RESUMEN
BACKGROUND: Preterm born infants are at risk for brain injury and subsequent developmental delay. Treatment options are limited, but optimizing postnatal nutrition may improve brain- and neurodevelopment in these infants. In pre-clinical animal models, combined supplementation of docosahexaenoic acid (DHA), choline, and uridine-5-monophosphate (UMP) have shown to support neuronal membrane formation. In two randomized controlled pilot trials, supplementation with the investigational product was associated with clinically meaningful improvements in cognitive, attention, and language scores. The present study aims to assess the effect of a similar nutritional intervention on brain development and subsequent neurodevelopmental outcome in infants born very and extremely preterm. METHODS: This is a randomized, placebo-controlled, double-blinded, parallel-group, multi-center trial. A total of 130 infants, born at less than 30 weeks of gestation, will be randomized to receive a test or control product between term-equivalent age and 12 months corrected age (CA). The test product is a nutrient blend containing DHA, choline, and UMP amongst others. The control product contains only fractions of the active components. Both products are isocaloric powder supplements which can be added to milk and solid feeds. The primary outcome parameter is white matter integrity at three months CA, assessed using diffusion-tensor imaging (DTI) on MRI scanning. Secondary outcome parameters include volumetric brain development, cortical thickness, cortical folding, the metabolic and biochemical status of the brain, and product safety. Additionally, language, cognitive, motor, and behavioral development will be assessed at 12 and 24 months CA, using the Bayley Scales of Infant Development III and digital questionnaires (Dutch version of the Communicative Development Inventories (N-CDI), Ages and Stages Questionnaire 4 (ASQ-4), and Parent Report of Children's Abilities - Revised (PARCA-R)). DISCUSSION: The investigated nutritional intervention is hypothesized to promote brain development and subsequent neurodevelopmental outcome in preterm born infants who have an inherent risk of developmental delay. Moreover, this innovative study may give rise to new treatment possibilities and improvements in routine clinical care. TRIAL REGISTRATION: WHO International Clinical Trials Registry: NL-OMON56181 (registration assigned October 28, 2021).
Asunto(s)
Encéfalo , Colina , Suplementos Dietéticos , Ácidos Docosahexaenoicos , Uridina Monofosfato , Humanos , Lactante , Recién Nacido , Encéfalo/crecimiento & desarrollo , Encéfalo/diagnóstico por imagen , Desarrollo Infantil , Ácidos Docosahexaenoicos/administración & dosificación , Método Doble Ciego , Recien Nacido Extremadamente Prematuro/crecimiento & desarrollo , Recien Nacido Prematuro/crecimiento & desarrollo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Infants developing necrotizing enterocolitis (NEC) have a different metabolomic profile compared to controls. The potential of specific metabolomics, i.e. amino acids and amino alcohols (AAA), as early diagnostic biomarkers for NEC is largely unexplored. In this multicenter prospective case-control study, longitudinally collected fecal samples from preterm infants (born <30 weeks of gestation) from 1-3 days before diagnosis of severe NEC (Bell's stage IIIA/IIIB), were analyzed by targeted high-performance liquid chromatography (HPLC). Control samples were collected from gestational and postnatal age-matched infants. Thirty-one NEC cases (15 NEC IIIA;16 NEC IIIB) with 1:1 matched controls were included. Preclinical samples of infants with NEC were characterized by five increased essential amino acids-isoleucine, leucine, methionine, phenylalanine and valine. Lysine and ethanolamine ratios were lower prior to NEC, compared to control samples. A multivariate model was rendered based on isoleucine, lysine, ethanolamine, tryptophan and ornithine, modestly discriminating cases from controls (AUC 0.67; p < 0.001). Targeted HPLC pointed to several specific AAA alterations in samples collected 1-3 days before NEC onset, compared to controls. Whether this reflects metabolic alterations and has a role in early biomarker development for NEC, has yet to be elucidated.
Asunto(s)
Enterocolitis Necrotizante , Enfermedades del Recién Nacido , Aminas , Estudios de Casos y Controles , Enterocolitis Necrotizante/diagnóstico , Enterocolitis Necrotizante/metabolismo , Etanolaminas , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro/metabolismo , Isoleucina , LisinaRESUMEN
Neonates with genetic disorders or congenital anomalies (CA) contribute considerably to morbidity and mortality in neonatal intensive care units (NICUs). The objective of this study is to study the prevalence of genetic disorders in an academic level IV NICU. We retrospective collected and analyzed both clinical and genetic data of all 1444 infants admitted to the NICU of the Radboudumc (October 2013 to October 2015). Data were collected until infants reached at least 2 years of age. A total of 13% (194/1444) of the patients were genetically tested, and 32% (461/1444) had a CA. A total of 37% (72/194) had a laboratory-confirmed genetic diagnosis. In 53%, the diagnosis was made post-neonatally (median age = 209 days) using assays including exome sequencing. Exactly 63% (291/461) of the patients with CA, however, never received genetic testing, despite being clinically similar those who did.Conclusions: Genetic disorders were suspected in 13% of the cohort, but only confirmed in 5%. Most received their genetic diagnosis in the post-neonatal period. Extrapolation of the diagnostic yield suggests that up to 6% of our cohort may have remained genetically undiagnosed. Our data show the need to improve genetic care in the NICU for more inclusive, earlier, and faster genetic diagnosis to enable tailored management. What is Known: ⢠Genetic disorders are suspected in many neonates but only genetically confirmed in a minority. ⢠The presence of a genetic disorder can be easily missed and will often lead to a diagnostic odyssey requiring extensive evaluations, both clinically and genetically. What is New: ⢠Different aspects of the clinical features and uptake of genetic test in a NICU cohort. ⢠The need to improve genetic care in the NICU for more inclusive, earlier, and faster genetic diagnosis to enable tailored management.
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Pruebas Genéticas , Unidades de Cuidado Intensivo Neonatal , Estudios de Cohortes , Humanos , Lactante , Recién Nacido , Morbilidad , Estudios RetrospectivosRESUMEN
BACKGROUND: Central line-associated bloodstream infections (CLABSI) are a main focus of infection prevention and control initiatives in neonatal care. Standardised surveillance of neonatal CLABSI enables intra- and interfacility comparisons which can contribute to quality improvement. To date, there is no national registration system for CLABSI in neonatal care in the Netherlands and several criteria are used for local monitoring of CLABSI incidence rates. To achieve standardised CLABSI surveillance we conducted a consensus procedure with regard to nationwide neonatal CLABSI surveillance criteria (SC). METHODS: A modified Delphi consensus procedure for the development of nationwide neonatal CLABSI SC was performed between January 2016 and January 2017 in the Netherlands. An expert panel was formed by members of the Working Group on Neonatal Infectious Diseases of the Section of Neonatology of the Dutch Paediatric Society. The consensus procedure consisted of three expert panel rounds. RESULTS: The expert panel achieved consensus on Dutch neonatal CLABSI SC. Neonatal CLABSI is defined as a bloodstream infection occurring more than 72 h after birth, associated with an indwelling central venous or arterial line and laboratory confirmed by one or more blood cultures. In addition, the blood culture finding should not be related to an infection at another site and one of the following criteria can be applied: 1. a bacterial or fungal pathogen is identified from one or more blood cultures; 2. the patient has clinical symptoms of sepsis and 2A) a common commensal is identified in two separate blood cultures or 2B) a common commensal is identified by one blood culture and C-reactive protein level is above 10 mg/L in the first 36 h following blood culture collection. CONCLUSIONS: The newly developed Dutch neonatal CLABSI SC are concise, specified to the neonatal population and comply with a single blood culture policy in actual neonatal clinical practice. International agreement upon neonatal CLABSI SC is needed to identify best practices for infection prevention and control.
Asunto(s)
Infecciones Relacionadas con Catéteres/diagnóstico , Cateterismo Venoso Central , Consenso , Técnica Delphi , Humanos , Recién Nacido , Control de Infecciones , Países Bajos , Sepsis/diagnósticoAsunto(s)
Ecocardiografía/normas , Cuidado Intensivo Neonatal/normas , Neonatología/normas , Enfermedad Crítica , Europa (Continente) , Hemodinámica , Humanos , Recién Nacido , Enfermedades del Recién Nacido , Recien Nacido Prematuro , Unidades de Cuidado Intensivo Neonatal , Neonatólogos , Sociedades MédicasRESUMEN
Neonatologist-performed echocardiography (NPE) is an indispensable tool in the haemodynamic management of critically ill newborn infants. NPE is used to facilitate timely diagnosis of a patent ductus arteriosus (PDA) in preterm infants and to assess its haemodynamic significance. Before treatment is considered, it is obligatory to confirm structural cardiac normality. Importantly, NPE offers the ability to guide therapeutic interventions, allowing an individualised haemodynamic management approach to the PDA. After discussing PDA pathophysiology, an overview is provided on the role of NPE in the assessment and management of PDA in preterm infants.
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Conducto Arterioso Permeable/diagnóstico por imagen , Ecocardiografía , Hemodinámica/fisiología , Conducto Arterioso Permeable/fisiopatología , Conducto Arterioso Permeable/terapia , Humanos , Recién Nacido , Recien Nacido Prematuro , NeonatólogosRESUMEN
Fetal growth restriction (FGR) affects 7-10% pregnancies. Conventional and tissue Doppler imaging has noted cardiac compromise during fetal and early neonatal periods in this cohort. In this article, we discuss the use of salient ultrasound parameters across age groups. During fetal life, certain feto-placental sonographic parameters have been linked to adverse perinatal outcomes and are predictive of later life hypertension. During the early postnatal period altered morphometry (hypertrophied and globular hearts) with sub-clinical impairment of cardiac function has been noted in both term and preterm infants with FGR. Vascular imaging has noted thickened and stiffer arteries in association with significantly elevated blood pressure. Similar findings in the pediatric age groups indicate persistence of these alterations, and have formed the basis of intervention studies. Assessment methodology and clinical relevance of these parameters, especially in designing and monitoring of intervention strategies is discussed. Frontline care givers (obstetricians and neonatologists) are increasingly using point of care ultrasound to discern these manifestations of FGR during the sub-clinical phase.
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Retardo del Crecimiento Fetal/diagnóstico por imagen , Placenta/diagnóstico por imagen , Arterias/diagnóstico por imagen , Arterias/patología , Ecocardiografía Doppler , Femenino , Retardo del Crecimiento Fetal/patología , Corazón Fetal/diagnóstico por imagen , Corazón Fetal/patología , Edad Gestacional , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/etiología , Humanos , Recién Nacido , Recien Nacido Prematuro , Muerte Perinatal , Placenta/irrigación sanguínea , Embarazo , Ultrasonografía PrenatalRESUMEN
Increased extravascular lung water (EVLW) may contribute to respiratory failure in neonates. Accurate measurement of EVLW in these patients is limited due to the lack of bedside methods. The aim of this pilot study was to investigate the reliability of the transpulmonary ultrasound dilution (TPUD) technique as a possible method for estimating EVLW in a neonatal animal model. Pulmonary edema was induced in 11 lambs by repeated surfactant lavages. In between the lavages, EVLW indexed by bodyweight was estimated by TPUD (EVLWItpud) and transpulmonary dye dilution (EVLWItpdd) (n = 22). Final EVLWItpud measurements were also compared with EVLWI estimations by gold standard post mortem gravimetry (EVLWIgrav) (n = 6). EVLWI was also measured in two additional lambs without pulmonary edema. Bland-Altman plots showed a mean bias between EVLWItpud and EVLWItpdd of -3.4 mL/kg (LOA ± 25.8 mL/kg) and between EVLWItpud and EVLWIgrav of 1.7 mL/kg (LOA ± 8.3 mL/kg). The percentage errors were 109 and 43 % respectively. The correlation between changes in EVLW measured by TPUD and TPDD was r2 = 0.22. Agreement between EVLWI measurements by TPUD and TPDD was low. Trending ability to detect changes between these two methods in EVLWI was questionable. The accuracy of EVLWItpud was good compared to the gold standard gravimetric method but the TPUD lacked precision in its current prototype. Based on these limited data, we believe that TPUD has potential for future use to estimate EVLW after adaptation of the algorithm. Larger studies are needed to support our findings.
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Agua Pulmonar Extravascular , Termodilución/métodos , Algoritmos , Animales , Gasto Cardíaco , Cateterismo , Arteria Femoral/patología , Hemodinámica , Lesión Pulmonar/patología , Edema Pulmonar/terapia , Reproducibilidad de los Resultados , Ovinos , Termogravimetría , UltrasonografíaRESUMEN
BACKGROUND: The transpulmonary thermodilution (TPTD) technique is widely used in clinical practice for measuring cardiac output (CO). This study was designed to investigate the influence of various levels of pulmonary oedema on the reliability of CO measurements by the TPTD method. METHODS: In 11 newborn lambs pulmonary oedema was induced using a surfactant washout technique. Serial CO measurements using TPTD (CO(TPTD)) were performed at various amounts of lung water. Simultaneously, CO was measured by an ultrasound flow probe around the main pulmonary artery (CO(MPA)) and used as the standard reference. CO was divided by the body surface area to calculate cardiac index (CI). Data were analysed using correlational statistics and Bland-Altman analysis. RESULTS: One lamb died prematurely. A total of 56 measurements in 10 lambs were analysed with a median CI(MPA) of 2.95 (IQR 1.04) litre min(-1) m(-2). Mean percentage increase in extravascular lung water (EVLW) between the start and the end of the study was 126.4% (SD 40.4). Comparison of the two CO methods showed a mean bias CI of -0.16 litre min(-1) m(-2) (limits of agreement ±0.73 litre min(-1) m(-2)) and a percentage error of 23.8%. Intraclass correlation coefficients were 0.91 (95% CI 0.81-0.95) for absolute agreement and 0.92 (95% CI 0.87-0.95) for consistency. Acceptable agreement was confirmed by a tolerability-agreement ratio of 0.39. The within-subject correlation between the amount of EVLWI and the bias between the two methods was not significant (-0.02; P=0.91). CONCLUSIONS: CO measurements by the transpulmonary thermodilution technique over a wide range of CI values are not affected by the presence of high EVLWI. The slight underestimation of the CO is independent of the amount of pulmonary oedema.
Asunto(s)
Gasto Cardíaco/fisiología , Edema Pulmonar/fisiopatología , Animales , Animales Recién Nacidos , Agua Pulmonar Extravascular/fisiología , Reproducibilidad de los Resultados , Oveja Doméstica , Termodilución/métodosRESUMEN
BACKGROUND: Transpulmonary ultrasound dilution (TPUD) is a promising method for cardiac output (CO) measurement in severely ill neonates. The incidence of lung injury in this population is high, which might influence CO measurement using TPUD because of altered lung perfusion. We evaluated the influence of lung injury on the accuracy and precision of CO measurement using TPUD in an animal model. METHODS: In nine neonatal lambs, central venous and arterial catheters were inserted and connected to the TPUD monitor. Repeated lavages with warmed isotonic saline were performed to gradually induce lung injury. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe around the main pulmonary artery (COufp). An increase in oxygenation index was used as an indicator of induced lung injury during the experiment. Post-mortem lung injury was confirmed by histopathological examination. RESULTS: Fifty-five sessions of three paired CO measurements were analysed. The mean COufp was 1.53 litre min(-1) (range 0.66-2.35 litre min(-1)), and the mean COtpud was 1.65 litre min(-1) (range 0.78-2.91 litre min(-1)). The mean bias (standard deviation) between the two methods was 0.13 (0.15) litre min(-1) with limits of agreement of ±0.29 litre min(-1). The overall percentage error was 19.1%. The accuracy and precision did not change significantly during progressive lung injury. Histopathological severity scores were consistent with heterogeneous lung injury. The capability to track changes in CO using TPUD was moderate to good. CONCLUSIONS: The accuracy and precision of CO measurement using TPUD is not influenced in the presence of heterogeneous lung injury in an animal model.
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Gasto Cardíaco , Lesión Pulmonar/veterinaria , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/veterinaria , Ultrasonografía/veterinaria , Animales , Animales Recién Nacidos , Cateterismo Venoso Central/instrumentación , Cateterismo Venoso Central/veterinaria , Cateterismo Periférico/instrumentación , Cateterismo Periférico/veterinaria , Modelos Animales de Enfermedad , Técnicas de Dilución del Indicador/instrumentación , Técnicas de Dilución del Indicador/veterinaria , Lesión Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Reproducibilidad de los Resultados , Oveja Doméstica , Ultrasonografía/instrumentaciónRESUMEN
BACKGROUND: Cardiac output (CO) monitoring remains complex in newborns as most of the current technologies fail to accurately measure systemic blood flow in the presence of shunts. We validated CO measurements using transpulmonary ultrasound dilution (TPUD) in a neonatal lamb model with a left-to-right shunt. METHODS: Regular arterial and central venous catheters were inserted into seven lambs (3.5-8.3 kg). A surgically constructed left-to-right aorto-pulmonary Gore-Tex(®) shunt was intermittently opened and closed, while CO was manipulated by creating haemorrhagic hypotension. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe positioned around the main pulmonary artery (COufp). RESULTS: We performed 72 sessions of three paired CO measurements. The mean COufp was 1.00 litre min(-1) (range 0.47-1.75 litre min(-1)) and mean COtpud 1.05 litre min(-1) (range 0.54-1.87 litre min(-1)). With an open shunt, the mean Qp/Qs ratio was 1.8 (range 1.3-2.6). A comparison between COufp and COtpud showed a mean bias (sd) of 0.03 (0.09) and 0.07 (0.10) litre min(-1), respectively, for measurements with a closed and an open shunt. The percentage error was 18% and 20% for measurements with a closed and an open shunt. Polar plot analysis showed good trending ability for both closed and open shunt groups. CONCLUSIONS: TPUD is a reliable technology to measure CO in the presence of a left-to-right shunt.
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Gasto Cardíaco/fisiología , Conducto Arterioso Permeable/diagnóstico por imagen , Técnicas de Dilución del Indicador , Animales , Animales Recién Nacidos , Cateterismo Cardíaco/métodos , Modelos Animales de Enfermedad , Conducto Arterioso Permeable/fisiopatología , Estudios de Factibilidad , Modelos Animales , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Flujo Sanguíneo Regional/fisiología , Oveja Doméstica , UltrasonografíaRESUMEN
BACKGROUND: The transpulmonary thermodilution (TPTD) technique for measuring cardiac output (CO) has never been validated in the presence of a left-to-right shunt. METHODS: In this experimental, paediatric animal model, nine lambs with a surgically constructed aorta-pulmonary left-to-right shunt were studied under various haemodynamic conditions. CO was measured with closed and open shunt using the TPTD technique (CO(TPTD)) with central venous injections of ice-cold saline. An ultrasound transit time perivascular flow probe around the main pulmonary artery served as the standard reference measurement (CO(MPA)). RESULTS: Seven lambs were eligible for further analysis. Mean (sd) weight was 6.6 (1.6) kg. The mean CO(MPA) was 1.21 litre min(-1) (range 0.61-2.06 l min(-1)) with closed shunt and 0.93 litre min(-1) (range 0.48-1.45 litre min(-1)) with open shunt. The open shunt resulted in a mean Q(p)/Q(s) ratio of 1.8 (range 1.6-2.4). The bias between the two CO methods was 0.17 litre min(-1) [limits of agreement (LOA) of 0.27 litre min(-1)] with closed shunt and 0.14 litre min(-1) (LOA of 0.32 litre min(-1)) with open shunt. The percentage errors were 22% with closed shunt and 34% with open shunt. The correlation (r) between the two methods was 0.93 (P<0.001) with closed shunt and 0.86 (P<0.001) with open shunt. The correlation (r) between the two methods in tracking changes in CO (ΔCO) during the whole experiment was 0.94 (P<0.0001). CONCLUSIONS: The TPTD technique is a feasible method of measuring CO in paediatric animals with a left-to-right shunt.
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Gasto Cardíaco , Cardiopatías Congénitas/fisiopatología , Termodilución/métodos , Animales , Aorta/fisiología , Modelos Animales de Enfermedad , Circulación Pulmonar , Ovinos , Choque Hemorrágico/fisiopatologíaRESUMEN
Automatic segmentation of the endocardial surface in three-dimensional (3D) echocardiographic images is an important tool to assess left ventricular (LV) geometry and cardiac output (CO). The presence of speckle noise as well as the nonisotropic characteristics of the myocardium impose strong demands on the segmentation algorithm. In the analysis of normal heart geometries of standardized (apical) views, it is advantageous to incorporate a priori knowledge about the shape and appearance of the heart. In contrast, when analyzing abnormal heart geometries, for example in children with congenital malformations, this a priori knowledge about the shape and anatomy of the LV might induce erroneous segmentation results. This study describes a fully automated segmentation method for the analysis of non-standard echocardiographic images, without making strong assumptions on the shape and appearance of the heart. The method was validated in vivo in a piglet model. Real-time 3D echocardiographic image sequences of five piglets were acquired in radiofrequency (rf) format. These ECG-gated full volume images were acquired intra-operatively in a non-standard view. Cardiac blood flow was measured simultaneously by an ultrasound transit time flow probe positioned around the common pulmonary artery. Three-dimensional adaptive filtering using the characteristics of speckle was performed on the demodulated rf data to reduce the influence of speckle noise and to optimize the distinction between blood and myocardium. A gradient-based 3D deformable simplex mesh was then used to segment the endocardial surface. A gradient and a speed force were included as external forces of the model. To balance data fitting and mesh regularity, one fixed set of weighting parameters of internal, gradient and speed forces was used for all data sets. End-diastolic and end-systolic volumes were computed from the segmented endocardial surface. The cardiac output derived from this automatic segmentation was validated quantitatively by comparing it with the CO values measured from the volume flow in the pulmonary artery. Relative bias varied between 0 and -17%, where the nominal accuracy of the flow meter is in the order of 10%. Assuming the CO measurements from the flow probe as a gold standard, excellent correlation (r = 0.99) was observed with the CO estimates obtained from image segmentation.
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Gasto Cardíaco , Ecocardiografía Tridimensional/métodos , Animales , Ecocardiografía Tridimensional/normas , Procesamiento de Imagen Asistido por Computador , Arteria Pulmonar/fisiología , Volumen Sistólico , Factores de Tiempo , Función Ventricular IzquierdaRESUMEN
Two patients with a Noonan phenotype and progressive hypertrophic obstructive cardiomyopathy are described, in whom abnormal histopathological changes in striated musculature were detected. In both patients an increased density of muscle spindles was found at biopsy. The significance of an increased density of muscle spindles in patients with Noonan phenotype can only be speculated. The question is raised of whether these changes are a distinct feature within the spectrum of patients with Noonan phenotype.
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Músculo Esquelético/patología , Miocardio/patología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Cardiomiopatía Hipertrófica/patología , Resultado Fatal , Femenino , Humanos , Recién Nacido , Masculino , Fibras Musculares Esqueléticas/ultraestructura , Husos Musculares/ultraestructura , FenotipoRESUMEN
With the aid of a questionnaire form we have gathered information about the clinical picture of patients suffering from primary ciliary dyskinesia. The study group numbered 34 persons, whose diagnosis was confirmed by electron microscopy. Chronic cough and common cold symptoms are present from shortly after birth. Twenty-three respondents reported respiratory tract problems in the neonatal period. The dysfunctional cilia result in chronic respiratory tract infections (chronic bronchitis; bronchiectasis; pneumonia; chronic sinusitis, rhinitis or otitis media). These lead to the following complaints: frequent blowing of the nose (in 32 pat.; 94%), chronic productive cough (in 28 pat.; 82%), chronic common cold (in 26 pat.; 77%), hearing problems (in 24 pat.; 71%), shortness of breath (in 23 pat.; 68%), frequent headache (in 13 pat.; 38%) and sore throat (in 9 pat.; 27%). In order to prevent the invalidating consequences of this disorder appropriate steps should be taken as soon as possible. These should include physiotherapy and adequate antibiotic therapy.