A Device for Respiratory Monitoring during Nutritive Sucking: Response to Neonatal Breathing Patterns

The quantitative monitoring of breathing, sucking, and swallowing is required to predict newborns' neurodevelopmental outcomes. In particular, the coordination of breathing timing with respect to sucking cycle is crucial. In this work, we present the characterization of a low-cost flowmeter designed for noninvasive recording of breathing pattern during bottle feeding. The transducer is designed to be integrated on a commercial feeding bottle also instrumented with a system for sucking monitoring. The flowmeter consists of two transistors (hot bodies) supplied at constant current, which are placed in a duct used to convey the inspiratory and expiratory flow coming from the newborn's nostrils. The transducer design, its static calibration, and its response time are discussed. Moreover, a custom-made active lung simulator was used to perform a feasibility assessment of the proposed flowmeter for respiratory monitoring of neonatal respiratory patterns. The flowmeter has a discrimination threshold <0.5 L·min−1and a response time of347±12 ms. The breathing period estimated by the proposed transducer was compared with the one measured by a high performance flowmeter, used as reference: the mean absolute error was <11%. Results highlighted the ability of the device to track respiratory patterns at frequencies typical of neonatal breathing

Regurgitation in healthy and non healthy infants

Uncomplicate regurgitation in otherwise healthy infants is not a disease. It consists of milk flow from mouth during or after feeding. Common causes include overfeeding, air swallowed during feeding, crying or coughing; physical exam is normal and weight gain is adequate. History and physical exam are diagnostic, and conservative therapy is recommended. Pathologic gastroesophageal reflux or gastroesophageal reflux disease refers to infants with regurgitation and vomiting associated with poor weight gain, respiratory symptoms, esophagitis. Reflux episodes occur most often during transient relaxations of the lower esophageal sphincter unaccompanied by swallowing, which permit gastric content to flow into the esophagus. A minor proportion of reflux episodes occurs when the lower esophageal sphincter fails to increase pressure during a sudden increase in intraabdominal pressure or when lower esophageal sphincter resting pressure is chronically reduced. Alterations in several protective mechanisms allow physiologic reflux to become gastroesophageal reflux disease; diagnostic approach is both clinical and instrumental: radiological series are useful to exclude anatomic abnormalities; pH-testing evaluates the quantity, frequency and duration of the acid reflux episodes; endoscopy and biopsy are performed in the case of esophagitis. Therapy with H2 receptor antagonists and proton pump inhibitors are suggested

Abnormal Nutritive Sucking as an Indicator of Neonatal Brain Injury

A term neonate is born with the ability to suck; this neuronal network is already formed and functional by 28 weeks gestational age and continues to evolve into adulthood. Because of the necessity of acquiring nutrition, the complexity of the neuronal network needed to suck, and neuroplasticity in infancy, the skill of sucking has the unique ability to give insight into areas of the brain that may be damaged either during or before birth. Interpretation of the behaviors during sucking shows promise in guiding therapies and how to potentially repair the damage early in life, when neuroplasticity is high. Sucking requires coordinated suck-swallow-breathe actions and is classified into two basic types, nutritive and non-nutritive. Each type of suck has particular characteristics that can be measured and used to learn about the infant\u27s neuronal circuitry. Basic sucking and swallowing are present in embryos and further develop to incorporate breathing ex utero. Due to the rhythmic nature of the suck-swallow-breathe process, these motor functions are controlled by central pattern generators. The coordination of swallowing, breathing, and sucking is an enormously complex sensorimotor process. Because of this complexity, brain injury before birth can have an effect on these sucking patterns. Clinical assessments allow evaluators to score the oral-motor pattern, however, they remain ultimately subjective. Thus, clinicians are in need of objective measures to identify the specific area of deficit in the sucking pattern of each infant to tailor therapies to their specific needs. Therapeutic approaches involve pacifiers, cheek/chin support, tactile, oral kinesthetic, auditory, vestibular, and/or visual sensorimotor inputs. These therapies are performed to train the infant to suck appropriately using these subjective assessments along with the experience of the therapist (usually a speech therapist), but newer, more objective measures are coming along. Recent studies have correlated pathological sucking patterns with neuroimaging data to get a map of the affected brain regions to better inform therapies. The purpose of this review is to provide a broad scope synopsis of the research field of infant nutritive and non-nutritive feeding, their underlying neurophysiology, and relationship of abnormal activity with brain injury in preterm and term infants

Non-Nutritive Suck Assessment Tool Development to Characterize Sucking Patterns in Infant with Various Hunger Levels

Sucking abilities are critical in early infant development, and the patterns of non-nutritive suck (NNS) have been found to potentially predict neurodevelopmental issues in the future. Proper NNS assessments are essential to ensure valid conclusions. Previous studies have shown that the level of infant arousal significantly affects NNS patterns. However, the author did not find any studies that observed the influence of infant hunger levels on NNS patterns. Therefore, this study aimed to develop an NNS assessment tool to characterize NNS patterns in infants with various hunger levels. The NNS assessment was conducted using a pressure transducer connected to a pacifier. The results showed that the level of hunger significantly affected the intra-burst frequency and the sucking pressure. The more hungry the infant, the more frequent the intra-burst frequency became, while the sucking pressure tended to decrease. The intra-burst frequency of infant sucking was 2.3, 2.46, and 2.5 Hz on average for a relative hunger index of 0.67, 0.83, and 1.0, respectively. The NNS pressure of infant sucking was 6.31, 4.51, and 2.62 kPa on average for a relative hunger index of 0.67, 0.83, and 1.0, respectively. This study's results suggest that during NNS assessments, the measurement time should consider the next feeding schedule for the infant

Parameterization of In Silico Oral Disposition Models: Focus on Pediatrics

Owing to their biologically relevant design, physiologically-based pharmacokinetic (PBPK) models require quantitative knowledge of organism anatomy and physiology to facilitate appropriate parameterization. Within such models, an intrinsic relationship exists between the quality of input parameters and the confidence bestowed upon simulated outputs. Therefore, in order to instil confidence in PBPK model predictions of pediatric pharmacokinetics (PK), a fundamental understanding of age-specific changes in anatomy and physiology is required. However, due to a lack of consensus and general paucity of biological data denoting pediatric gastrointestinal (GI) physiology, parameterization of mechanistic oral disposition models in this population is quite challenging. The current dissertation expands our understanding of the ontogeny of key physiological aspects regulating oral drug disposition and serves to highlight differences between children and adults. In addition, the thesis describes essential processes involved in the development of pediatric PBPK models as well as demonstrates the use of such models as tools for identification of human physiological values – a utility that is of potential interest particularly for children, where several biological knowledge gaps persist. To illustrate the key processes involved in the rational development of pediatric PBPK models, a structured workflow was proposed and subsequently utilized to develop age-specific PK predictions for the benzodiazepine, lorazepam. Literature-based assessments of the age-dependency of small intestinal transit time (SITT), GI solubility, and α-1-acid glycoprotein (AAG) employed different methodologies. To discern the influence of age on SITT, random-effects meta-regression models were employed. Investigations assessing age-specific changes in GI fluid parameters (i.e. pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of a novel set of pediatric biorelevant media representative of the stomach and upper small intestine. Solubility assessments were conducted for seven BCS Class II compounds within the developed pediatric media and a set of reference adult media. Plasma AAG concentrations were assessed in both healthy subjects and those suspected of infection. The analysis evaluated use of linear, power, exponential, log-linear, and sigmoid Emax models to describe the ontogeny of AAG. Predictive performance of the most suitable ontogeny model was evaluated with regards to its ability to estimate pediatric fraction unbound in plasma (fu,p). Predictive performance was measured using average-fold error (AFE) and absolute average-fold error (AAFE) as measures of bias and precision, respectively. To demonstrate the use of PBPK modeling to facilitate predictions of human physiology, plasma concentration-time data depicting oral administration of acyclovir and chlorothiazide in adults were utilized to generate model-based estimates of small intestinal water volume (SIWV). Estimates were based on a framework that consisted of a whole-body PBPK model integrated with a compartmental absorption and transit (CAT) model. Use of the proposed workflow permitted for the development of age-specific PBPK models that provided relatively accurate estimates of lorazepam PK in children in comparison to a competing modeling technique (i.e. Population PK modeling). For SITT, age was not found to be a significant modulator. With regards to the age-dependency of GI solubility, for six of the seven BCS class II compounds investigated, solubility fell outside an 80-125% range from adult values in at least one of the developed pediatric media. The ontogeny of AAG was best approximated using a sigmoid Emax model in both healthy and infected subjects. For estimation of pediatric fu,p, the AAG ontogeny equation derived from this work (AFE 0.97; AAFE 1.24) provided a superior predictive performance in comparison to a previously proposed equation (AFE 0.74; AAFE 1.45). Model-based predictions of SIWV (~116 mL) closely approximated experimentally determined in vivo estimates, demonstrating the utility PBPK modeling as a rational method for investigating aspects of human physiology. The presented work serves to improve the parameterization of PBPK models tasked with simulating oral drug disposition in children; however, more research is still required to address additional knowledge gaps associated with pediatric GI physiology

Informing the design of a trial of kangaroo mother care initiated before stabilisation amongst small and sick newborns in a sub-Saharan African context using mixed methods

An estimated 2.5 million neonates die every year, with preterm birth being the leading cause. Sub-Saharan Africa and southern Asia account for 78% of neonatal deaths. The WHO recommends kangaroo mother care (KMC) for stabilised newborns ≤2000g; however, most deaths occur before stabilisation. An evidence gap exists regarding KMC for this population. The overall aim of this PhD was to inform the design of a trial of KMC initiated before stabilisation in a sub-Saharan African context. The first part focused on assessing facility readiness and quantifying neonatal mortality risk. Cascade models were developed and used to assess 23 East African facilities. A logistic model was derived and validated using data from 187 UK hospitals and one Gambian hospital. The final model, including three parameters, demonstrated very good performance. The score requires further validation in low-resource contexts, but has potential to improve neonatal resource allocation. The second part of this PhD focused on evaluating the feasibility of initiating KMC before stabilisation and designing the trial. This study showed it was feasible to monitor and provide care in the KMC position, and found the intervention was acceptable to parents and providers. Launched in 2020, the OMWaNA trial will determine the mortality impact of this intervention within 7 days relative to standard care at four Ugandan hospitals. Process and economic evaluations will explore causal pathways for clinical effects, estimate incremental cost and costeffectiveness, and examine barriers and facilitators to inform uptake and sustainability. This PhD has developed a cascade model to assess facility readiness, validated a score to assess individual risk, and demonstrated the feasibility of initiating KMC before stabilisation. These studies have informed the design of a trial evaluating the mortality impact of this intervention in Uganda. The findings are expected to have broad applicability to low-resource hospitals and important policy implications

2022 - The Third Annual Fall Symposium of Student Scholars

The full program book from the Fall 2022 Symposium of Student Scholars, held on November 17, 2022. Includes abstracts from the presentations and posters.https://digitalcommons.kennesaw.edu/sssprograms/1026/thumbnail.jp

Autonomic control in preterm infants - what we can learn from mathematical descriptions of vital signs

Background: Preterm birth is a major burden, affecting approximately 15 million infants each year. Recent advances in reproductive medicine increases that number even more. The population of preterm infants in particular suffers from autonomic dysregulation that manifests as temperature instability and poor control of heart rate and breathing. Thermal care, monitoring of vital signs in a neonatal intensive care unit, pharmacotherapy, and respiratory support over weeks to months is necessary. Improvements in neonatal care in the past years lead to a decrease in mortality, especially in very preterm infants. However, former preterm infants still are a high-risk population for acute and chronic sequelae as a result of the interruption of the physiological development. A better understanding of the pathophysiology of the autonomic dysregulation in that population would be very useful. Unfortunately, accurate diagnostic tools that objectively assess and quantify the immature autonomic control in neonates are lacking. Methods: In this PhD thesis we examined different effects of the immature autonomic control in very preterm infants under clinically relevant conditions. We conducted a prospective single center observational study, where we assessed fluctuations in body temperature, sleep behavior, and heart rate variability in very preterm infants. We described the different regulatory systems using distinct mathematical expressions, such as detrended fluctuation analysis and sample entropy. We assessed associations between these outcome parameters and relevant factors of the infant’s history, such as demographic parameters and co-morbidities. Besides that, we analyzed lung function measurements of preterm infants and healthy term controls at a comparable postconceptional age, to describe respiratory control. Results: This study is systematically assessing different physiological signals of autonomic dysregulation in preterm infants during their first days of life. We found associations between parameters describing the complexity of time series analysis and maturity or relevant co-morbidities of the infants. In the analysis of heart rate variability we even found that parameters derived from time series analysis, assessed during the infants first days of life, improve our ability to predict future evolution of the infants’ autonomic stability. Lastly, several weeks after the expected due date, tidal breathing pattern of preterm infants showed a different reaction in response to a sigh when compared to term born controls at equivalent postmenstrual age indicating that autonomic dysregulation in preterm infants is still present well beyond the expected due date. Conclusion: A better understanding about the resolution of autonomic dysregulation in this population is not only important for the infant and its family but has the potential to support resource allocation and identification of patients with elevated risk for future deterioration. We thus think that the insights about the immature autonomic control in preterm infants, gained through this PhD work, are of substantial scientific and clinical relevance