Apnoea-triggered increase in fraction of inspired oxygen in preterm infants: a randomised cross-over study.

OBJECTIVES: To investigate the impact of a pre-emptive apnoea triggered oxygen response on oxygen saturation (SpO2) targeting following central apnoea in preterm infants. DESIGN: Interventional crossover study of a 12-hour period of automated oxygen control with an apnoea response (AR) module, nested within a crossover study of a 24-hour period of automated oxygen control compared with aggregated data from two flanking 12-hour periods of manual control. SETTING: Neonatal intensive care unit PATIENTS: Preterm infants receiving non-invasive respiratory support and supplemental oxygen; median (IQR) birth gestation 27 (26-28) weeks, postnatal age 17 (12-23) days. INTERVENTION: Automated oxygen titration with an automated control algorithm modified to include an AR module. Alterations to inspired oxygen concentration (FiO2) were actuated by a motorised blender. Desired SpO2 range was 90-94%. Apnoea detection was by capsule pneumography. MAIN OUTCOME MEASURES: Duration, magnitude and area under the curve (AUC) of SpO2 deviations following apnoea; frequency and duration of apnoeic events. Comparisons between periods of manual, automated and automated control with AR module. RESULTS: In 60 studies in 35 infants, inclusion of the AR module significantly reduced AUC for SpO2 deviations below baseline compared with both automated and manual control (manual: 87.1%±107.6% s, automated: 84.6%±102.8% s, AR module: 79.4%±102.7% s). However, there was a coincident increase in SpO2 overshoot (AUC (SpO2>SpO2(onset)); manual: 44.3±99.9% s, automated: 54.7%±103.4% s, AR module: 65.7%±126.2% s). CONCLUSION: Automated control with a pre-emptive apnoea-triggered FiO2 boost resulted in a modest reduction in post-apnoea hypoxaemia, but was followed by a greater SpO2 overshoot. TRIAL REGISTRATION NUMBER: ACTRN12616000300471.

Detection of respiratory activity in newborn infants using a noncontact vision-based monitor.

OBJECTIVE: To examine the effectiveness of a noncontact vision-based infrared respiratory monitor (IRM) in the detection of authentic respiratory motion in newborn infants. STUDY DESIGN: Observational study in a neonatal intensive care unit. METHODS: Eligible infants lay supine with torso exposed under the IRM's infrared depth-map camera and torso images were recorded at 30 frames/s. Respiratory motion waveforms were subsequently derived from upper (IRMupper ) and lower (IRMlower ) torso region images and compared with contemporaneous impedance pneumography (IP) and capsule pneumography (CP). Waveforms, in 15 s investigative epochs, were scanned with an 8 s sliding window for authentic respiratory waveform (spectral purity index [SPI] ≥ 0.75, minimum five complete breaths). Maximum SPI and frequency of occurrence of authentic respiratory waveform in 15 s epochs were compared between monitoring modalities in pooled and per patient data (Friedman ANOVA). RESULTS: Recordings comprised 532 min of images from 35 infants, yielding 2131 investigative epochs, with authentic respiratory motion detected in all infants. For CP, IP, IRMupper , and IRMlower , the proportion of epochs containing authentic respiratory motion in pooled data were 65%, 50%, 36%, and 48%, with median SPImax of 0.79, 0.75, 0.70, and 0.74, respectively. Per-patient average SPImax was 0.79, 0.75, 0.69, and 0.74 for CP, IP, IRMupper , and IRMlower with proportion of authentic respiratory motion being 64%, 50%, 29%, and 49%, respectively. CONCLUSION: An IRM focused on the lower torso detected authentic respiratory motion with comparable performance to IP in newborn infants in intensive care and deserves further investigation.

Should obstructive hypopneas be included when analyzing sleep studies in infants with Robin Sequence?

OBJECTIVE: We have used an obstructive apnea index of ≥3 as treatment indication for infants with Robin sequence (RS), while the obstructive apnea-hypopnea index (OAHI) and a threshold of ≥5 is often used internationally. We wanted to know whether these two result in similar indications, and what the interobserver variability is with either asessement. METHODS: Twenty lab-based overnight sleep recordings from infants with isolated RS (median age: 7 days, range 2-38) were scored based on the 2020 American Academy of Sleep Medicine guidelines, including or excluding obstructive hypopneas. RESULTS: Median obstructive apnea index (OAI) was 18 (interquartile range: 7.6-38) including only apneas, and 35 (18-54) if obstructive hypopneas were also considered as respiratory events (OAHI). Obstructive sleep apnea (OSA) severity was re-classified from moderate to severe for two infants when obstructive hypopneas were also considered, but this did not lead to a change in clinical treatment decisions for either infant. Median interobserver agreement was 0.86 (95% CI 0.70-0.94) for the OAI, and 0.60 (0.05-0.84) for the OAHI. CONCLUSION: Inclusion of obstructive hypopneas when assessing OSA severity in RS infants doubled the obstructive event rate, but impaired interobserver agreement and would not have changed clinical management.

Automated control of oxygen titration in preterm infants on non-invasive respiratory support.

OBJECTIVE: To evaluate the performance of a rapidly responsive adaptive algorithm (VDL1.1) for automated oxygen control in preterm infants with respiratory insufficiency. DESIGN: Interventional cross-over study of a 24-hour period of automated oxygen control compared with aggregated data from two flanking periods of manual control (12 hours each). SETTING: Neonatal intensive care unit. PARTICIPANTS: Preterm infants receiving non-invasive respiratory support and supplemental oxygen; median birth gestation 27 weeks (IQR 26-28) and postnatal age 17 (12-23) days. INTERVENTION: Automated oxygen titration with the VDL1.1 algorithm, with the incoming SpO2 signal derived from a standard oximetry probe, and the computed inspired oxygen concentration (FiO2) adjustments actuated by a motorised blender. The desired SpO2 range was 90%-94%, with bedside clinicians able to make corrective manual FiO2 adjustments at all times. MAIN OUTCOME MEASURES: Target range (TR) time (SpO2 90%-94% or 90%-100% if in air), periods of SpO2 deviation, number of manual FiO2 adjustments and oxygen requirement were compared between automated and manual control periods. RESULTS: In 60 cross-over studies in 35 infants, automated oxygen titration resulted in greater TR time (manual 58 (51-64)% vs automated 81 (72-85)%, p<0.001), less time at both extremes of oxygenation and considerably fewer prolonged hypoxaemic and hyperoxaemic episodes. The algorithm functioned effectively in every infant. Manual FiO2 adjustments were infrequent during automated control (0.11 adjustments/hour), and oxygen requirements were similar (manual 28 (25-32)% and automated 26 (24-32)%, p=0.13). CONCLUSION: The VDL1.1 algorithm was safe and effective in SpO2 targeting in preterm infants on non-invasive respiratory support. TRIAL REGISTRATION NUMBER: ACTRN12616000300471.

Sensory stimulation for apnoea mitigation in preterm infants.

Apnoea, a pause in respiration, is ubiquitous in preterm infants and are often associated with physiological instability, which may lead to longer-term adverse neurodevelopmental consequences. Despite current therapies aimed at reducing the apnoea burden, preterm infants continue to exhibit apnoeic events throughout their hospital admission. Bedside staff are frequently required to manually intervene with different forms of stimuli, with the aim of re-establishing respiratory cadence and minimizing the physiological impact of each apnoeic event. Such a reactive approach makes apnoea and its associated adverse consequences inevitable and places a heavy reliance on human intervention. Different approaches to improving apnoea management in preterm infants have been investigated, including the use of various sensory stimuli. Despite studies reporting sensory stimuli of various forms to have potential in reducing apnoea frequency, non-invasive intermittent positive pressure ventilation is the only automated stimulus currently used in the clinical setting for infants with persistent apnoeic events. We find that the development of automated closed-looped sensory stimulation systems for apnoea mitigation in preterm infants receiving non-invasive respiratory support is warranted, including the possibility of stimulation being applied preventatively, and in a multi-modal form. IMPACT: This review examines the effects of various forms of sensory stimulation on apnoea mitigation in preterm infants, namely localized tactile, generalized kinesthetic, airway pressure, auditory, and olfactory stimulations. Amongst the 31 studies reviewed, each form of sensory stimulation showed some positive effects, although the findings were not definitive and comparative studies were lacking. We find that the development of automated closed-loop sensory stimulation systems for apnoea mitigation is warranted, including the possibility of stimulation being applied preventatively, and in a multi-modal form.

Mask versus nasal prong leak and intermittent hypoxia during continuous positive airway pressure in very preterm infants.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) can be applied via binasal prongs or nasal masks; both may be associated with air leak and intermittent hypoxia. We investigated whether the latter is more frequent with nasal masks or prongs. METHODS: Continuous 24 hours recordings of inspired oxygen fraction (FiO2), pulse rate, respiratory rate, pulse oximeter saturation (SpO2) and CPAP level were made in preterm infants with respiratory insufficiency (n=20) managed on CPAP in the NICU at the Royal Hobart Hospital. As part of routine care, nasal interfaces were alternated 4-hourly between mask and prongs. In each recording, the first two segments containing at least 3 hours of artefact-free signal for each interface were selected. Recordings were analysed for episodes with hypoxaemia (SpO2 <80% for ≥10 s) and bradycardia (pulse rate <80/min for ≥4 s) and for episodes of pressure loss at the nasal interface. Data were compared using Wilcoxon-matched pairs test and are reported as median (IQR). RESULTS: Infants had a gestational age at birth of 26 (25-27) weeks and postnatal age of 17 (14-24) days. There was no difference in %time with interface leak between prong and mask (0.9 (0-8)% vs 1.1 (0-18)%, p=0.82), %time with SpO2 <80% (0.15 (0-1.2)% vs 0.06 (0-0.8)%, p=0.74) or heart rate <80/min (0.03 (0-0.2)% vs 0 (0-0.2)%, p=0.64). Three infants had interface leak for >10% of the time with prongs and 5 with the mask. CONCLUSION: Both interfaces resulted in a similarly stable provision of positive airway pressure, and there was also no difference in the occurrence of intermittent hypoxia.

Predicting Apnoeic Events in Preterm Infants.

Apnoea, a pause in respiration, is almost ubiquitous in preterm infants born before completing 30 weeks gestation. Apnoea often begets hypoxemia and/or bradycardia, and has the potential to result in adverse neurodevelopmental consequences. Our current inability to predict apnoeic events in preterm infants requires apnoea to first be detected by monitoring device/s in order to trigger an intervention by bedside (medical or nursing) staff. Such a reactive management approach is laborious, and makes the consequences of apnoeic events inevitable. Recent technological advances and improved signal processing have allowed the possibility of developing prediction models for apnoeic events in preterm infants. However, the development of such models has numerous challenges and is only starting to show potential. This paper identifies requisite components and current gaps in developing prediction models for apnoeic events, and reviews previous studies on predicting apnoeic events in preterm infants.

Physiological instability after respiratory pauses in preterm infants.

BACKGROUND: The factors influencing the severity of apnea-related hypoxemia and bradycardia are incompletely characterized, especially in infants receiving noninvasive respiratory support. OBJECTIVES: To identify the frequency and predictors of physiological instability (hypoxemia-oxygen saturation (SpO2 ) <80%, or bradycardia-heart rate (HR) < 100 bpm) following respiratory pauses in infants receiving noninvasive respiratory support. METHODS: Respiratory pause duration, derived from capsule pneumography, was measured in 30 preterm infants of gestation 30 (24-32) weeks [median (interquartile range)] receiving noninvasive respiratory support and supplemental oxygen. For identified pauses of 5 to 29 seconds duration, we measured the magnitude and duration of SpO2 and HR reductions over a period starting at the pause onset and ending 60 seconds after resumption of breathing. Temporally clustered pauses (<60 seconds separation) were analyzed separately. The relative contribution of respiratory pauses to overall physiological instability was determined, and predictors of instability were sought in regression analysis, including demographic, clinical and situational variables as inputs. RESULTS: In total, 17 105 isolated and 9180 clustered pauses were identified. Hypoxemia and bradycardia were more likely after longer duration and temporally-clustered pauses. However, the majority of such episodes occurred after 5 to 9 second pauses given their numerical preponderance, and short-lived pauses made a substantial contribution to physiological instability overall. Birth gestation, hemoglobin concentration, form of respiratory support, caffeine treatment, respiratory pause duration and temporal clustering were identified as predictors of instability. CONCLUSIONS: Brief respiratory pauses, especially when clustered, contribute substantially to hypoxemia and bradycardia in preterm infants.

Development and preclinical testing of an adaptive algorithm for automated control of inspired oxygen in the preterm infant.

OBJECTIVE: To assess the performance of a novel algorithm for automated oxygen control using a simulation of oxygenation founded on in vivo data from preterm infants. METHODS: A proportional-integral-derivative (PID) control algorithm was enhanced by (i) compensation for the non-linear SpO2-PaO2 relationship, (ii) adaptation to the severity of lung dysfunction and (iii) error attenuation within the target range. Algorithm function with and without enhancements was evaluated by iterative linking with a computerised simulation of oxygenation. Data for this simulation (FiO2 and SpO2 at 1 Hz) were sourced from extant recordings from preterm infants (n=16), and converted to a datastream of values for ventilation:perfusion ratio and shunt. Combination of this datastream second by second with the FiO2 values from the algorithm under test produced a sequence of novel SpO2 values, allowing time in the SpO2 target range (91%-95%) and in various degrees of hypoxaemia and hyperoxaemia to be determined. A PID algorithm with 30 s lockout after each FiO2 adjustment, and a proportional-derivative (PD) algorithm were also evaluated. RESULTS: Separate addition of each enhancing feature to the PID algorithm showed a benefit, but not with uniformly positive effects. The fully enhanced algorithm was optimal for the combination of targeting the desired SpO2 range and avoiding time in, and episodes of, hypoxaemia and hyperoxaemia. This algorithm performed better than one with a 30 s lockout, and considerably better than PD control. CONCLUSIONS: An enhanced PID algorithm was very effective for automated oxygen control in a simulation of oxygenation, and deserves clinical evaluation.

Characterisation of the Oxygenation Response to Inspired Oxygen Adjustments in Preterm Infants.

BACKGROUND: Oxygen saturation (SpO2) targeting in the preterm infant may be improved with a better understanding of the SpO2 responses to changes in inspired oxygen (FiO2). OBJECTIVE: We investigated the first-order FiO2-SpO2 relationship, aiming to quantify the parameters governing that relationship, the influences on these parameters and their variability. METHODS: In recordings of FiO2 and SpO2 from preterm infants on continuous positive airway pressure and supplemental oxygen, we identified unique FiO2 adjustments and mapped the subsequent SpO2 responses. For responses identified as first-order, the delay, time constant and gain parameters were determined. Clinical and physiological predictors of these parameters were sought in regression analysis, and intra- and inter-subject variability was evaluated. RESULTS: In 3,788 h of available data from 47 infants at 31 (28-33) post-menstrual weeks [median (interquartile range)], we identified 993 unique FiO2 adjustments followed by a first-order SpO2 response. All response parameters differed between FiO2 increments and decrements, with increments having a shorter delay, longer time constant and higher gain [2.9 (1.7-4.8) vs. 1.3 (0.58-2.6), p < 0.05]. Gain was also higher in less mature infants and in the setting of recent SpO2 instability, and was diminished with increasing severity of lung dysfunction. Intra-subject variability in all parameters was prominent. CONCLUSIONS: First-order SpO2 responses show variable gain, influenced by the direction of FiO2 adjustment and the severity of lung disease, as well as substantial intra-subject parameter variability. These findings should be taken into account in adjustment of FiO2 for SpO2 targeting in preterm infants.

Lost without trace: oximetry signal dropout in preterm infants.

Oxygen saturation (SpO2) signal dropout leaves caregivers without a reliable measure to guide oxygen therapy. We studied SpO2 dropout in preterm infants on continuous positive airway pressure, noting the SpO2 values at signal loss and recovery and thus the resultant change in SpO2, and the factors influencing this parameter. In 32 infants of median gestation 26 weeks, a total of 3932 SpO2 dropout episodes were identified (1.1 episodes/h). In the episodes overall, SpO2 decreased by 1.1%, with the SpO2 change influenced by starting SpO2 (negative correlation), but not dropout duration. For episodes starting in hypoxia (SpO2 <85%), SpO2 recovered at a median of 3.2% higher than at SpO2 dropout, with a downward trajectory in a quarter of cases. We conclude that after signal dropout SpO2 generally recovers in a relative normoxic range. Blind FiO2 adjustments are thus unlikely to be of benefit during most SpO2 dropout episodes.

Oxygen saturation targeting in preterm infants receiving continuous positive airway pressure.

OBJECTIVE: The precision of oxygen saturation (SpO2) targeting in preterm infants on continuous positive airway pressure (CPAP) is incompletely characterized. We therefore evaluated SpO2 targeting in infants solely receiving CPAP, aiming to describe their SpO2 profile, to document the frequency of prolonged hyperoxia and hypoxia episodes and of fraction of inspired oxygen (FiO2) adjustments, and to explore the relationships with neonatal intensive care unit operational factors. STUDY DESIGN: Preterm infants <37 weeks' gestation in 2 neonatal intensive care units were studied if they were receiving CPAP and in supplemental oxygen at the beginning of each 24-hour recording. SpO2, heart rate, and FiO2 were recorded (sampling interval 1-2 seconds). We measured the proportion of time spent in predefined SpO2 ranges, the frequency of prolonged episodes (≥30 seconds) of SpO2 deviation, and the effect of operational factors including nurse-patient ratio. RESULTS: A total of 4034 usable hours of data were recorded from 45 infants of gestation 30 (27-32) weeks (median [IQR]). When requiring supplemental oxygen, infants were in the target SpO2 range (88%-92%) for only 31% (19%-39%) of total recording time, with 48 (6.9-90) episodes per 24 hours of severe hyperoxia (SpO2 ≥98%), and 9.0 (1.6-21) episodes per 24 hours of hypoxia (SpO2 <80%). An increased frequency of prolonged hyperoxia in supplemental oxygen was noted when nurses were each caring for more patients. Adjustments to FiO2 were made 25 (16-41) times per day. CONCLUSION: SpO2 targeting is challenging in preterm infants receiving CPAP support, with a high proportion of time spent outside the target range and frequent prolonged hypoxic and hyperoxic episodes.

A Phase 1 study of imatinib mesylate in combination with cytarabine and daunorubicin for c-kit positive relapsed acute myeloid leukemia.

The c-kit receptor is expressed in 95% of relapsed acute myeloid leukemias (AMLs) and mediates leukemic proliferation. We conducted a Phase 1 study of the c-kit inhibitor, imatinib mesylate (IM), in combination with cytarabine and daunorubicin (7+3) in c-kit+ relapsed AML. IM was dose escalated using a 3 by 3 design. Phosphorylated STAT5 was absent to minimally present in residual blasts on day 14 bone marrows. The maximum tolerated dose of IM was 300 mg. The dose-limiting toxicity was Grade 3-4 hepatic toxicity. The CR/CRp rate was 57%. Cytotoxic therapy that includes IM for relapsed AML is well-tolerated and effective.

OCT-2 expression and OCT-2/BOB.1 co-expression predict prognosis in patients with newly diagnosed acute myeloid leukemia.

OCT-2 and its co-activator, BOB.1, are B-cell associated transcription factors expressed in a subset of patients with acute myeloid leukemia (AML). We evaluated OCT-2 and BOB.1 expression by immunohistochemistry in patients with newly diagnosed AML. The median overall survival (OS) for patients with varying levels of OCT-2 expression was statistically different (p = 0.03) (OCT-2 <10%: 21.7 months; OCT-2 10-50%: 18.4 months; OCT-2 >50%: 11.6 months). On multivariate analysis, co-expression of OCT-2/BOB.1 remained predictive for achievement of complete remission (HR 0.44, p = 0.010) and increased risk of relapse (HR 2.30, p = 0.047). OCT-2 (per 10% increase) was associated with a decreased progression-free survival (HR 1.10, p = 0.036) and a trend toward a worse OS (HR 1.10, p = 0.063). OCT-2 may act as a cell survival factor in AML by mediating expression of downstream targets, such as BCL-2. These results will need to be validated prospectively.