Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study.

OBJECTIVE: To evaluate associations between neurologic outcomes and early measurements of basal ganglia (BG) and thalamic (Th) perfusion using color Doppler ultrasonography (CDUS) in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Prospective study of infants with mild (n = 18), moderate (n = 17), and severe HIE (n = 14) and controls (n = 17). Infants with moderate-severe HIE received therapeutic hypothermia (TH). CDUS was performed at 24-36 hours and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5-5 years. The primary outcome was the association between BG and Th perfusion and brain MRI injury. Secondary analyses focused on associations between perfusion measurements and admission neurologic examinations, MRI scores in infants treated with TH, and motor and sensory disability, or death. An exploratory analysis assessed the accuracy of BG and Th perfusion to predict brain MRI injury in infants treated with TH. RESULTS: Increased BG and Th perfusion on CDUS was observed in infants with severe MRI scores and those with significant motor and neurosensory disability or death through 2.5-5 years (P < .05). Infants with severe HIE showed increased BG and Th perfusion (P < .005) compared with infants with moderate HIE. No differences were identified between the between the control and mild HIE groups. Th perfusion ≥0.237 cm/second (Area under the curve of 0.824) correctly classified 80% of infants with severe MRI scores. CONCLUSIONS: Early dynamic CDUS of the BG and Th is a potential biomarker of severe brain injury in infants with HIE and may be a useful adjunct to currently used assessments.

Age at First Extubation Attempt and Death or Respiratory Morbidities in Extremely Preterm Infants.

OBJECTIVE: To describe the timing of first extubation in extremely preterm infants and explore the relationship between age at first extubation, extubation outcome, and death or respiratory morbidities. STUDY DESIGN: In this subanalysis of a multicenter observational study, infants with birth weights of 1250 g or less and intubated within 24 hours of birth were included. After describing the timing of first extubation, age at extubation was divided into early (within 7 days from birth) vs late (days of life 8-35), and extubation outcome was divided into success vs failure (reintubation within 7 days after extubation), to create 4 extubation groups: early success, early failure, late success, and late failure. Logistic regression analyses were performed to evaluate associations between the 4 groups and death or bronchopulmonary dysplasia, bronchopulmonary dysplasia among survivors, and durations of respiratory support and oxygen therapy. RESULTS: Of the 250 infants included, 129 (52%) were extubated within 7 days, 93 (37%) between 8 and 35 days, and 28 (11%) beyond 35 days of life. There were 93, 36, 59, and 34 infants with early success, early failure, late success, and late failure, respectively. Although early success was associated with the lowest rates of respiratory morbidities, early failure was not associated with significantly different respiratory outcomes compared with late success or late failure in unadjusted and adjusted analyses. CONCLUSIONS: In a contemporary cohort of extremely preterm infants, early extubation occurred in 52% of infants, and only early and successful extubation was associated with decreased respiratory morbidities. Predictors capable of promptly identifying infants with a high likelihood of early extubation success or failure are needed.

Automated prediction of extubation success in extremely preterm infants: the APEX multicenter study.

BACKGROUND: Extremely preterm infants are frequently subjected to mechanical ventilation. Current prediction tools of extubation success lacks accuracy. METHODS: Multicenter study including infants with birth weight ≤1250 g undergoing their first extubation attempt. Clinical data and cardiorespiratory signals were acquired before extubation. Primary outcome was prediction of extubation success. Automated analysis of cardiorespiratory signals, development of clinical and cardiorespiratory features, and a 2-stage Clinical Decision-Balanced Random Forest classifier were used. A leave-one-out cross-validation was done. Performance was analyzed by ROC curves and determined by balanced accuracy. An exploratory analysis was performed for extubations before 7 days of age. RESULTS: A total of 241 infants were included and 44 failed (18%) extubation. The classifier had a balanced accuracy of 73% (sensitivity 70% [95% CI: 63%, 76%], specificity 75% [95% CI: 62%, 88%]). As an additional clinical-decision tool, the classifier would have led to an increase in extubation success from 82% to 93% but misclassified 60 infants who would have been successfully extubated. In infants extubated before 7 days of age, the classifier identified 16/18 failures (specificity 89%) and 73/105 infants with success (sensitivity 70%). CONCLUSIONS: Machine learning algorithms may improve a balanced prediction of extubation outcomes, but further refinement and validation is required. IMPACT: A machine learning-derived predictive model combining clinical data with automated analyses of individual cardiorespiratory signals may improve the prediction of successful extubation and identify infants at higher risk of failure with a good balanced accuracy. Such multidisciplinary approach including medicine, biomedical engineering and computer science is a step forward as current tools investigated to predict extubation outcomes lack sufficient balanced accuracy to justify their use in future trials or clinical practice. Thus, this individualized assessment can optimize patient selection for future trials of extubation readiness by decreasing exposure of low-risk infants to interventions and maximize the benefits of those at high risk.

Cardiorespiratory behavior of preterm infants receiving continuous positive airway pressure and high flow nasal cannula post extubation: randomized crossover study.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) and high flow nasal cannula (HFNC) are modes of non-invasive respiratory support commonly used after extubation in extremely preterm infants. However, the cardiorespiratory physiology of these infants on each mode is unknown. METHODS: Prospective, randomized crossover study in infants with birth weight ≤1250 g undergoing their first extubation attempt. NCPAP and HFNC were applied randomly for 45 min each, while ribcage and abdominal movements, electrocardiogram, oxygen saturation, and fraction of inspired oxygen (FiO2) were recorded. Respiratory signals were analyzed using an automated method, and differences between NCPAP and HFNC features and changes in FiO2 were analyzed. RESULTS: A total of 30 infants with median [interquartile range] gestational age of 27 weeks [25.7, 27.9] and birth weight of 930 g [780, 1090] were studied. Infants were extubated at 5 days [2, 13] of life with 973 g [880, 1170] and three failed (10%). No differences in cardiorespiratory behavior were noted, except for longer respiratory pauses (9.2 s [5.0, 11.5] vs. 7.3 s [4.6, 9.3]; p = 0.04) and higher FiO2 levels (p = 0.02) during HFNC compared to NCPAP. CONCLUSIONS: In extremely preterm infants studied shortly after extubation, the use of HFNC was associated with longer respiratory pauses and higher FiO2 requirements.

COVID-19 and Neonatal Respiratory Care: Current Evidence and Practical Approach.

The novel coronavirus disease 2019 (COVID-19) pandemic has urged the development and implementation of guidelines and protocols on diagnosis, management, infection control strategies, and discharge planning. However, very little is currently known about neonatal COVID-19 and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections. Thus, many questions arise with regard to respiratory care after birth, necessary protection to health care workers (HCW) in the delivery room and neonatal intensive care unit (NICU), and safety of bag and mask ventilation, noninvasive respiratory support, deep suctioning, endotracheal intubation, and mechanical ventilation. Indeed, these questions have created tremendous confusion amongst neonatal HCW. In this manuscript, we comprehensively reviewed the current evidence regarding COVID-19 perinatal transmission, respiratory outcomes of neonates born to mothers with COVID-19 and infants with documented SARS-CoV-2 infection, and the evidence for using different respiratory support modalities and aerosol-generating procedures in this specific population. The results demonstrated that to date, neonatal COVID-19 infection is uncommon, generally acquired postnatally, and associated with favorable respiratory outcomes. The reason why infants display a milder spectrum of disease remains unclear. Nonetheless, the risk of severe or critical illness in young patients exists. Currently, the recommended respiratory approach for infants with suspected or confirmed infection is not evidence based but should include all routinely used types of support, with the addition of viral filters, proper personal protective equipment, and placement of infants in isolation rooms, ideally with negative pressure. As information is changing rapidly, clinicians should frequently watch out for updates on the subject. KEY POINTS: · Novel coronavirus disease 2019 (COVID-19) pandemic urged development of guidelines.. · Neonatal COVID-19 disease is uncommon.. · Respiratory outcomes in neonates seems favorable.. · Current neonatal respiratory care should continue.. · Clinicians should watch frequently for updates..

The Impact of Time Interval between Extubation and Reintubation on Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants.

OBJECTIVE: To explore the relation between time to reintubation and death or bronchopulmonary dysplasia (BPD) in extremely preterm infants. STUDY DESIGN: This was a subanalysis from an ongoing multicenter observational study. Infants with birth weight ≤1250 g, requiring mechanical ventilation, and undergoing their first elective extubation were prospectively followed throughout hospitalization. Time to reintubation was defined as the time interval between first elective extubation and reintubation. Univariate and multivariate logistic regression analyses were performed to evaluate associations between time to reintubation, using different observation windows after extubation (24-hour intervals), and death/BPD (primary outcome) or BPD among survivors (secondary outcome). aORs were computed with and without the confounding effects of cumulative mechanical ventilation duration. RESULTS: Of 216 infants included for analysis, 103 (48%) were reintubated at least once after their first elective extubation. Reintubation was associated with lower gestational age/weight and greater morbidities compared with infants never reintubated. After adjusting for confounders, reintubation within observation windows ranging between 24 hours and 3 weeks postextubation was associated with increased odds of death/BPD (but not BPD among survivors), independent of the cumulative mechanical ventilation duration. Reintubation within 48 hours from extubation conferred higher risk-adjusted odds of death/BPD vs other observation windows. CONCLUSIONS: Although reintubation after elective extubation was independently associated with increased likelihood of death/BPD in extremely preterm infants, the greatest risk was attributable to reintubation within the first 48 hours postextubation. Prediction models capable of identifying the highest-risk infants may further improve outcomes.

Therapeutic Hypothermia in Brazil: A MultiProfessional National Survey.

OBJECTIVE: To determine the rate of therapeutic hypothermia (TH) use, current practices, and long-term follow-up. STUDY DESIGN: Prospective cross-sectional national survey with 19 questions related to the assessment of hypoxic-ischemic encephalopathy (HIE) and TH practices. An online questionnaire was made available to health care professionals working in neonatal care in Brazil. RESULTS: A total of 1,092 professionals replied, of which 681 (62%) reported using TH in their units. Of these, 624 (92%) provided TH practices details: 136 (20%) did not use any neurologic score or amplitude-integrated electroencephalogram (aEEG) to assess encephalopathy and 81(13%) did not answer this question. Any specific training for encephalopathy assessment was provided to only 81/407 (19%) professionals. Infants with mild HIE are cooled according to 184 (29%) of the respondents. Significant variations in practice were noticed concerning time of initiation and cooling methods, site of temperature measurements and monitoring, and access to aEEG, electroencephalogram (EEG), and neurology consultation. Only 19% could perform a brain magnetic resonance imaging (MRI), and 31% reported having a well-established follow-up program for these infants. CONCLUSION: TH has been implemented in Brazil but with significant heterogeneity for most aspects of hypothermia practices, which may affect safety or efficacy of the therapy. A step forward toward quality improvement is important.

Patterns of reintubation in extremely preterm infants: a longitudinal cohort study.

BackgroundThe optimal approach for reporting reintubation rates in extremely preterm infants is unknown. This study aims to longitudinally describe patterns of reintubation in this population over a broad range of observation windows following extubation.MethodsTiming and reasons for reintubation following a first planned extubation were collected from infants with birth weight ≤1,250 g. An algorithm was generated to discriminate between reintubations attributable to respiratory and non-respiratory causes. Frequency and cumulative distribution curves were constructed for each category using 24 h intervals. The ability of observation windows to capture respiratory-related reintubations while limiting non-respiratory reasons was assessed using a receiver operating characteristic curve.ResultsOut of 194 infants, 91 (47%) were reintubated during hospitalization; 68% for respiratory and 32% for non-respiratory reasons. Respiratory-related reintubation rates steadily increased from 0 to 14 days post-extubation before reaching a plateau. In contrast, non-respiratory reintubations were negligible in the first post-extubation week, but became predominant after 14 days. An observation window of 7 days captured 77% of respiratory-related reintubations while only including 14% of non-respiratory cases.ConclusionReintubation patterns are highly variable and affected by the reasons for reintubation and observation window used. Ideally, reintubation rates should be reported using a cumulative distribution curve over time.

Prediction of Extubation readiness in extremely preterm infants by the automated analysis of cardiorespiratory behavior: study protocol.

BACKGROUND: Extremely preterm infants (≤ 28 weeks gestation) commonly require endotracheal intubation and mechanical ventilation (MV) to maintain adequate oxygenation and gas exchange. Given that MV is independently associated with important adverse outcomes, efforts should be made to limit its duration. However, current methods for determining extubation readiness are inaccurate and a significant number of infants fail extubation and require reintubation, an intervention that may be associated with increased morbidities. A variety of objective measures have been proposed to better define the optimal time for extubation, but none have proven clinically useful. In a pilot study, investigators from this group have shown promising results from sophisticated, automated analyses of cardiorespiratory signals as a predictor of extubation readiness. The aim of this study is to develop an automated predictor of extubation readiness using a combination of clinical tools along with novel and automated measures of cardiorespiratory behavior, to assist clinicians in determining when extremely preterm infants are ready for extubation. METHODS: In this prospective, multicenter observational study, cardiorespiratory signals will be recorded from 250 eligible extremely preterm infants with birth weights ≤1250 g immediately prior to their first planned extubation. Automated signal analysis algorithms will compute a variety of metrics for each infant, and machine learning methods will then be used to find the optimal combination of these metrics together with clinical variables that provide the best overall prediction of extubation readiness. Using these results, investigators will develop an Automated system for Prediction of EXtubation (APEX) readiness that will integrate the software for data acquisition, signal analysis, and outcome prediction into a single application suitable for use by medical personnel in the neonatal intensive care unit. The performance of APEX will later be prospectively validated in 50 additional infants. DISCUSSION: The results of this research will provide the quantitative evidence needed to assist clinicians in determining when to extubate a preterm infant with the highest probability of success, and could produce significant improvements in extubation outcomes in this population. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01909947 . Registered on July 17 2013. Trial sponsor: Canadian Institutes of Health Research (CIHR).

Intestinal ultrasonography in infants with moderate or severe hypoxic-ischemic encephalopathy receiving hypothermia.

BACKGROUND: Infants with hypoxic-ischemic encephalopathy (HIE) may develop multiorgan dysfunction, but assessment of intestinal involvement is imprecise and based on nonspecific clinical signs that may occur several days later. Ultrasound imaging has been described as a helpful tool in assessing intestinal involvement in many gastrointestinal disorders. OBJECTIVE: Describe abdominal ultrasonography findings in infants receiving therapeutic hypothermia and investigate its association with the severity of the hypoxic-ischemic insult and death. MATERIALS AND METHODS: Studies were performed within the first 36 h of life to assess intestinal appearance (normal bowel, bowel wall echogenicity and thickness, and sloughed mucosa), free fluid, peristalsis and intramural perfusion. These findings were compared between infants with moderate and severe encephalopathy. Ultrasound findings were also categorized in three major groups and compared with markers of severity of the hypoxic-ischemic insult and with mortality. RESULTS: Nineteen infants with moderate and 9 with severe HIE at admission were studied (17.7 ± 9.5 h of life). Major ultrasonography findings were increased bowel wall echogenicity (78%), free fluid (75%), decreased or absent peristalsis (50%) and sloughing of the intestinal mucosa (21%). Abnormal intestinal findings such as increased bowel wall echogenicity in all quadrants and presence of sloughed mucosa were associated with more severe hypoxic-ischemic insult. All 12 patients with normal bowel appearance or increased bowel wall echogenicity restricted to only one quadrant survived, whereas 7/15 (47%) patients with increased bowel wall echogenicity in all four quadrants died during hospitalization. The presence of sloughed mucosa was associated with increased mortality (P < 0.001). CONCLUSION: In infants receiving therapeutic hypothermia, a high prevalence of intestinal involvement was noted by using ultrasonographic assessment. An association between intestinal findings and severity of hypoxic-ischemic insult was observed. The presence of sloughed mucosa is a potential ultrasonographic sign of severity.

Optimal timing of extubation in preterm infants.

In neonatal intensive care, endotracheal intubation is usually performed as an urgent or semi-urgent procedure in infants with critical or unstable conditions related to progressive respiratory failure. Extubation is not. Patients undergoing extubation are typically stable, with improved respiratory function. The key elements to facilitating extubation are to recognize improvement in respiratory status, promote weaning of mechanical ventilation, and accurately identify readiness for removal of the endotracheal tube. Therefore, extubation should be a planned and well-organized procedure. In this review, we will appraise the evidence for existing predictors of extubation readiness and provide patient-specific, pathophysiology-derived strategies to optimize the timing and success of extubation in neonates, with a focus on extremely preterm infants.

Clinical usefulness of reintubation criteria in extremely preterm infants: a cohort study.

OBJECTIVE: To describe the thresholds of instability used by clinicians at reintubation and evaluate the accuracy of different combinations of criteria in predicting reintubation decisions. DESIGN: Secondary analysis using data obtained from the prospective observational Automated Prediction of Extubation Readiness study (NCT01909947) between 2013 and 2018. SETTING: Multicentre (three neonatal intensive care units). PATIENTS: Infants with birth weight ≤1250 g, mechanically ventilated and undergoing their first planned extubation were included. INTERVENTIONS: After extubation, hourly O2 requirements, blood gas values and occurrence of cardiorespiratory events requiring intervention were recorded for 14 days or until reintubation, whichever came first. MAIN OUTCOME MEASURES: Thresholds at reintubation were described and grouped into four categories: increased O2, respiratory acidosis, frequent cardiorespiratory events and severe cardiorespiratory events (requiring positive pressure ventilation). An automated algorithm was used to generate multiple combinations of criteria from the four categories and compute their accuracies in capturing reintubated infants (sensitivity) without including non-reintubated infants (specificity). RESULTS: 55 infants were reintubated (median gestational age 25.2 weeks (IQR 24.5-26.1 weeks), birth weight 750 g (IQR 640-880 g)), with highly variable thresholds at reintubation. After extubation, reintubated infants had significantly greater O2 needs, lower pH, higher pCO2 and more frequent and severe cardiorespiratory events compared with non-reintubated infants. After evaluating 123 374 combinations of reintubation criteria, Youden indices ranged from 0 to 0.46, suggesting low accuracy. This was primarily attributable to the poor agreement between clinicians on the number of cardiorespiratory events at which to reintubate. CONCLUSIONS: Criteria used for reintubation in clinical practice are highly variable, with no combination accurately predicting the decision to reintubate.

Wireless broadband acousto-mechanical sensing system for continuous physiological monitoring.

The human body generates various forms of subtle, broadband acousto-mechanical signals that contain information on cardiorespiratory and gastrointestinal health with potential application for continuous physiological monitoring. Existing device options, ranging from digital stethoscopes to inertial measurement units, offer useful capabilities but have disadvantages such as restricted measurement locations that prevent continuous, longitudinal tracking and that constrain their use to controlled environments. Here we present a wireless, broadband acousto-mechanical sensing network that circumvents these limitations and provides information on processes including slow movements within the body, digestive activity, respiratory sounds and cardiac cycles, all with clinical grade accuracy and independent of artifacts from ambient sounds. This system can also perform spatiotemporal mapping of the dynamics of gastrointestinal processes and airflow into and out of the lungs. To demonstrate the capabilities of this system we used it to monitor constrained respiratory airflow and intestinal motility in neonates in the neonatal intensive care unit (n = 15), and to assess regional lung function in patients undergoing thoracic surgery (n = 55). This broadband acousto-mechanical sensing system holds the potential to help mitigate cardiorespiratory instability and manage disease progression in patients through continuous monitoring of physiological signals, in both the clinical and nonclinical setting.

Neonatal hypoxic-ischemic injury: sonography and dynamic color Doppler sonography perfusion of the brain and abdomen with pathologic correlation.

OBJECTIVE: The purpose of this article is to describe the role of cerebral and abdominal sonography with color Doppler sonography, including assessment of multiorgan tissue perfusion, in neonates with hypoxic-ischemic injury. CONCLUSION: Bedside sonography and color Doppler sonography of the brain and abdominal organs can provide reliable and comprehensive information in asphyxiated neonates with hypoxic-ischemic injury. This article, which includes pathologic correlation, illustrates the major sonographic findings in this critical population.

Implementation of a multidisciplinary team approach and fish oil emulsion administration in the management of infants with short bowel syndrome and parenteral nutrition-associated liver disease.

OBJECTIVE: To describe the authors' experience with the implementation of a multidisciplinary approach and use of fish oil emulsion (FOE) in the management of infants with short bowel syndrome (SBS) and parenteral nutrition-associated liver disease (PNALD). METHODS: Between August 2006 and June 2009, four cases of SBS and severe PNALD were managed by the team using specifically developed protocols. The FOE was initiated if serum direct bilirubin levels were ≥100 µmol/L. To quantify the degree of exposure to high serum direct bilirubin levels over time, the area under the curve (AUC) for each patient was calculated before and after initiation of FOE. Linear regression analyses were performed to evaluate correlations between the AUC, duration of cholestasis and initiation of FOE. RESULTS: All patients survived and no complications were observed during the study period. After the first patient, FOE was initiated progressively earlier, but poor correlation between the AUC before and after its introduction was observed (r(2)=0.41924). However, there was strong correlation between the duration of PNALD before FOE initiation and time to resolution (r(2)=0.72133): the earlier the FOE was initiated, the shorter the time to resolution. CONCLUSION: The authors report a positive experience with the implementation of a multidisciplinary approach and the use of FOE in infants with SBS and severe PNALD. The earlier the FOE was initiated during the cholestatic process, the shorter the time to resolution. The present study is a hypothesis generator, raising the question of whether an earlier introduction of this particular therapy can effectively shorten the cholestasis process in these patients.

Expectant management of pneumothorax in preterm infants receiving assisted ventilation: report of 4 cases and review of the literature.

Pneumothorax is a common complication in infants receiving assisted ventilation. The appropriate management of this condition is not always clearly defined, especially when a large air leak and mediastinal shift are present but the infant is hemodynamically stable. Despite the complications associated with chest tube placement, this remains the most common approach in such cases. We report 4 cases of preterm infants who developed large pneumothoraces with mediastinal shift while on assisted ventilation and were managed conservatively, with substantial improvement within 12-96 hours. In this report we also review the literature on pneumothorax in preterm infants.

Decision to extubate extremely preterm infants: art, science or gamble?

In the modern era of neonatology, mechanical ventilation has been restricted to a smaller and more immature population of extremely preterm infants. Given the adverse outcomes associated with mechanical ventilation, every effort is made to extubate these infants as early as possible. However, the scientific basis for determining extubation readiness remains imprecise and primarily guided by clinical judgement, which is highly variable and subjective. In the absence of accurate tools to assess extubation readiness, many infants fail their extubation attempt and require reintubation, which also increases complications. Recent advances in the field have led to unravelling some of the complexities surrounding extubation in this population. This review aims to synthesise the available knowledge and provide a more evidence-based approach towards the reporting of extubation outcomes and assessment of extubation readiness in extremely preterm infants.

Xanthan- and Rice Cereal-Based Thickeners in Infants: A Multidisciplinary Single-Center Experience.

Some infants aspirate thin liquids and must be fed thickened liquids in order to protect the lungs. However, thickeners have not been fully studied for safety. Xanthan-based thickeners have been implicated in the development of necrotizing enterocolitis and rice cereal-based thickeners have been associated with constipation and excessive weight gain. The aim of this study was to compare rates of adverse events between both thickeners. Methods: Single-center retrospective chart review conducted at a tertiary pediatric care center between January 2013 and July 2017. All infants deemed unsafe for oral feeding and treated with xanthan- or rice cereal-based milk thickeners were included. Data were extracted from the medical records and patients categorized according to the type of thickener. Primary outcome was the occurrence of diarrhea, constipation, overweight, and obesity at 3-6 and 6-12 months after thickener initiation. Appropriate statistical tests were used. In addition, an e-mail was sent to 14 level III Canadian Pediatric hospitals inquiring about their practice. Results: We identified 53 patients to be included in the study; 20 used xanthan-based- and 33 used rice cereal-based milk thickeners. Rates of diarrhea, constipation, overweight, and obesity at 3-6 and 6-12 months after initiation were not different between thickeners. Important variability concerning thickening practices was reported by the 8 centers that responded. Conclusions: In infants treated with milk thickeners, xanthan-based or rice cereal-based thickeners may have similar safety profiles that require further investigation including a larger number of patients.