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.

Cardiorespiratory measures shortly after extubation and extubation outcomes in extremely preterm infants.

BACKGROUND: Nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, and non-invasive neurally adjusted ventilatory assist are modes of non-invasive respiratory support. The objective was to investigate if cardiorespiratory measures performed shortly after extubation are associated with extubation outcomes and predictors of extubation success. METHODS: Randomized crossover trial of infants with birth weight (BW) ≤ 1250 g undergoing their first extubation. Shortly after extubation, electrocardiogram and electrical activity of the diaphragm (Edi) were recorded during 40 min on each mode. Measures of heart rate variability (HRV), diaphragmatic activity (Edi area, breath area and amplitude), and respiratory variability (RV) were computed on each mode and compared between infants with extubation success or failure (reintubation ≤ 7 days). RESULTS: Twenty-three extremely preterm infants with median [IQR] gestational age 25.9 weeks [25.2-26.4] and BW 760 g [595-900] were included: 14 success and 9 failures. There were significant differences for HRV (very low-frequency power and sample entropy) and RV parameters (breath areas, amplitudes and expiratory times) between groups, with moderate strength (0.75-0.80 areas under ROC curves) in predicting success. Diaphragmatic activity measures were similar between groups. CONCLUSIONS: In extremely preterm infants receiving non-invasive respiratory support shortly after extubation, several cardiorespiratory variability parameters were associated with successful extubation with moderate predictive accuracy. IMPACT: Measures of cardiorespiratory variability, performed in extremely preterm infants while receiving NCPAP, NIPPV, and NIV-NAVA shortly after extubation, were significantly different between patients that succeeded or failed extubation. Cardiorespiratory variability measures had a moderate predictive accuracy for extubation success and can be potentially used as biomarkers, in recently extubated infants. Future investigations in this population may also consider including cardiorespiratory variability measures when assessing types of post-extubation respiratory support and promote individualized care.

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.

Diaphragmatic activity and neural breathing variability during a 5-min endotracheal continuous positive airway pressure trial in extremely preterm infants.

BACKGROUND: Extremely preterm infants are often exposed to endotracheal tube continuous positive airway pressure (ETT-CPAP) trials to assess extubation readiness. The effects of ETT-CPAP trial on their diaphragmatic activity (Edi) and breathing variability is unknown. METHODS: Prospective observational study enrolling infants with birth weight ≤1250 g undergoing their first extubation attempt. Diaphragmatic activity, expressed as the absolute minimum (Edi min) and maximum values (Edi max), area under the Edi signal, and breath-by-breath analyses for breath areas, amplitudes, widths, and neural inspiratory and expiratory times, were analyzed during mechanical ventilation (MV) and ETT-CPAP. Neural breathing variability of each of these parameters was also calculated and compared between MV and ETT-CPAP. RESULTS: Thirteen infants with median (interquartile range) birth weight of 800 g [610-920] and gestational age of 25.4 weeks [24.4-26.3] were included. Diaphragmatic activity significantly increased during ETT-CPAP when compared to MV:Edi max (44.2 vs. 38.1 µV), breath area (449 vs. 312 µV·s), and amplitude (10.12 vs. 7.46 µV). Neural breathing variability during ETT-CPAP was characterized by increased variability for amplitude and area under the breath, and decreased for breath time and width. CONCLUSIONS: A 5-min ETT-CPAP in extremely preterm infants undergoing extubation imposed significant respiratory load with changes in respiratory variability. IMPACT: ETT-CPAP trials are often used to assess extubation readiness in extremely preterm infants, but its effects upon their respiratory system are not well known. Diaphragmatic activity analysis demonstrated that these infants are able to mount an important response to a short trial. A 5-min trial imposed a significant respiratory load evidenced by increased diaphragmatic activity and changes in breathing variability. Differences in breathing variability were observed between successful and failed extubations, which should be explored further in extubation readiness investigations. This type of trial cannot be recommended for preterm infants in clinical practice until clear standards and accuracy are established.

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.

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.

Cardiorespiratory effects of NIV-NAVA, NIPPV, and NCPAP shortly after extubation in extremely preterm infants: A randomized crossover trial.

OBJECTIVE: Investigate the cardiorespiratory effects of noninvasive neurally adjusted ventilatory assist (NIV-NAVA), nonsynchronized nasal intermittent positive pressure ventilation (NIPPV), and nasal continuous positive airway pressure (NCPAP) shortly after extubation. HYPOTHESIS: Types of noninvasive pressure support and the presence of synchronization may affect cardiorespiratory parameters. STUDY DESIGN: Randomized crossover trial. PATIENT-SUBJECT SELECTION: Infants with birth weight (BW) 1250 g or under, undergoing their first planned extubation were randomly assigned to all three modes using a computer-generated sequence. METHODOLOGY: Electrocardiogram and electrical activity of the diaphragm (Edi) were recorded for 30 min on each mode. Analysis of heart rate variability (HRV), diaphragmatic activity (Edi area, breath area, amplitude, inspiratory and expiratory times), and respiratory variability were compared between modes. RESULTS: Twenty-three infants had full data recordings and analysis: Median (IQR) gestational age = 25.9 weeks (25.2-26.4), BW = 760 g (595-900), and postnatal age 7 (4-19) days. There were no differences in HRV between modes. A significantly reduced Edi area and breath amplitude, and increased coefficient of variation (CV) of breath amplitude were observed during NIV-NAVA and NIPPV compared to NCPAP. A higher proportion of assisted breaths (99% vs. 51%; p < .001) provided a higher mean airway pressure (MAP; 9.4 vs. 8.2 cmH2 O; p = .002) with lower peak inflation pressures (PIPs; 14 vs. 16 cmH2 O; p < .001) during NIV-NAVA compared to NIPPV. CONCLUSIONS: NIV-NAVA and NIPPV applied shortly after extubation were associated with lower respiratory efforts and higher respiratory variability. These effects were more evident for NIV-NAVA where optimal patient-ventilator synchronization provided a higher MAP with lower PIPs.

Neonatal heart rate variability: a contemporary scoping review of analysis methods and clinical applications.

BACKGROUND: Neonatal heart rate variability (HRV) is widely used as a research tool. However, HRV calculation methods are highly variable making it difficult for comparisons between studies. OBJECTIVES: To describe the different types of investigations where neonatal HRV was used, study characteristics, and types of analyses performed. ELIGIBILITY CRITERIA: Human neonates ≤1 month of corrected age. SOURCES OF EVIDENCE: A protocol and search strategy of the literature was developed in collaboration with the McGill University Health Center's librarians and articles were obtained from searches in the Biosis, Cochrane, Embase, Medline and Web of Science databases published between 1 January 2000 and 1 July 2020. CHARTING METHODS: A single reviewer screened for eligibility and data were extracted from the included articles. Information collected included the study characteristics and population, type of HRV analysis used (time domain, frequency domain, non-linear, heart rate characteristics (HRC) parameters) and clinical applications (physiological and pathological conditions, responses to various stimuli and outcome prediction). RESULTS: Of the 286 articles included, 171 (60%) were small single centre studies (sample size <50) performed on term infants (n=136). There were 138 different types of investigations reported: physiological investigations (n=162), responses to various stimuli (n=136), pathological conditions (n=109) and outcome predictor (n=30). Frequency domain analyses were used in 210 articles (73%), followed by time domain (n=139), non-linear methods (n=74) or HRC analyses (n=25). Additionally, over 60 different measures of HRV were reported; in the frequency domain analyses alone there were 29 different ranges used for the low frequency band and 46 for the high frequency band. CONCLUSIONS: Neonatal HRV has been used in diverse types of investigations with significant lack of consistency in analysis methods applied. Specific guidelines for HRV analyses in neonates are needed to allow for comparisons between studies.

Assessment of Extubation Readiness Using Spontaneous Breathing Trials in Extremely Preterm Neonates.

Importance: Spontaneous breathing trials (SBTs) are used to determine extubation readiness in extremely preterm neonates (gestational age ≤28 weeks), but these trials rely on empirical combinations of clinical events during endotracheal continuous positive airway pressure (ET-CPAP). Objectives: To describe clinical events during ET-CPAP and to assess accuracy of comprehensive clinical event combinations in predicting successful extubation compared with clinical judgment alone. Design, Setting, and Participants: This multicenter diagnostic study used data from 259 neonates seen at 5 neonatal intensive care units from the prospective Automated Prediction of Extubation Readiness (APEX) study from September 1, 2013, through August 31, 2018. Neonates with birth weight less than 1250 g who required mechanical ventilation were eligible. Neonates deemed to be ready for extubation and who underwent ET-CPAP before extubation were included. Interventions: In the APEX study, cardiorespiratory signals were recorded during 5-minute ET-CPAP, and signs of clinical instability were monitored. Main Outcomes and Measures: Four clinical events were documented during ET-CPAP: apnea requiring stimulation, presence and cumulative durations of bradycardia and desaturation, and increased supplemental oxygen. Clinical event occurrence was assessed and compared between extubation pass and fail (defined as reintubation within 7 days). An automated algorithm was developed to generate SBT definitions using all clinical event combinations and to compute diagnostic accuracies of an SBT in predicting extubation success. Results: Of 259 neonates (139 [54%] male) with a median gestational age of 26.1 weeks (interquartile range [IQR], 24.9-27.4 weeks) and median birth weight of 830 g (IQR, 690-1019 g), 147 (57%) had at least 1 clinical event during ET-CPAP. Apneas occurred in 10% (26 of 259) of neonates, bradycardias in 19% (48), desaturations in 53% (138), and increased oxygen needs in 41% (107). Neonates with successful extubation (71% [184 of 259]) had significantly fewer clinical events (51% [93 of 184] vs 72% [54 of 75], P = .002), shorter cumulative bradycardia duration (median, 0 seconds [IQR, 0 seconds] vs 0 seconds [IQR, 0-9 seconds], P < .001), shorter cumulative desaturation duration (median, 0 seconds [IQR, 0-59 seconds] vs 25 seconds [IQR, 0-90 seconds], P = .003), and less increase in oxygen (median, 0% [IQR, 0%-6%] vs 5% [0%-18%], P < .001) compared with neonates with failed extubation. In total, 41 602 SBT definitions were generated, demonstrating sensitivities of 51% to 100% (median, 96%) and specificities of 0% to 72% (median, 22%). Youden indices for all SBTs ranged from 0 to 0.32 (median, 0.17), suggesting low accuracy. The SBT with highest Youden index defined SBT pass as having no apnea (with desaturation requiring stimulation) or increase in oxygen requirements by 15% from baseline and predicted extubation success with a sensitivity of 93% and a specificity of 39%. Conclusions and Relevance: The findings suggest that extremely preterm neonates commonly show signs of clinical instability during ET-CPAP and that the accuracy of multiple clinical event combinations to define SBTs is low. Thus, SBTs may provide little added value in the assessment of extubation readiness.

Predictors of extubation readiness in preterm infants: a systematic review and meta-analysis.

CONTEXT: A variety of extubation readiness tests have already been incorporated into clinical practice in preterm infants. OBJECTIVE: To identify predictor tests of successful extubation and determine their accuracy compared with clinical judgement alone. METHODS: MEDLINE, Embase, PubMed, Cochrane Library and Web of Science were searched between 1984 and June 2016. Studies evaluating predictors of extubation success during a period free of mechanical inflations in infants less than 37 weeks' gestation were included. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. After identifying and describing all predictor tests, pooled sensitivity and specificity estimates for the different test categories were generated using a bivariate random-effects model. RESULTS: Thirty-five studies were included, showing wide heterogeneities in population characteristics, methodologies and definitions of extubation success. Assessments ranged from a few seconds to 24 hours, provided 0-6 cmH2O positive end-expiratory pressure and measured several clinical and/or physiological parameters. Thirty-one predictor tests were identified, showing good sensitivities but low and variable specificities. Given the high variation in test definitions across studies, pooling could only be performed on a subset. The commonly performed spontaneous breathing trials had pooled sensitivity of 95% (95% CI 87% to 99%) and specificity of 62% (95% CI 38% to 82%), while composite tests offered the best performance characteristics. CONCLUSIONS: There is a lack of strong evidence to support the use of extubation readiness tests in preterm infants. Although spontaneous breathing trials are attractive assessment tools, higher quality studies are needed for determining the optimal strategies for improving their accuracy.

The effects of nasal continuous positive airway pressure and high flow nasal cannula on heart rate variability in extremely preterm infants after extubation: A randomized crossover trial.

BACKGROUND: NCPAP and High flow nasal cannula (HFNC) are common modes of non-invasive respiratory support used after extubation. Heart rate variability (HRV) has been demonstrated as a marker of well-being in neonates and differences in HRV were described in preterm infants receiving respiratory care. The objective was to investigate the effects of NCPAP and HFNC on HRV after extubation. METHODS: Randomized crossover trial in infants with birth weight (BW) ≤1250 g after undergoing their first elective extubation. ECG recordings were performed during 45 min while on HFNC and nasal continuous positive airway pressure (NCPAP). Time domain, non-linear, and frequency domain parameters were calculated and compared during HFNC and NCPAP using paired nonparametric tests. A secondary analysis was performed in the subgroup of infants that were successfully extubated. RESULTS: Thirty infants with median [range] gestational age of 27 weeks [24.1-29.3] and BW of 930 g [610-1220] were studied at 5 days [1-39] of age. No differences in HRV parameters were observed between HFNC and NCPAP. In the secondary analysis, infants successfully extubated (n = 27) had a significantly higher HRV during HFNC for some time domain parameters. For instance, the standard deviation of the RR intervals (SDRR) was more likely to be higher during HFNC compared to NCPAP (HFNC: 18/27 vs NCPAP: 9/27, P = 0.017) . CONCLUSION: During the first hours after extubation, no differences in HRV were detected between HFNC and NCPAP in the overall cohort. However, a significantly higher HRV was noted during HFNC in the subgroup of infants successfully extubated.

A review of the conundrum of mild hypoxic-ischemic encephalopathy: Current challenges and moving forward.

A review of the conundrum called mild hypoxic-ischemic encephalopathy (HIE) is provided. During the past decades, the definition of HIE has evolved to accommodate the short window of time required for the initiation of therapeutic hypothermia. Also, neurological evaluations have changed with the use of simpler staging systems that can be applied within the first 6 h of life. In this review, we discuss the challenges in the identification of newborns with "mild HIE" within 6 h after birth, the limitations in the existing early biomarkers of brain injury, and the current knowledge gaps in the long term neurodevelopmental outcomes of infants diagnosed with mild HIE. Progress in the understanding of mild HIE and its sequelae continues to be hindered by the lack of a standardized definition for mild HIE that will reliably identify at-risk infants who may benefit from neuroprotective strategies.

Heart Rate Variability in Extremely Preterm Infants Receiving Nasal CPAP and Non-Synchronized Noninvasive Ventilation Immediately After Extubation.

INTRODUCTION: There is a paucity of studies comparing the physiological effects of nasal CPAP or non-synchronized noninvasive ventilation (ns-NIV) during the postextubation phase in preterm infants. Heart rate variability (HRV) can identify system instability before clinical or laboratory signs of deterioration. Thus, we sought to investigate any differences in HRV between those modes. METHODS: 15 preterm infants with birthweight ≤1,250 g and undergoing their first extubation attempt were studied immediately after disconnection from mechanical ventilation. Electrocardiogram (ECG) recordings were obtained while on nasal CPAP and ns-NIV in a random order (30-60 min on each). Time and frequency domain analyses were used to calculate HRV from 5-min segments of ECG. RESULTS: 12 of 15 infants were analyzed (3 were excluded for low ECG quality): 7 successes and 5 failures. HRV parameters were higher during ns-NIV when compared to nasal CPAP, but differences were not statistically different. However, absolute and relative differences in HRV values (all time domain parameters) were significantly higher in infants who failed extubation during ns-NIV. CONCLUSIONS: Nasal CPAP or ns-NIV provided immediately postextubation did not affect HRV. Interestingly, in an exploratory analysis, changes in HRV did occur during ns-NIV in the subgroup of infants who failed extubation. Hence, changes in HRV as early as 2 h after extubation should be further explored in larger studies as a potential predictor of postextubation respiratory failure.