reduce the rate to that seen following leuprolide acetate. The hypothesis tested was that the higher estradiol levels might suppress the pre-ovulatory follicle stimulating hormone (FSH) surge which, in turn, would inhibit plasmin production, thus preventing detachment of the oocyte from the follicle. The data did show a reduced rate of LUF incidence with either hCG or leuprolide acetate in ultra low-dose human menopausal gonadotropin-(hMG-) treated patients compared to data from previous studies with conventional hMG/hCG therapy. Pregnancy rates were also similar following hCG or leuprolide acetate for release in low-dose hMG-treated patients. Preliminary data show that leuprolide acetate is superior to hCG for causing oocyte release when stimulation is with low-dose purified FSH, and possibly also that low-dose hMG is superior to low-dose purified FSH for producing superior pregnancy rates.

Measurement of placental protein 14 (PP14) not helpful in predicting infertility or spontaneous abortion.

Placental protein 14 (PP14) can be measured in the serum by radioimmunoassay. The level rises from mid to late luteal phase in a manner similar to the endometrial biopsy. A study was initiated to determine if a clinical association could be found between the late luteal phase serum PP14 level and subsequent pregnancy and spontaneous abortion rate. No difference was found in the preconception PP14 level in patients conceiving versus those not conceiving, nor in those aborting versus those not aborting. A trend toward higher levels in conception versus non-conception cycles was noted, but a large patient group will be needed to demonstrate statistical significance.

Origin of first trimester 17-hydroxyprogesterone levels as determined in pregnancies by donor oocyte fertilization.

The study presented herein measured 17-hydroxyprogesterone (17-OHP) levels in women with ovarian failure who conceived by transfer of embryos which resulted from donor oocytes fertilization. A significant increase in 17-OHP during the first trimester was seen compared to baseline nonpregnant levels. The 17-OHP levels increased from a baseline average of 47.7 +/- 9.7 ng/dl to a first-trimester average of 175.8 +/- 80.6 ng/dl in the donor oocytes recipients vs. 63.0 +/- 38.0 ng/dl baseline to 295.0 +/- 83.9 ng/dl first-trimester in the control group. Initially these data may appear to contradict previous findings demonstrating a lack of 17-OHP secretion by the first-trimester placenta. However, by comparing the first-trimester progesterone (P) levels of normal pregnant women, and also measuring 17-OHP in patients with natural menopause and surgical menopause given exogenous P we concluded the following about the origin of first-trimester sera 17-OHP levels: hydroxylation of P to 17-OHP by the ovaries, some secretion by the first trimester placenta; and also increased adrenal conversion of P to 17-OHP. Contributing to the total serum 17-OHP level is the fact that there is cross-reactivity with P to 17-OHP.

Late luteal phase progestogen-dependent endometrial protein levels in women with in-phase biopsies--can low levels predict a subfertile group?

A group of infertile women who had luteal phase defects (LPD), but in whom follicular maturation was deemed normal, were treated with progesterone until the endometrial biopsy was corrected. At the time the corrected biopsy was obtained, serum was taken and the progestogen-dependent endometrial protein (PEP) concentration was determined. Serum PEP concentration in patients who successfully conceived was 102.5 +/- 62.6% units/mL, while PEP concentrations in patients who failed to conceive were 57.9 +/- 34.4% (P = .003). In patients whose PEP value was more than two standard deviations below the corresponding mean control PEP, pregnancy was achieved in 6/17 (35.3%). The conception rate was significantly greater (25/35, 71.4%) in patients with values higher than this. Thus, the PEP concentration in serum may identify a group of patients with persistent LPD despite apparent normalization of the morphology of late secretory phase endometrium, which might explain some cases of cryptic, unexplained infertility.

Comparison of first trimester serum estradiol levels in aborters versus nonaborters during maintenance of normal progesterone levels.

This study was designed to measure the average serum estradiol (E2) levels in the first trimester for women whose serum progesterone (P) levels were carefully maintained at normal levels by the use of exogenous P, and to compare the mean serum E2 levels in women who aborted with those in women who did not. The study group consisted of 94 pregnant women supported with exogenous natural P therapy from the luteal phase through the first trimester. Beginning at week 5, and continuing through the first trimester, the mean serum E2 levels for nonaborters were significantly higher than those for aborters.

[Therapeutic possibilities of sympathoadrenergic reactions during general anesthesia using sublingual application of glycerol trinitrate]. / Untersuchungen zur Therapiemöglichkeit sympathoadrenerger Reaktionen unter Allgemeinanästhesie mittels sublingual applizierten Glyzeroltrinitrats.

Strong surgical stimulation (for e. g. sternotomy, mediastinal preparation and aortic dissection in heart surgery) leads to an adrenergic reaction with the so-called haemodynamic break-through phenomenon. The inhibition of this reaction by means of narcotics is always connected with a dangerous decrease of cardiac index. Therefore, the sublingual application of nitroglycerin (GTN: 7 micrograms/kg), well established in the therapy of angina pectoris, was used as a rapidly applicable alternative. Patients with coronary heart disease under neuroleptanaesthesia (n = 10) were investigated in comparison to volunteers (n = 5). Beside the registration of haemodynamic parameters by invasive monitoring, the determination of arterial plasma concentrations of GTN and its metabolites 1.2- and 1.3-glyceryl dinitrate (GDN) were performed using gas-chromatographic technique. Using the same doses the haemodynamic changes are more marked and of longer duration in the anaesthetised patients than in the awake volunteers. The cause seems to be the higher and longer detectable active concentrations of GTN and GDN (the average maximum GTN concentrations greater than 0.5 ng/ml still after 12 minutes in contrast to 7 minutes). After discussing various different pharmacokinetic possibilities this effect is probably related to the simple fact of an improved resorption of the drug in the anaesthetised patient (no salivation, no swallow movements). On the basis of this investigation the sublingual application of GTN is a very useful therapy for the blockade of sympathoadrenergic reactions under anaesthesia, but the commonly used doses of GTN has to be reduced by half (3-4 micrograms/kg).

Correlation of serum progestagen-associated endometrial protein levels with endometrial biopsies serum steroid levels and therapy for luteal phase defects.

The progestagen-associated endometrial protein (PEP) level rises from the early to the late luteal phase. A study was performed in infertile women where late luteal phase endometrial biopsies and serum PEP levels were obtained. The objective of the study was to evaluate the correlation between the PEP levels and the endometrial biopsies and to determine if subnormal PEP levels could be improved by the same therapies used to correct endometrial defects. There was a poor correlation between PEP levels and endometrial biopsies (r = 0.17). Similarly, there was no significant correlation between PEP levels and levels of the following hormones: mid- and late-luteal phase progesterone (P) (r = 0.186 and 0.282 respectively), mid-luteal phase 17-hydroxyprogesterone (17-OHP) (r = 0.139) and mid-luteal phase oestradiol (r = 0.135). Furthermore, there was no correlation between PEP levels and the dosage of progesterone used in therapy (r = 0.07). There were no statistically significant differences in PEP values (U/ml) depending on whether any fertility drug was taken. Thus our data suggest that progesterone may only have a permissive role, with some other factor(s) controlling the actual rise and fall of PEP.

17-Hydroxyprogesterone level as a marker for corpus luteum function in aborters versus nonaborters.

Weekly serum levels of 17-hydroxyprogesterone (17-OHP) levels and serum progesterone (P) levels were measured in 378 pregnant women. Normal levels of 17-OHP were established in women taking ovulation-inducing drugs (OVID) versus those conceiving on normal cycles. Weekly levels of 17-OHP were measured in women who aborted and were compared with the established norms. The levels of 17-OHP in aborters were lower than in normals for their specific category established in nonaborters. These results suggest that a failing corpus luteum may contribute to some abortions. Careful attention to 17-OHP levels dropping below normal during the first trimester may alert the clinician to the need to increase progesterone exogenously and possibly prevent an abortion.

[Determination of the basic data on fentanyl dosage in neuroleptanalgesia for heart surgery]. / Ermittlung von Basisdaten zur Fentanyl-Dosierung in der Neuroleptanalgesie für kardiochirurgische Eingriffe.

The use of high-dose fentanyl (50-150 micrograms/kg) in anaesthesia for cardiac surgery includes the need of prolonged ventilatory support in the postoperative period. Therefore, the possibility of choosing a useful dosage regimen of smaller doses of fentanyl (up to 20 micrograms/kg) leading to analgesic serum levels of greater than 3 ng/ml is investigated in this study. Fentanyl was determined by radioimmunoassay in 20 patients during and after typical cardiosurgical operations. Three bolus injections of 7 micrograms/kg were applied in the first group (n = 8). Analgesic fentanyl concentrations were reached 12-24 minutes after the first injections. The characteristic pharmacokinetic influences - especially the enlarged volume of distribution and the prolonged elimination time - were visible following repetitive doses during extracorporeal circulation. Based on these results the injection mode was changed in the second investigation group (n = 6) - 2/3 of the total dose before the start of extracorporeal circulation - resulting in analgesic fentanyl concentrations for the whole course of the operation. More stable serum levels were obtained with the combination of primary bolus injection followed by continuous infusion (3rd group, n = 6), but a higher fentanyl amount and prolonged postoperative ventilation times were registered in this group. Bolus injections adapted to the special pharmacokinetic situation seem to be the best variant for the desired effect of producing sufficient analgesic levels without long-lasting ventilatory depression with a limited total dose of fentanyl.

[Pharmacokinetic studies on the causes of increased neurotoxicity of lidocaine during heart surgery]. / Pharmakokinetische Untersuchungen zu den Ursachen der erhöhten Neurotoxizität des Lidokains während kardiochirurgischer Operationen.

A high incidence of pathological EEG changes were registered following the treatment of arrhythmias using intravenous bolus injections of lidocaine during heart surgery with cardiopulmonary bypass. Lidocaine plasma concentrations were analysed by gas chromatography in order to detect reasons for this phenomenon. No dangerously high plasma levels of lidocaine were observed. The pharmacokinetic data show initially a larger volume of distribution and a shortening of distribution halflife. As causes for the increased neurotoxicity, a decrease of plasma binding and changed conditions for faster uptake by the brain are discussed. A reduction of lidocaine doses is recommended for this special clinical setting.

Rapid micromethod for the analysis of mitotane and its metabolite in plasma by gas chromatography with electron-capture detection.

A rapid micromethod for 50-microliter samples is described for the analysis in plasma of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE), using p,p'-DDD as internal standard. The compounds are extracted with heptane without sample pretreatment, and an aliquot is directly analysed by gas chromatography with electron-capture detection. Absolute recoveries for all three compounds were ca. 87% and coefficients of variation were less than 5%. The method is being used successfully for monitoring patients with Cushing's syndrome who receive chronic oral mitotane therapy.