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Primary microcephaly and severe developmental delay are complex but unspecific signs pointing to various genetic or acquired diseases. A concomitant finding of hematological failure may lead to the differential diagnosis of rare genetic diseases such as chromosome breakage disorders or diseases associated with telomere dysfunction. X-linked Hoyeraal-Hreidarsson syndrome (HHS) is a rare heterogenic disorder characterized by severe neurological impairment and progressive bone marrow failure. The latter represents the main cause of mortality, usually in early childhood. We report on the clinical course of an infant with HHS due to a novel mutation in the DKC1 gene and the particular finding of pontocerebellar hypoplasia., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: The "Long-term Active Surveillance Study for Oral Contraceptives" investigated the risks of long-term use of a 21-day regimen of drospirenone and ethinylestradiol (DRSP) compared to established oral contraceptives (OCs) in a routine clinical setting., Study Design: Prospective, controlled, non-interventional cohort study conducted in seven European countries with three main exposure groups: new users of DRSP, levonorgestrel-containing OCs (LNG), and OCs containing other progestogens (Other OCs). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular cardiovascular events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models., Results: A total of 1,113 study centers enrolled 59,510 women. Overall 28%, 26% and 45% of these women used DRSP, LNG and Other OCs, respectively. Study participants were followed for up to ten years (mean value, 5.4years), which generated 318,784 woman-years (WY) of observation. Low loss to follow-up and drop-out rates of 2.9% and 16.8% were achieved. DRSP, LNG, and Other OCs showed similar incidence rates of venous thromboembolism. Corresponding hazard ratios (HRs) were close to unity. For arterial thromboembolic events (ATE) and initiation of antihypertensive treatment statistically significant lower risks were found for DRSP compared to LNG and Other OCs., Conclusion: DRSP use was associated with similar general health risks and a low risk of ATE compared to OCs containing other progestogens., Implication Statement: The 21-day regimen of drospirenone-containing combined oral contraceptives is associated with similar risk of VTE compared to other combined oral contraceptives as well as potentially with a lower risk of ATE., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Liver dysfunction is an early event in sepsis-related multi-organ failure. We here report the establishment and characterization of a microfluidically supported in vitro organoid model of the human liver sinusoid. The liver organoid is composed of vascular and hepatocyte cell layers integrating non-parenchymal cells closely reflecting tissue architecture and enables physiological cross-communication in a bio-inspired fashion. Inflammation-associated liver dysfunction was mimicked by stimulation with various agonists of toll-like receptors. TLR-stimulation induced the release of pro- and anti-inflammatory cytokines and diminished expression of endothelial VE-cadherin, hepatic MRP-2 transporter and apolipoprotein B (ApoB), resulting in an inflammation-related endothelial barrier disruption and hepatocellular dysfunction in the liver organoid. However, interaction of the liver organoid with human monocytes attenuated inflammation-related cell responses and restored MRP-2 transporter activity, ApoB expression and albumin/urea production. The cellular events observed in the liver organoid closely resembled pathophysiological responses in the well-established sepsis model of peritoneal contamination and infection (PCI) in mice and clinical observations in human sepsis. We therefore conclude that this human liver organoid model is a valuable tool to investigate sepsis-related liver dysfunction and subsequent immune cell-related tissue repair/remodeling processes.

Background: This study examined the association of 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) with postoperative medical complications and one year mortality of elderly patients sustaining a low-energy cervical hip fracture scheduled for surgery. We hypothesized that vitamin D deficiency and CRP in these patients might be associated with an increased 1-year mortality., Methods: The prospective single-center cohort study included 209 patients with a low-energy medial femoral neck fracture; 164 women aged over 50 years and 45 men aged over 60 years. Referring to 1-year mortality and postoperative medical complications multiple logistic regression analysis including 10 co-variables (age, sex, BMI, ASA, creatinine, CRP, leukocytes hemoglobin, 25(OH)D, vitamin D supplementation at follow-up) was performed., Results: Vitamin D deficiency was prevalent in 87 % of all patients. In patients with severe (<10 ng/ml) and moderate (10-20 ng/ml) vitamin D deficiency one year mortality was 29 % and 13 %, respectively, compared to 9 % in patients with > 20 ng/ml 25(OH)D levels (p =0.027). Patients with a mild (CRP 10-39.9 mg/l) or active inflammatory response (CRP ≥ 40 mg/l) showed a higher one year mortality of 33 % and 40 % compared to 16 % in patients with no (CRP < 10 mg/l) inflammatory response (p = 0.002). Multiple logistic regression analysis identified CRP (OR 1.01, 95 % CI 1.00-1.02; p = 0.007), but not 25(OH)D (OR 0.97, 95 % CI 0.89-1.05; p = 0.425) as an independent predictor for one year mortality. 20 % of patients suffered in-hospital postoperative medical complications (i.e. pneumonia, thromboembolic events, etc.). 25(OH)D (OR 0.89, 95 % CI 0.81-0.97; p = 0.010), but not CRP (OR 1.01, 95 % CI 1.00-1.02; p = 0.139), was identified as an independent risk factor., Conclusion: In elderly patients with low-energy cervical hip fracture, 25(OH)D is independently associated with postoperative medical complications and CRP is an independent predictor of one year mortality.

In vitro cytochrome P450 (CYP) inhibition assays are common approaches for testing the inhibition potential of drugs for predicting potential interactions. In contrast to marketed medicaments, drugs of abuse, particularly the so-called novel psychoactive substances, were not tested before distribution and consumption. Therefore, the inhibition potential of methylenedioxy-derived designer drugs (MDD) of different drug classes such as aminoindanes, amphetamines, benzofurans, cathinones, piperazines, pyrrolidinophenones, and tryptamines should be elucidated. The FDA-preferred test substrates, split in two cocktails, were incubated with pooled human liver microsomes and analysed after protein precipitation using LC-high-resolution-MS/MS. IC50 values were determined of MDD showing more than 50 % inhibition in the prescreening. Values were calculated by plotting the relative metabolite concentration formed over the logarithm of the inhibitor concentration. All MDD showed inhibition against CYP2D6 activity and most of them in the range of the clinically relevant CYP2D6 inhibitors quinidine and fluoxetine. In addition, the beta-keto compounds showed inhibition of the activity of CYP2B6, 5,6-MD-DALT of CYP1A2 and CYP3A, and MDAI of CYP2A6, all in the range of clinically relevant inhibitors. In summary, all MDD showed inhibition of the activity of CYP2D6, six of CYP1A2, three of CYP2A6, 13 of CYP2B6, two of CYP2C9, six of CYP2C19, one of CYP2E1, and six of CYP3A. These results showed that the CYP inhibition by MDD might be clinically relevant, but further studies are needed for final conclusions.

New psychoactive substances (NPS) are not tested for their cytochrome P450 (CYP) inhibition potential before consumption. Therefore, this potential was explored for tryptamine-derived NPS (TDNPS) including alpha-methyl tryptamines (AMTs), dimethyl tryptamines (DMTs), diallyl tryptamines (DALTs), and diisopropyl tryptamines (DiPTs) using test substrates preferred by the Food and Drug Administration in a cocktail assay. All tested TDNPS with the exception of DMT inhibited CYP2D6 activity with IC50 values below 100μM. DALTs inhibited CYP2D6 activity similar to paroxetine and quinidine and CYP1A2 activity comparable to fluvoxamine. 5-Methoxy-N,N-diallyltryptamine reduced in vivo the caffeine metabolism in rats consistent with in vitro results. Five of the AMTs also inhibited CYP1A2 activity comparable to amiodarone. AMT and 6-F-AMT inhibited CYP2A6 activity in the range of the test inhibitor tranylcypromine. CYP2B6 activity was inhibited by 19 tryptamines, but weakly compared to efavirenz. CYP2C8 activity was inhibited by five of the tested TDNPS and three showed values comparable to trimethoprim and gemfibrozil. Six tryptamines inhibited CYP2C9 and seven CYP2C19 activities comparable to fluconazole and chloramphenicol, respectively. Nineteen compounds showed inhibition of CYP2E1 and 18 of CYP3A activity, respectively. These results showed that the CYP inhibition by TDNPS might be clinically relevant, but clinical studies are needed to explore this further., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation of hepatocyte polarization and maintenance of metabolic function. We here report the establishment of a liver organoid that integrates NPCs in a vascular layer composed of endothelial cells and tissue macrophages and a hepatic layer comprising stellate cells co-cultured with hepatocytes. The three-dimensional liver organoid is embedded in a microfluidically perfused biochip that enables sufficient nutrition supply and resembles morphological aspects of the human liver sinusoid. It utilizes a suspended membrane as a cell substrate mimicking the space of Disse. Luminescence-based sensor spots were integrated into the chip to allow online measurement of cellular oxygen consumption. Application of microfluidic flow induces defined expression of ZO-1, transferrin, ASGPR-1 along with an increased expression of MRP-2 transporter protein within the liver organoids. Moreover, perfusion was accompanied by an increased hepatobiliary secretion of 5(6)-carboxy-2',7'-dichlorofluorescein and an enhanced formation of hepatocyte microvilli. From this we conclude that the perfused liver organoid shares relevant morphological and functional characteristics with the human liver and represents a new in vitro research tool to study human hepatocellular physiology at the cellular level under conditions close to the physiological situation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: To determine how often infants are suctioned during delivery and how it affects the neonate., Methods: Single-center analysis of video-recorded delivery room management after c-section from January 2012 until April 2013. Time point, duration, and frequency of suctioning in term and preterm newborns were analyzed along with vital parameters (heart rate (HR) and saturation values)., Results: Three hundred forty-six videos were analyzed. Twenty-three percent of term and 66% of preterm newborns were suctioned. Newborns were suctioned up to 14 times; total duration spent for suctioning was between 2 and 154 s. Suctioning before face mask application occurred in 31% of the suctioned newborns requiring respiratory support. No severe bradycardia (<60 bpm) was noticed. Suctioning did not have an effect on HR and saturation in preterm infants but was associated with significantly higher HR in term infants requiring respiratory support. Term infants who did not require respiratory support showed significantly higher saturation values at 3, 5, 6, 7, 8, 9, and 10 min if they were not suctioned., Conclusions: Suctioning of newborns in the delivery room does not adhere to recommendations of international guidelines. However, previously described side effects of suctioning could not be confirmed.

Drugs of abuse are not tested for cytochrome P450 (CYP) inhibition potential before distribution. Therefore, a cocktail assay should be developed for testing the inhibition potential for all relevant CYPs. The following CYP test substrates and selective inhibitors were incubated in pooled human liver microsomes: phenacetin (alpha-naphthoflavone for CYP1A2), coumarin (tranylcypromine, CYP2A6), bupropion (sertraline, CYP2B6), amodiaquine (trimethoprim, CYP2C8), diclofenac (sulfaphenazole, CYP2C9), omeprazole (fluconazole, CYP2C19), dextromethorphan (quinidine, CYP2D6), chlorzoxazone (clomethiazole, CYP2E1), testosterone (verapamil, CYP3A). Samples were analyzed after protein precipitation using a Thermo Fisher Q-Exactive LC-high-resolution-MS/MS. The IC50 values were calculated by plotting the concentration of the formed metabolite, relative to the control sample, over the logarithm of the inhibitor concentration. They were determined either for single substrate or the cocktail incubation. Unfortunately, the cocktail assay had to be split because of interferences during incubation caused by substrates or metabolites, but the mixture of both incubates could be analyzed in one analytical run. The IC50 values determined in the single substrate or both cocktail incubations were comparable among themselves and with published data. In conclusion, the new inhibition cocktail assay was reproducible and applicable for testing the inhibition potential of drugs of abuse as exemplified for 2,5-dimethoxy-4-iodo-amfetamine (DOI)., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Whereas good data are available on the resuscitation of infants, little is known regarding support of postnatal transition in low-risk term infants after c-section. The present study was performed to describe current delivery room (DR) management of term infants born by c-section in our institution by analyzing videos that were recorded within a quality assurance program., Methods: DR- management is routinely recorded within a quality assurance program. Cross-sectional study of videos of term infants born by c-section. Videos were analyzed with respect to time point, duration and number of all medical interventions. Study period was between January and December 2012., Results: 186 videos were analyzed. The majority of infants (73%) were without support of postnatal transition. In infants with support of transition, majority of infants received respiratory support, starting in median after 3.4 minutes (range 0.4-14.2) and lasting for 8.8 (1.5-28.5) minutes. Only 33% of infants with support had to be admitted to the NICU, the remaining infants were returned to the mother after a median of 13.5 (8-42) minutes. A great inter- and intra-individual variation with respect to the sequence of interventions was found., Conclusions: The study provides data for an internal quality improvement program and supports the benefit of using routine video recording of DR-management. Furthermore, data can be used for benchmarking with current practice in other centers.

Knowledge about the cytochrome P450 (CYP) inhibition potential of new drug candidates is important for drug development because of its risk of interactions. For novel psychoactive substances (NPS), corresponding data are not available. For developing a general drug inhibition cocktail assay, a liquid-chromatography high-resolution tandem mass spectrometry multi-analyte approach was developed and validated for quantifying low concentrations of O-diethyl phenacetin for CYP 1A2, 7-hydroxy coumarin for CYP 2A6, 4-hydroxy bupropion for CYP 2B6, N-diethyl amodiaquine for CYP 2C8, 4-hydroxy diclofenac for CYP 2C9, 5-hydroxy omeprazole for CYP 2C19, O-dimethyl dextromethorphan for CYP 2D6, 6-hydroxy chlorzoxazone for CYP 2E1, and 6-beta-hydroxy testosterone for CYP 3A in the incubation mixture in the presence of substrates and inhibitors. The tested matrix effects ranged from 63 to 141 % and the recoveries from 95 to 110 %. Time-saving one-point calibration allowed sufficient quantification, although some of the validation results for 7-hydroxy coumarin, 4-hydroxy bupropion, 4-hydroxy diclofenac, and 6-beta-hydroxy testosterone were outside the acceptance criteria (AC) but without influence of the IC50 calculation. Validation showed also that the approach was sensitive and selective using mass spectral multiplexing. In conclusion, the presented assay was suitable for the quantification of the model substrate metabolites and could be used for the development of a CYP inhibition assay for testing most CYPs and a wide range of drugs of abuse.

3',4'-Methylenedioxy-alpha-pyrrolidinobutyrophenone (MDPBP), a designer drug of the pyrrolidinophenone-type, was first seized in Germany in 2009. It was also identified in 'legal high' samples investigated in the UK. Therefore, the aim of the presented work was to identify its in vivo and in vitro phase I and II metabolites using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-ion trap mass spectrometry (LC-MS(n) ). Furthermore, detectability of MDPBP in rat and human urine using standard urine screening approaches (SUSA) by GC-MS and LC-MS(n) was studied. The metabolites were isolated either directly or after enzymatic cleavage of conjugates by solid-phase extraction (C18, HCX). The metabolites were then analyzed and structures proposed after GC-MS (phase I) and LC-MS(n) (phase II). Based on these identified metabolites, the following main metabolic steps could be proposed: demethylenation followed by methylation of one hydroxy group, aromatic and side chain hydroxylation, oxidation of the pyrrolidine ring to the corresponding lactam as well as ring opening to the corresponding carboxylic acid. Furthermore, in rat urine after a typical user's dose as well as in human urine, mainly the metabolites could be detected using the authors' SUSA by GC-MS and LC-MS(n) . Thus, it should be possible to monitor an application of MDPBP assuming similar toxicokinetics in humans. Finally, CYP2C19 and CYP2D6 could be identified as the isoenzymes mainly responsible for demethylenation., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objectives: The "International Active Surveillance Study of Women Taking Oral Contraceptives" investigated the risks of short- and long-term use of an extended 24-day regimen of drospirenone and ethinylestradiol (DRSP24d) compared to established oral contraceptives (OCs) in a routine clinical setting., Study Design: Prospective, controlled, noninterventional cohort study conducted in the United States and six European countries with three main cohorts: new users of DRSP24d, DRSP21d (21-day regimens of DRSP-containing OCs), and non-DRSP (OCs without DRSP). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular venous thromboembolism (VTE). Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Primary statistical variable was the VTE hazard ratio (HR) for DRSP24d vs. non-DRSP., Results: A total of 2285 study centers enrolled 85,109 women. Study participants were followed for 2 to 6 years, which generated 206,296 woman-years (WY) of observation. A low loss to follow-up of 3.3% was achieved. DRSP24d, DRSP21d, non-DRSP and levonorgestrel-containing OCs (LNG) showed similar incidence rates of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events. VTE incidence rates for DRSP24d, DRSP21d, non-DRSP and LNG were 7.2, 9.4, 9.6 and 9.8 VTE/10,000 WY, respectively. Adjusted HRs for DRSP24d vs. non-DRSP and DRSP24d vs. LNG were 0.8 [95% confidence interval (CI), 0.5-1.3] and 0.8 (95% CI, 0.4-1.5)., Conclusion: DRSP24d, DRSP21d, non-DRSP and LNG use was associated with similar risks of serious adverse events, and particularly VTE, during routine clinical use., Implication Statement: The 24-day regimen of drospirenone-containing combined OCs is associated with similar risks of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events compared to 21-day regimens of drospirenone-containing combined OCs, OCs without drospirenone and LNGs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To compare the risks of short-term and long-term use of an etonogestrel-containing and ethinylestradiol-containing vaginal ring and combined oral contraceptive pills (OCPs) in a routine clinical study population., Methods: This was a prospective, controlled, noninterventional cohort study performed in the United States and five European countries with the following two cohorts: new users of the vaginal ring and new users of combined OCPs (starters, switchers, or restarters). The study population included 33,295 users of the vaginal ring or combined OCPs recruited by 1,661 study centers. Follow-up of study participants occurred for 2 to 4 years. Main clinical outcomes of interest were cardiovascular outcomes, particularly venous and arterial thromboembolism. These outcomes were validated by attending physicians and further adjudicated by an independent board. Comprehensive follow-up ensured low loss to follow-up. Statistical analyses were based on Cox regression models. Primary statistical variable was the venous thromboembolic hazard ratio (HR) for the vaginal ring compared with combined OCPs., Results: Study participants were followed-up for 66,489 woman-years. Loss to follow-up was 2.9%. The venous thromboembolism incidence rates for the vaginal ring users and combined OCPs users were 8.3 and 9.2 per 10,000 woman-years, respectively. Cox regression analysis yielded crude and adjusted HRs for the vaginal ring users compared with combined OCPs users of 0.9 and 0.8 for venous thromboembolism (95% confidence intervals [CIs] 0.5-1.6 and 0.5-1.5) and 0.8 and 0.7 (95% CIs 0.2-2.5 and 0.2-2.3) for arterial thromboembolism, respectively., Conclusion: Vaginal ring use and combined OCP use were associated with a similar venous and arterial thromboembolic risk during routine clinical use., Level of Evidence: : II.

The opioid 3-methylfentanyl, a designer drug of the fentanyl type, was scheduled by the Controlled Substance Act due to its high potency and abuse potential. To overcome this regulation, isofentanyl, another designer fentanyl, was synthesized in a clandestine laboratory and seized by the German police. The aims of the presented study were to identify the phase I and phase II metabolites of 3-methylfentanyl and isofentanyl in rat urine, to identify the cytochrome P450 (CYP) isoenzymes involved in their initial metabolic steps, and, finally, to test their detectability in urine. Using liquid chromatography (LC)-linear ion trap-mass spectrometry (MS(n)), nine phase I and five phase II metabolites of 3-methylfentanyl and 11 phase I and four phase II metabolites of isofentanyl could be identified. The following metabolic steps could be postulated for both drugs: N-dealkylation followed by hydroxylation of the alkyl and aryl moiety, hydroxylation of the propanamide side chain followed by oxidation to the corresponding carboxylic acid, and, finally, hydroxylation of the benzyl moiety followed by methylation. In addition, N-oxidation of isofentanyl could also be observed. All hydroxy metabolites were partly excreted as glucuronides. Using recombinant human isoenzymes, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were found to be involved in the initial metabolic steps. Our LC-MS(n) screening approach allowed the detection of 0.01 mg/L of 3-methylfentanyl and isofentanyl in spiked urine. However, in urine of rats after the administration of suspected recreational doses, the parent drugs could not be detected, but their common nor metabolite, which should therefore be the target for urine screening.

Background: This study compares the risk of breast cancer for levonorgestrel-releasing intrauterine devices (LNG(IUD)) versus copper IUDs (CU(IUD)) in women younger than 50 years of age., Study Design: Retrospective, population-based, case-control study using cancer registers in Finland and Germany, powered to exclude a 1.5-fold risk of breast cancer., Results: Analysis of 5113 breast cancer cases diagnosed 2000-2007 and 20,452 controls - matched by year of birth and area of residence - yielded relative risk estimates approaching unity with 95% CI crossing 1.0 for all comparisons, including ever-use of LNG(IUD) versus CU(IUD) (adjusted OR, 0.99; 95% CI, 0.88-1.12) and current use at time of diagnosis (adjusted OR, 0.85; 95% CI, 0.52-1.39), as well as for sub-analyses by country, age, tumor characteristics and period, recency and duration of use prior to diagnosis., Conclusion: This study does not indicate an increased risk of breast cancer for users of LNG(IUD). No indications for tumor promotion or tumor induction were found., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Neonatal seizures are common, especially in prematurity. Phenobarbital (PB) currently represents the antiepileptic drug (AED) of choice, despite being related to increased neuronal apoptosis in animal models and cognitive impairment in human subjects. Levetiracetam (LEV) may have a more favorable profile since it does not cause neuronal apoptosis in infant rodents., Methods: In a prospective feasibility study, LEV was applied as first-line treatment in 38 newborns with EEG-confirmed seizures, after ruling out hypoglycemia, hypocalcaemia, hypomagnesaemia and pyridoxin dependency. Initial intravenous doses of 10 mg/kg LEV were gradually increased to 30 mg/kg over 3 days with a further titration to 45-60 mg/kg at the end of the week. Acute intervention with up to 2 intravenous doses of PB 20 mg/kg was tolerated during LEV titration. LEV was switched to oral as soon as the infants' condition allowed. Based on clinical observation, EEG tracings (aEEG/routine EEGs), and lab data, drug safety and anticonvulsant efficacy were assessed over 12 months., Results: In 19 newborns a single PB dose of 20 mg/kg was administered, while 3 newborns received 2 PB doses. 30 infants were seizure free under LEV at the end of the first week and 27 remained seizure free at four weeks, while EEGs markedly improved in 24 patients at 4 weeks. In 19 cases, LEV was discontinued after 2-4 weeks, while 7 infants received LEV up to 3 months. No severe adverse effects were observed., Conclusions: These results illustrate the safety of LEV treatment in neonatal seizures, including prematurity and suggest LEV anticonvulsant efficacy. Additional PB treatment admittedly constitutes a methodological shortcoming due to the prolonged anticonvulsive efficacy of PB. Double blind prospective controlled studies and long-term evaluation of cognitive outcome are called for., (© 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To estimate real-life effectiveness of oral contraceptive pills by progestogen, length of pill-free interval, and body mass index while focusing on the effect of progestogens with a long half-life and on 24-day oral contraceptive pills regimens., Methods: Outcome data from 52,218 U.S. participants in the International Active Surveillance of Women Taking Oral Contraceptives—a large, prospective, controlled, noninterventional, long-term cohort study with active surveillance of the study participants—were used to analyze contraceptive failure in association with oral contraceptive pills use. Low loss to follow-up is ensured by a comprehensive follow-up procedure. Contraceptive failure rates are described by Pearl Index and life-table analysis. Inferential statistics for contraceptive failure are based on Cox regression models., Results: Analyses are based on 1,634 unintended pregnancies during 73,269 woman-years of oral contraceptive pills exposure. Life-table estimates of contraceptive failure for a 24-day regimen of drospirenone and ethinyl estradiol and 21-day regimens of other progestogens were 2.1% and 3.5% after the first study year, and 4.7% and 6.7% after the third year. The adjusted hazard ratio was 0.7 (95% confidence interval 0.6–0.8). Direct comparisons of the 24-day and 21-day regimens of drospirenone and norethisterone, respectively, showed also lower contraceptive failure rates for 24-day regimens. Contraceptive failure rates adjusted for age, parity and educational level showed a slight increase with higher body mass index., Conclusion: The 24-day oral contraceptive regimens containing a progestogen with a long half-life show higher contraceptive effectiveness under routine medical conditions compared with conventional 21-day regimens. Obesity seems to be associated with a slight reduction of contraceptive effectiveness., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00335257., Level of Evidence: II

Aim: To determine growth, neurological and cognitive development at 5 years of preterm infants with birthweights <501 g born in three German tertiary perinatal centres between 1998 and 2001., Methods: Structured neurological examination, the Gross Motor Function Classification Scale and the Kaufman-Assessment-Battery Test for Children., Results: Of 107 infants, 48 received immediate life support (gestational age 25.2 weeks [21-30.7]; birth weight 435 g [290-500]) median [range]), 27 (56%) survived until follow-up [95% CI 39-69%], 19 (70%) could be tested. In few infants had catch-up growth taken place. Neurological test results were normal in five infants (26%) and mildly abnormal/severely abnormal in 11 (58%)/3 (16%) infants. Visual impairment was present in eight (42%), and hearing disability in three (16%). The mean mental processing composite (IQ) was 82 [50-104] (median [range])., Conclusion: Of all resuscitated infants with a birthweight <501 g, 56% survived to school age. Of these, composite outcome score showed normal development or mild disability in one-half, and moderate or severe disability in the other half of them. Investigators should include such infants in studies and their reports should give specific information about them., (© 2010 The Author(s)/Journal Compilation © 2010 Foundation Acta Paediatrica.)

Objective: The primary objective of the study was to clarify whether the use of the oral contraceptive 2 mg dienogest/30 microg ethinylestradiol (DNG/EE) is associated with a higher risk of venous thromboembolism (VTE) than the use of other combined oral low-dose contraceptives (i.e. containing < or =30 microg EE), particularly oral contraceptives containing levonorgestrel (LNG). The secondary objective was to investigate the VTE risk associated with drospirenone/ethinylestradiol (DRSP/EE) in comparison to low-dose LNG/EE., Methods: This German community-based, case-control study recruited VTE cases from the primary care sector. Eligible cases were women aged 15-49 years with a VTE between January 2002 and February 2008. Four controls (women without a confirmed or potential VTE before the index date) were matched by age and region to each case. Medical information relevant for the assessment of VTE was abstracted from patient charts. Data on personal characteristics of the patients were collected via self-administered questionnaires. At the end of the study a blinded adjudication of the reported VTE was conducted. Conditional logistic regression techniques were used, adjusting for nine potential confounders, including personal history of VTE, family history of VTE, body mass index, duration of current combined oral contraceptive (COC) use and smoking., Results: A total of 680 VTE cases and 2720 corresponding controls were analysed. The mean age of cases and controls was - as a result of matching - almost identical (36.1 years). A total of 35, 25, and 60 of the cases had used DNG-, DRSP- and LNG-containing low-dose COCs, respectively, at the time of the VTE diagnosis. The crude odds ratio (OR) for VTE associated with current COC use in comparison to women who had never used a COC before the index date was 1.9 (95% CI 1.5-2.5), the adjusted OR was 2.3 (95% CI 1.7-3.0). The point estimate of the crude OR of DNG/EE vs any other low-dose COCs was 0.9 (95% CI 0.6-1.3), the adjusted OR was 0.9 (95% CI 0.6-1.4). The crude ORs for DNG/EE and DRSP/EE vs low-dose LNG/EE were 1.1 (95% CI 0.7-1.8) and 1.0 (95% CI 0.6-1.6), respectively; the adjusted ORs were 1.1 (95% CI 0.7-1.9) and 1.0 (95% CI 0.6-1.8)., Conclusions: The study confirms that COC use is associated with an increased risk of VTE. The VTE ORs (adjusted and crude) that compared DNG/EE and DRSP/EE with other low-dose COCs (including LNG/EE) were close to unity and do not indicate a higher risk for users of DNG/EE or DRSP/EE.

Background: Two recent studies, a cohort study from Denmark, and a case-control study from The Netherlands, have reported increased risks of venous thromboembolism (VTE) among users of oral contraceptives (OCs) containing desogestrel, gestodene, drospirenone and cyproterone, relative to the use of levonorgestrel., Critique: In the Danish study the comparisons were not valid. (1) VTE risk is highest soon after commencement of OC use, and duration of use was underestimated for levonorgestrel users, but not for drospirenone users; for the remaining compounds duration was only slightly underestimated. The underestimation for levonorgestrel resulted in systematic overestimation of the relative risks for the compared OCs. (2) Duration was also incorrectly estimated: only the duration of current use, not duration of all episodes of use was relevant to VTE risk. (3) Confounding was not adequately controlled. In The Netherlands study the comparisons were not valid. (1) The relative risk for drospirenone versus levonorgestrel was not statistically significant. (2) Extensive publicity had been given to the risk of VTE among users of desogestrel, gestodene, drospirenone and cyproterone: information bias and detection bias were therefore likely. (3) Inadequate allowance was made for duration of use. (4) The combination of two different control groups, both of them likely to have been biased, into a single category was not valid., Conclusion: The best evidence continues to suggest that the increased risk of VTE in OC users is a class effect, dependent on the estrogen dose and duration of use, and independent of the progestogen used.

Objectives: To determine whether prior oral-contraceptive use has a negative effect on the ability of women to conceive in both the short-term and long-term., Methods: The European Active Surveillance Study on Oral Contraceptives (EURAS-OC) was a controlled, prospective, noninterventional cohort study of 59,510 users of oral contraceptives containing drospirenone or other progestins in clinical practice in seven European countries. In a planned secondary analysis, pregnancy outcomes were investigated in 2,064 participants in EURAS-OC who stopped oral-contraceptive use after study entry because of planned pregnancy. The influence of age, parity, progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and smoking status on the rate of pregnancy was assessed., Results: Overall, 21.1% (95% confidence interval [CI] 19.4-23.0%) of the past oral-contraceptive users were pregnant one cycle after oral-contraceptive cessation. This rate increased to 79.4% (95% CI 77.6-81.1%) at 1 year (13 cycles). Progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and parity had no major influence on the rate of pregnancy after oral-contraceptive cessation. Up to age 35 years, age had only a minor influence on the rate of pregnancy. Rates of pregnancy were reduced in women older than 35 years and in current smokers., Conclusion: Previous oral-contraceptive use does not negatively affect initial and 1-year rates of pregnancy after oral-contraceptive cessation. A comparison of these data with data external to this study indicates that the negative effect of aging on fecundity is not amplified by oral-contraceptive use., Level of Evidence: II.

Background: The Menopause Rating Scale is a health-related Quality of Life scale developed in the early 1990s and step-by-step validated since then. Recently the MRS scale was validated as outcomes measure for hormone therapy. The suspicion however was expressed that the data were too optimistic due to methodological problems of the study. A new study became available to check how founded this suspicion was., Method: An open post-marketing study of 3282 women with pre- and post- treatment data of the self-administered version of the MRS scale was analyzed to evaluate the capacity of the scale to detect hormone treatment related effects with the MRS scale. The main results were then compared with the old study where the interview-based version of the MRS scale was used., Results: The hormone-therapy related improvement of complaints relative to the baseline score was about or less than 30% in total or domain scores, whereas it exceeded 30% improvement in the old study. Similarly, the relative improvement after therapy, stratified by the degree of severity at baseline, was lower in the new than in the old study, but had the same slope. Although we cannot exclude different treatment effects with the study method used, this supports our hypothesis that the individual MRS interviews performed by the physician biased the results towards over-estimation of the treatment effects. This hypothesis is underlined by the degree of concordance of physician's assessment and patient's perception of treatment success (MRS results): Sensitivity (correct prediction of the positive assessment by the treating physician) of the MRS and specificity (correct prediction of a negative assessment by the physician) were lower than the results obtained with the interview-based MRS scale in the previous publication., Conclusion: The study confirmed evidence for the capacity of the MRS scale to measure treatment effects on quality of life across the full range of severity of complaints before treatment. The difference of the relative improvement after therapy between the old and current study as well as the observed different sensitivity/specificity is--as a matter of probability--more likely to be caused by a bias introduced by the different application of the MRS scale than by real differences in the efficacy of the therapy. A randomized clinical trial would be needed to test the impact of the latter. The message for future studies is: The MRS scale should be only used as self-administered tool where the suggestive effect of questions raised by health professionals ("therapeutic optimism") can be largely excluded.

This is the second paper in a review series that will summarize available data and discuss the potential role of lung function testing in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses the expansive subject of measurements of lung volume using plethysmography and gas dilution/washout techniques. Following orientation of the reader to the subject area, we focus our comments on areas of inquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically, and recommendations are provided to guide future investigation in this field. Measurements of lung volume are important both for assessing growth and development of lungs in health and disease, and for interpreting volume-dependent lung function parameters such as respiratory compliance, resistance, forced expiratory flows, and indices of gas-mixing efficiency. Acute neonatal lung disease is characterized by severely reduced functional residual capacity (FRC), with treatments aimed at securing optimal lung recruitment. While FRC may remain reduced in established chronic lung disease of infancy, more commonly it becomes normalized or even elevated due to hyperinflation, with or without gas-trapping, secondary to airway obstruction. Ideally, accurate and reliable bedside measurements of FRC would be feasible from birth, throughout all phases of postnatal care (including assisted ventilation), and during subsequent long-term follow-up. Although lung volume measurements in extremely preterm infants were described in a research environment, resolution of several issues is required before such investigations can be translated into routine clinical monitoring., (Copyright 2005 Wiley-Liss, Inc.)

Aim: To report survival and morbidity until discharge in preterm infants <501 g with life support started immediately after birth., Methods/study Design: Cohort study of all preterm infants with birthweights < 501 g born in three tertiary perinatal centres between 1 January 1998 and 31 December 2001 (gestational age (GA) 25.2 [21.0-30.7] wk; birthweight 435 [290-500] g; median [range])., Results: A total of 107 infants with birthweights <501 g were born. Twenty-nine were stillborn. A prenatal decision to initiate life support immediately after birth was reached in 9/37 (24%) infants <24.0 wk GA and in 39/42 (93%) infants > or =24.0 wk GA. Survival was 3/37 (8%) and 26/41 (63%) in infants <24 wk GA and > or =24.0 wk GA, respectively. Twenty-nine of the 48 infants with immediate life support (60%) survived (95% CI: 46-75%). Forty-two of these 48 (88%) infants were small for gestational age. No infant without immediate life support survived (0/30). Twenty-three (79%) survivors developed chronic lung disease (CLD) and eight (28%) received photocoagulation for retinopathy of prematurity (ROP)., Conclusion: In this population of extremely low birthweight infants, survival was higher than in previous studies when life support was provided immediately after birth. Short-term morbidity was similar to other studies. The presented data on survival support our concept to offer immediate life support after birth in preterm infants with birthweights <501 g. The long-term outcome of these infants needs to be assessed urgently.

Unlabelled: To understand the mechanisms behind improved oxygenation after intratracheal surfactant instillation, the immediate and late effects on lung volume and compliance of the respiratory system (CRS) were analysed. Infants received modified porcine surfactant (Curosurf) or modified bovine surfactant (Alveofact). Measurements of functional residual capacity (FRC) and CRS were successfully performed in 90 ventilated preterm infants (birth weight 1264 +/- 435 g; gestational age 28.2 +/- 2.5 weeks) with severe respiratory distress syndrome. FRC and CRS were measured during mechanical ventilation prior to and 1, 3, 6, 24, 48, 72, 96, 120 and 168 h after surfactant replacement. Oxygenation rapidly improved. FRC increased significantly from 7.64 +/- 1.58 ml/kg to 15.35 +/- 3.27 ml/kg (P < 0.01) at 1 h after surfactant instillation. CRS remained virtually unchanged during the first hours after surfactant replacement and a concomitant decrease in specific compliance was seen., Conclusion: the changes in lung function following surfactant treatment can only be explained by initial stabilisation of already aerated alveoli followed by recruitment of new gas exchange units as mechanisms involved in mediating the effect of surfactant on gas exchange. However, since no significant correlation between changes in functional residual capacity and improvement in arterial-to-alveolar oxygen tension ratio was seen, other effects of surfactant must be considered. These include local and/or systemic changes in haemodynamics.

A term female infant developed late onset group B streptococcal disease on Day 12 of life. The source of the organism appeared to be expressed maternal breast milk in the absence of clinical mastitis. Asymptomatic excretion of group B Streptococcus in breast milk may be an underrecognized cause of neonatal infection.

We report on the case of a healthy young boy who developed a fulminant myocarditis due to acute coinfection with erythrovirus (parvovirus B19) and human herpesvirus 6 (HHV-6) in the absence of an antiviral immune response. We suggest that the HHV-6-induced immunosuppression enhanced dissemination of parvovirus B19, which led to fatal myocarditis.

For the improvement of thrombolytic therapy with recombinant tissue-plasminogen activator (rt-PA) in children, more clinical data are needed. We retrospectively analyzed the clinical course of 20 patients (age ranging from 1 day to 16 years) with venous thrombosis (n = 16), arterial thrombosis (n = 2), and purpura fulminans by meningococcosis (n = 2). The venous thromboses were localized in the iliac-femoral veins (n = 9), brachiocephalic-jugular-subclavian veins (n = 6), and the superior caval vein (n = 1). The arterial occlusions were localized in the abdominal aorta and in the left pulmonary artery. Central venous catheters were of pathogenetic importance in seven cases. The patients were treated with rt-PA for 3 hours to 13 days. The dose ranged between 0.2 and 0.5 mg/kg for the initial bolus and 1.0 to 2.0 mg/kg/d for the continuous infusion. Nineteen patients received simultaneously low-dose unfractionated heparin. Complete clot lysis was detected in 11 cases, a partial lysis in 1, and in 8 patients thrombolytic therapy was not successful. An episode of hematemesis in one patient represented the only serious side effect observed in our study. A systemic decrease in fibrinogen concentration was also rare. In conclusion, thrombolysis with rt-PA represents an effective and safe therapy for children at the dosage used.

Unlabelled: Positive end expiratory pressure is routinely used when ventilating preterm infants. Elevation of PEEP increases lung volume, as does surfactant treatment. The purpose of this study was to investigate the effect of various levels of PEEP within the range of 0.2 to 0.4 kPa on lung volume, compliance and gas exchange. We measured functional residual capacity, compliance of the respiratory system and arterial blood gases in 20 infants (median birth weight 1240 g, range 660-1690 g; median gestational age 28 weeks, range 24-32 weeks; postnatal age 3-4 days). The infants were studied at 72 hours after their last dose of natural surfactant. At this time the patients were routinely nursed at 0.3 kPa of PEEP, the PEEP level was lowered to 0.2 kPa or raised to 0.4 kPa in random order. The PEEP level was then changed to the third level 0.4 kPa or 0.2 kPa. Each new setting was maintained for 20 min before FRC, compliance and blood gases were measured. FRC was assessed using SF6 washout technique. Increasing PEEP from 0.2 to 0.3 to 0.4 kPa resulted in increases in FRC (p < 0.01) and oxygenation (ns) in all infants. In 16 infants compliance decreased and paCO2 increased with elevation of PEEP. Only in 4 infants compliance increased and CO2 fell., Conclusion: In the majority of our infants reduction of PEEP from 0.4 to 0.2 kPa resulted in increases in compliance and CO2 reduction. Our results might suggest that relatively low levels of PEEP < 0.3 kPa may be appropriate at 72 hours after surfactant replacement. Furthermore, these results underline the importance of PEEP test in clinical practice.

Background/purpose: Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia that limits survival. The authors' knowledge on lung mechanics and lung volumes in these patients with hypoplastic lungs is still limited. Therefore, the authors performed measurements of functional residual capacity (FRC), compliance of the respiratory system (CRS), and tidal volume in 5 full-term infants (gestational age, 38 to 40 weeks; birth weight, 2,800 to 3,530 g) before and after surgical repair of neonatal CDH., Methods: The authors studied the influence of different levels of positive end-expiratory pressure (PEEP) and suction via inserted ipsilateral chest tube connected to a water seal on lung volume and lung mechanics. A computerized tracer gas (SF6) washout method was used for serial measurements of FRC. Compliance of the respiratory system was determined according to insufflatory method., Results: The authors found a preoperative compliance between 1.5 and 3.9 mL/kPa/kg and a preoperative FRC between 9.1 and 12.9 mL/kg indicating severe hypoplasia of the lungs in all patients. Immediately after surgical repair of CDH, compliance decreased to 85% (78% to 91%) of preoperative value, and FRC increased to 132% (110% to 150%) of preoperative value under mechanical ventilation while at 4 cm of water of PEEP and at -10 cm of water of suction via chest drain with the need of high fraction of inspired oxygen. After reduction of PEEP from 4 to 2 or 1 cm of water and lowering suction from -10 cm of water to -2 or 0 cm of water FRC decreased to 103% (80% to 122%) of preoperative value and compliance, and tidal volume improved to 135% (110% to 147%) of preoperative value resulting in increased alveolar ventilation, correction of acidosis and improvement in oxygenation. During the first days after surgery inadequate high PEEP or strong suction via chest tube drainage resulted in increase in FRC paralleled by decrease in compliance indicating overdistension of these hypoplastic lungs., Conclusions: The data show that overdistension of hypoplastic lungs in infants with CDH can be detected and excluded by repeated measurements of FRC and compliance in these critical ill infants. These data might help setting appropriate ventilator parameters, adequate suction via chest drain, and thereby improve gas exchange and outcome.

Background: In the literature we found only five reports about noninvasive ventilation in cases with central hypoventilation syndrome., Patient and Method: We report about a 4-year-old boy with severe late onset hypoventilation syndrome. During an interval of 3 months with nasal mask ventilation during sleep he showed an excellent cognitive and statomotoric development. After this time, he needed a noninvasive ventilation with a negative pressure system., Results and Discussion: In our opinion, noninvasive nasal mask ventilation is a modern method in the treatment of patients with central hypoventilation syndrome. Tracheotomy is only necessary during the first year of life.

The aims of this study were to determine the incidence of typical chest radiography findings - (1) uniform improvement, (2) asymmetrical improvement, (3) no improvement or (4) interstitial emphysema - after therapeutic use of surfactant and to analyse clinical course and outcome. Chest radiographs of 138 infants of very low birth weight treated with surfactant were analysed. Twenty-eight infants with a diagnosis other than typical respiratory distress syndrome (RDS), i. e., sepsis, congenital pneumonia and congenital malformation, were excluded. In 110 patients with clinical and radiological evidence of typical RDS (median gestational age 28 weeks, median birth weight 1070 g) adequate chest radiographs from before and within 72 h after surfactant treatment were available. The time of surfactant application ranged between 1 and 12 h after birth. The most common finding after surfactant treatment was uniform or asymmetrical improvement of pulmonary aeration (80 of 110 patients). Patients with uniform clearing had the best long-term outcome. Asymmetrical clearance was often localised on the right side or in central regions of the lung, and usually disappeared after retreatment with surfactant without clinical significance. In 11 patients no change in aeration was found and retreatment was absolutely ineffective. Development of pulmonary inter- stitial emphysema after surfactant treatment was a grave prognostic sign: 73 % of these infants died within the first 2 weeks of life compared with 10 % of those with uniform or asymmetrical improvement of ventilation.

Background: There are only small experiences with mechanical ventilation via nasal mask in childhood., Patients and Methods: Eleven patients using NIPPV (9 patients aged 4 to 18 years and 2 patients with cystic fibrosis aged 20 and 25 years)., Results: NIPPV was effective in all 11 patients. Seven patients needed supplemental oxygen. Theophyllin, Almitrin and Salbutamol could support the nasal ventilation in special conditions., Conclusion: Intermittent ventilation via nasal mask is a noninvasive and effective treatment of chronic respiratory failure in childhood. Monitoring with continuous pulse-oximetry is necessary.

10 anaesthetized and tracheotomized rabbits were used to test the possibility for calculation of total respiratory system compliance from resonance frequency (CR). Reference values were obtained by inflation method compliance (CI). A new servocontrolled infant ventilator was used with an integrated negative ventilator resistance mode for resistive unloading of combined resistances of lung, endotracheal tube and ventilator. This evoked oscillation at resonant frequency. By analogy with electrical circuit theory compliance was calculated as follows: CR = 1/(4 pi 2 x square root I.RF2). Pairs of CI and CR values were obtained from each animal during spontaneous breathing, after pancuronium relaxation and after surfactant depletion by lavage. There was found a significant linear correlation between CR and CI values (CR = 1.1 x CI-0.74; r = 0.97).

Neuromuscular disorder can cause neonatal respiratory insufficiency. One male term newborn with Werdnig-Hoffmann disease and two preterm infants with congenital myotonic dystrophy Curshmann-Steinert-Batten are reported. Hydramnion, few spontaneous movements, prematurity, increasing respiratory insufficiency, hypotonia and myopathic facies of the mother are typical for congenital myotonic dystrophy.

Gd-DTPA is the first paramagnetic contrast agent approved for clinical use in cranial and spinal MRI in the F.R.G., U.S.A., Japan and several other countries. After submission 13,439 patients were enrolled in standardized protocolled clinical trials. The observed adverse drug reactions (ADRs) after i.v. injection of Gd-DTPA were comparable to those after administration of iodinated non-ionic roentgen contrast media (CM). However, the overall incidence of ADRs after intravenous injection of 0.1 or 0.2 mmol/kg body weight Gd-DTPA was found to be even lower. Adverse events were observed in only 1.46% of the patients - or 1.14% if localized warmth is excluded. None of them was critical. There was no correlation between patient age and the incidence of ADRs. In patients with a known history of allergy the incidence of ADRs was increased by a factor 3-4, which is still lower than the incidence reported after intravenous administration of iodinated non-ionic roentgen CM to patients without known allergy. Good renal tolerance was seen in all patients, irrespective of pre-existing renal impairment. Fast bolus injections of Gd-DTPA were tolerated without added risk. The favorable safety profile is also reflected in the post marketing surveillance reports since Gd-DTPA became available as a commercial drug.

It has been suggested that high frequency oscillatory ventilation (HFV) might improve gas exchange and reduce the risk of pressure-related side-effects compared to conventional mechanical ventilation (CMV). Whereas most studies have used arbitrarily set frequencies for HFV, we evaluated the effects of HFV near resonant frequency (fr). Anaesthetised and tracheotomized adult rabbits (n = 10; 3.8-5.1 kg body weight) were ventilated by alternating periods of CMV and HFV near fr. Negative ventilator resistance was used for complete resistive unloading of the respiratory system before each HFV period. This enabled a continuous swinging at resonance thus allowing measurement of fr and selection of exactly that frequency for the HFV run. Intra-animal CMV-HFV comparisons (n = 4) were performed on each animal: with healthy lungs at a mean airway pressure (MAP) of 0.5 kPa and after saline lung lavage at MAPs of less than 1.5 kPa; 1.5-1.8 kPa; greater than 1.8 kPa. Surfactant removal caused total respiratory system compliance (Ctot) to decrease from 44 +/- 5 to 22 +/- 3 ml/kPa. Corresponding fr was 244 +/- 48 and 360 +/- 30 min-1, respectively. HFV produced effective pulmonary gas exchange but did not improve arterial oxygenation in comparison with CMV at matched MAPs both before and after surfactant depletion. Volume amplitudes of oscillation necessary to achieve normocapnia were slightly above the natural plus equipment (2 ml) dead space. Maximum intra-alveolar pressure (Pmax) was calculated for the HFV runs from MAP, Ctot, and the volume amplitude of oscillation. Pmax during CMV was nearly twice that during HFV at equivalent PaCO2 and equivalent MAPs throughout the experiments.

Ten anesthetized, tracheotomized, adult rabbits were used to test the validity of a method for calculation of total respiratory system compliance from resonant frequency (Cr). Reference values were obtained during constant flow inflation of the relaxed respiratory system by dividing the volume gain by the related difference in pressure at the airway opening (inflation method compliance, Ci). The animals were connected to a new type of servo-controlled infant ventilator. Besides volume-controlled mechanical ventilation at constant inspiratory flow rate and intermittent mandatory ventilation, there is a negative ventilator resistance mode integrated in this device for resistive unloading (Schulze A, Schaller P, Gehrhardt B, Mädler H-J, Gmyrek D: Pediatr Res 28:79-82, 1990). To measure resonant frequency (fr), the respiratory system was totally unloaded for a short period by a negative ventilator resistance exceeding the combined resistances of the endotracheal tube and airways. This evoked a continuous oscillation at fr. By analogy with electrical circuit theory, Cr was calculated according to C = 1/(4 pi 2.I.fr2) where C is compliance and I is inertance. The inertance of the endotracheal tube is given and that of the bronchial tree was ignored assuming a much greater total cross-sectional area and therefore much lower inertance when compared with the endotracheal tube. Three pairs of Ci - Cr values were obtained from each animal: 1) during intact respiratory muscle activity; 2) after pancuronium relaxation, and 3) after surfactant depletion by saline washout.(ABSTRACT TRUNCATED AT 250 WORDS)