Novel breathing pattern analysis: Symmetric Projection Attractor Reconstruction improves identification of impending COPD re-exacerbations - a retrospective cohort analysis.

Respiratory waveforms can be reduced to simple metrics, such as rate, but this may miss information about waveform shape and whole breathing pattern. A novel analysis method quantifying the whole waveform shape identifies AECOPD earlier. https://bit.ly/3M6uIEB.

The clinical utility of the Breathing Pattern Assessment Tool (BPAT) to identify dysfunctional breathing (DB) in individuals living with postural orthostatic tachycardia syndrome (POTS).

BACKGROUND: Dysfunctional breathing (DB) resulting in inappropriate breathlessness is common in individuals living with postural orthostatic tachycardia syndrome (POTS). DB in POTS is complex, multifactorial, and not routinely assessed clinically outside of specialist centres. To date DB in POTS has been identified and diagnosed predominately via cardiopulmonary exercise testing (CPEX), hyperventilation provocation testing and/or specialist respiratory physiotherapy assessment. The Breathing Pattern Assessment Tool (BPAT) is a clinically validated diagnostic tool for DB in Asthma. There are, however, no published data regarding the use of the BPAT in POTS. The aim of this study was therefore to assess the potential clinic utility of the BPAT in the diagnosis of DB in individuals with POTS. METHODS: A retrospective observational cohort study of individuals with POTS referred to respiratory physiotherapy for formal assessment of DB. DB was determined by specialist respiratory physiotherapist assessment which included physical assessment of chest wall movement/breathing pattern. The BPAT and Nijgmegen questionnaire were also completed. Receiver operating characteristics (ROC) analysis was used to compare the physiotherapy assessment based diagnosis of DB to the BPAT score. RESULTS: Seventy-seven individuals with POTS [mean (sd) age 32 (11) years, 71 (92 %) female] were assessed by a specialist respiratory physiotherapist, with 65 (84 %) being diagnosed with DB. Using the established BPAT cut off of four or more, receiver operating characteristics (ROC) analysis indicated a sensitivity of 87 % and specificity of 75 % for diagnosing DB in individuals with POTS with an area under the curve (AUC) of 0.901 (95 % CI 0.803-0.999), demonstrating excellent discriminatory ability. CONCLUSION: BPAT has high sensitivity and moderate specificity for identifying DB in individuals living with POTS.

Operational Definitions Related to Pediatric Ventilator Liberation.

BACKGROUND: Common, operational definitions are crucial to assess interventions and outcomes related to pediatric mechanical ventilation. These definitions can reduce unnecessary variability among research and quality improvement efforts, to ensure findings are generalizable, and can be pooled to establish best practices. RESEARCH QUESTION: Can we establish operational definitions for key elements related to pediatric ventilator liberation using a combination of detailed literature review and consensus-based approaches? STUDY DESIGN AND METHODS: A panel of 26 international experts in pediatric ventilator liberation, two methodologists, and two librarians conducted systematic reviews on eight topic areas related to pediatric ventilator liberation. Through a series of virtual meetings, we established draft definitions that were voted upon using an anonymous web-based process. Definitions were revised by incorporating extracted data gathered during the systematic review and discussed in another consensus meeting. A second round of voting was conducted to confirm the final definitions. RESULTS: In eight topic areas identified by the experts, 16 preliminary definitions were established. Based on initial discussion and the first round of voting, modifications were suggested for 11 of the 16 definitions. There was significant variability in how these items were defined in the literature reviewed. The final round of voting achieved ≥ 80% agreement for all 16 definitions in the following areas: what constitutes respiratory support (invasive mechanical ventilation and noninvasive respiratory support), liberation and failed attempts to liberate from invasive mechanical ventilation, liberation from respiratory support, duration of noninvasive respiratory support, total duration of invasive mechanical ventilation, spontaneous breathing trials, extubation readiness testing, 28 ventilator-free days, and planned vs rescue use of post-extubation noninvasive respiratory support. INTERPRETATION: We propose that these consensus-based definitions for elements of pediatric ventilator liberation, informed by evidence, be used for future quality improvement initiatives and research studies to improve generalizability and facilitate comparison.

Executive Summary: International Clinical Practice Guidelines for Pediatric Ventilator Liberation, A Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Document.

Rationale: Pediatric-specific ventilator liberation guidelines are lacking despite the many studies exploring elements of extubation readiness testing. The lack of clinical practice guidelines has led to significant and unnecessary variation in methods used to assess pediatric patients' readiness for extubation. Methods: Twenty-six international experts comprised a multiprofessional panel to establish pediatrics-specific ventilator liberation clinical practice guidelines, focusing on acutely hospitalized children receiving invasive mechanical ventilation for more than 24 hours. Eleven key questions were identified and first prioritized using the Modified Convergence of Opinion on Recommendations and Evidence. A systematic review was conducted for questions that did not meet an a priori threshold of ⩾80% agreement, with Grading of Recommendations, Assessment, Development, and Evaluation methodologies applied to develop the guidelines. The panel evaluated the evidence and drafted and voted on the recommendations. Measurements and Main Results: Three questions related to systematic screening using an extubation readiness testing bundle and a spontaneous breathing trial as part of the bundle met Modified Convergence of Opinion on Recommendations criteria of ⩾80% agreement. For the remaining eight questions, five systematic reviews yielded 12 recommendations related to the methods and duration of spontaneous breathing trials, measures of respiratory muscle strength, assessment of risk of postextubation upper airway obstruction and its prevention, use of postextubation noninvasive respiratory support, and sedation. Most recommendations were conditional and based on low to very low certainty of evidence. Conclusions: This clinical practice guideline provides a conceptual framework with evidence-based recommendations for best practices related to pediatric ventilator liberation.

Noninvasive Assessment of Neuromechanical and Neuroventilatory Coupling in COPD.

This study explored the use of parasternal second intercostal space and lower intercostal space surface electromyogram (sEMG) and surface mechanomyogram (sMMG) recordings (sEMGpara and sMMGpara, and sEMGlic and sMMGlic, respectively) to assess neural respiratory drive (NRD), neuromechanical (NMC) and neuroventilatory (NVC) coupling, and mechanical efficiency (MEff) noninvasively in healthy subjects and chronic obstructive pulmonary disease (COPD) patients. sEMGpara, sMMGpara, sEMGlic, sMMGlic, mouth pressure (Pmo), and volume (Vi) were measured at rest, and during an inspiratory loading protocol, in 16 COPD patients (8 moderate and 8 severe) and 9 healthy subjects. Myographic signals were analyzed using fixed sample entropy and normalized to their largest values (fSEsEMGpara%max, fSEsMMGpara%max, fSEsEMGlic%max, and fSEsMMGlic%max). fSEsMMGpara%max, fSEsEMGpara%max, and fSEsEMGlic%max were significantly higher in COPD than in healthy participants at rest. Parasternal intercostal muscle NMC was significantly higher in healthy than in COPD participants at rest, but not during threshold loading. Pmo-derived NMC and MEff ratios were lower in severe patients than in mild patients or healthy subjects during threshold loading, but differences were not consistently significant. During resting breathing and threshold loading, Vi-derived NVC and MEff ratios were significantly lower in severe patients than in mild patients or healthy subjects. sMMG is a potential noninvasive alternative to sEMG for assessing NRD in COPD. The ratios of Pmo and Vi to sMMG and sEMG measurements provide wholly noninvasive NMC, NVC, and MEff indices that are sensitive to impaired respiratory mechanics in COPD and are therefore of potential value to assess disease severity in clinical practice.

Noninvasive Assessment of Neuromechanical Coupling and Mechanical Efficiency of Parasternal Intercostal Muscle during Inspiratory Threshold Loading.

This study aims to investigate noninvasive indices of neuromechanical coupling (NMC) and mechanical efficiency (MEff) of parasternal intercostal muscles. Gold standard assessment of diaphragm NMC requires using invasive techniques, limiting the utility of this procedure. Noninvasive NMC indices of parasternal intercostal muscles can be calculated using surface mechanomyography (sMMGpara) and electromyography (sEMGpara). However, the use of sMMGpara as an inspiratory muscle mechanical output measure, and the relationships between sMMGpara, sEMGpara, and simultaneous invasive and noninvasive pressure measurements have not previously been evaluated. sEMGpara, sMMGpara, and both invasive and noninvasive measurements of pressures were recorded in twelve healthy subjects during an inspiratory loading protocol. The ratios of sMMGpara to sEMGpara, which provided muscle-specific noninvasive NMC indices of parasternal intercostal muscles, showed nonsignificant changes with increasing load, since the relationships between sMMGpara and sEMGpara were linear (R2 = 0.85 (0.75-0.9)). The ratios of mouth pressure (Pmo) to sEMGpara and sMMGpara were also proposed as noninvasive indices of parasternal intercostal muscle NMC and MEff, respectively. These indices, similar to the analogous indices calculated using invasive transdiaphragmatic and esophageal pressures, showed nonsignificant changes during threshold loading, since the relationships between Pmo and both sEMGpara (R2 = 0.84 (0.77-0.93)) and sMMGpara (R2 = 0.89 (0.85-0.91)) were linear. The proposed noninvasive NMC and MEff indices of parasternal intercostal muscles may be of potential clinical value, particularly for the regular assessment of patients with disordered respiratory mechanics using noninvasive wearable and wireless devices.

Performance Evaluation of Fixed Sample Entropy for Lung Sound Intensity Estimation.

Lung sound (LS) signals are often contaminated by impulsive artifacts that complicate the estimation of lung sound intensity (LSI) using conventional amplitude estimators. Fixed sample entropy (fSampEn) has proven to be robust to cardiac artifacts in myographic respiratory signals. Similarly, fSampEn is expected to be robust to artifacts in LS signals, thus providing accurate LSI estimates. However, the choice of fSampEn parameters depends on the application and fSampEn has not previously been applied to LS signals. This study aimed to perform an evaluation of the performance of the most relevant fSampEn parameters on LS signals, and to propose optimal fSampEn parameters for LSI estimation. Different combinations of fSampEn parameters were analyzed in LS signals recorded in a heterogeneous population of healthy subjects and chronic obstructive pulmonary disease patients during loaded breathing. The performance of fSampEn was assessed by means of its cross-covariance with flow signals, and optimal fSampEn parameters for LSI estimation were proposed.

Spatial Distribution of Normal Lung Sounds in Healthy Individuals under Varied Inspiratory Load and Flow Conditions.

Respiratory sounds yield pertinent information about respiratory function in both health and disease. Normal lung sound intensity is a characteristic that correlates well with airflow and it can therefore be used to quantify the airflow changes and limitations imposed by respiratory diseases. The dual aims of this study are firstly to establish whether previously reported asymmetries in normal lung sound intensity are affected by varying the inspiratory threshold load or the airflow of respiration, and secondly to investigate whether fixed sample entropy can be used as a valid measure of lung sound intensity. Respiratory sounds were acquired from twelve healthy individuals using four contact microphones on the posterior skin surface during an inspiratory threshold loading protocol and a varying airflow protocol. The spatial distribution of the normal lung sounds intensity was examined. During the protocols explored here the normal lung sound intensity in the left and right lungs in healthy populations was found to be similar, with asymmetries of less than 3 dB. This agrees with values reported in other studies. The fixed sample entropy of the respiratory sound signal was also calculated and compared with the gold standard root mean square representation of lung sound intensity showing good agreement.

Neurally adjusted ventilatory assist versus pressure support ventilation: a randomized controlled feasibility trial performed in patients at risk of prolonged mechanical ventilation.

BACKGROUND: The clinical effectiveness of neurally adjusted ventilatory assist (NAVA) has yet to be demonstrated, and preliminary studies are required. The study aim was to assess the feasibility of a randomized controlled trial (RCT) of NAVA versus pressure support ventilation (PSV) in critically ill adults at risk of prolonged mechanical ventilation (MV). METHODS: An open-label, parallel, feasibility RCT (n = 78) in four ICUs of one university-affiliated hospital. The primary outcome was mode adherence (percentage of time adherent to assigned mode), and protocol compliance (binary-≥ 65% mode adherence). Secondary exploratory outcomes included ventilator-free days (VFDs), sedation, and mortality. RESULTS: In the 72 participants who commenced weaning, median (95% CI) mode adherence was 83.1% (64.0-97.1%) and 100% (100-100%), and protocol compliance was 66.7% (50.3-80.0%) and 100% (89.0-100.0%) in the NAVA and PSV groups respectively. Secondary outcomes indicated more VFDs to D28 (median difference 3.0 days, 95% CI 0.0-11.0; p = 0.04) and fewer in-hospital deaths (relative risk 0.5, 95% CI 0.2-0.9; p = 0.032) for NAVA. Although overall sedation was similar, Richmond Agitation and Sedation Scale (RASS) scores were closer to zero in NAVA compared to PSV (p = 0.020). No significant differences were observed in duration of MV, ICU or hospital stay, or ICU, D28, and D90 mortality. CONCLUSIONS: This feasibility trial demonstrated good adherence to assigned ventilation mode and the ability to meet a priori protocol compliance criteria. Exploratory outcomes suggest some clinical benefit for NAVA compared to PSV. Clinical effectiveness trials of NAVA are potentially feasible and warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01826890. Registered 9 April 2013.

The effects of hypoxia and fatigue on skeletal muscle electromechanical delay.

NEW FINDINGS: What is the central question of this study? What are the mechanisms underlying impaired muscular endurance and accelerated fatigue during acute hypoxia? What is the main finding and its importance? Hypoxia had no effect on the electrochemical latency associated with muscle contraction elicited by supramaximal electrical motor nerve stimulation in vivo. This provides greater insight into the effects of hypoxia and fatigue on the mechanisms of muscle contraction in vivo. ABSTRACT: Acute hypoxia impairs muscle endurance and accelerates fatigue, but the underlying mechanisms, including any effects on muscle electrical activation, are incompletely understood. Electromyographic, mechanomyographic and force signals, elicited by common fibular nerve stimulation, were used to determine electromechanical delay (EMDTOT ) of the tibialis anterior muscle in normoxia and hypoxia ( FIO2 0.125) at rest and following fatiguing ankle dorsiflexor exercise (60% maximum voluntary contraction, 5 s on, 3 s off) in 12 healthy participants (mean (SD) age 27.4 (9.0) years). EMDTOT was determined from electromyographic to force signal onset, electrical activation latency from electromyographic to mechanomyographic (EMDE-M ) and mechanical latency from mechanomyographic to force (EMDM-F ). Twitch force fell significantly following fatiguing exercise in normoxia (46.8 (14.7) vs. 20.6 (14.3) N, P = 0.0002) and hypoxia (52.9 (15.4) vs. 28.8 (15.2) N, P = 0.0006). No effect of hypoxia on twitch force at rest was observed. Fatiguing exercise resulted in significant increases in mean (SD) EMDTOT in normoxia (Δ 4.7 (4.57) ms P = 0.0152) and hypoxia (Δ 3.7 (4.06) ms P = 0.0384) resulting from increased mean (SD) EMDM-F only (normoxia Δ 4.1 (4.1) ms P = 0.0391, hypoxia Δ 3.4 (3.6) ms P = 0.0303). Mean (SD) EMDE-M remained unchanged during normoxic (Δ 0.6 (1.08) ms) and hypoxic (Δ 0.25 (0.75) ms) fatiguing exercise. No differences in percentage change from baseline for twitch force, EMDTOT , EMDE-M and EMDM-F between normoxic and hypoxic fatigue conditions were observed. Hypoxia in isolation or in combination with fatigue had no effect on the electrochemical latency associated with electrically evoked muscle contraction.

Breathlessness and dysfunctional breathing in patients with postural orthostatic tachycardia syndrome (POTS): The impact of a physiotherapy intervention.

Postural orthostatic tachycardia syndrome (POTS) is a chronic, multifactorial syndrome with complex symptoms of orthostatic intolerance. Breathlessness is a prevalent symptom, however little is known about the aetiology. Anecdotal evidence suggests that breathless POTS patients commonly demonstrate dysfunctional breathing/hyperventilation syndrome (DB/HVS). There are, however, no published data regarding DB/HVS in POTS, and whether physiotherapy/breathing retraining may improve patients' breathing pattern and symptoms. The aim of this study was to explore the potential impact of a physiotherapy intervention involving education and breathing control on DB/HVS in POTS. A retrospective observational cohort study of all patients with POTS referred to respiratory physiotherapy for treatment of DB/HVS over a 20-month period was undertaken. 100 patients (99 female, mean (standard deviation) age 31 (12) years) with a clinical diagnosis of DB/HV were referred, of which data was available for 66 patients pre - post intervention. Significant improvements in Nijmegen score, respiratory rate and breath hold time (seconds) were observed following treatment. These data provide a testable hypothesis that breathing retraining may provide breathless POTS patients with some symptomatic relief, thus improving their health-related quality of life. The intervention can be easily protocolised to ensure treatment fidelity. Our preliminary findings provide a platform for a subsequent randomised controlled trial of breathing retraining in POTS.

A home-based lower limb-specific resistance training programme for patients with COPD: an explorative feasibility study.

It is feasible and acceptable to deliver a home-based lower limb-specific resistance training (LLSRT) programme to patients with COPD. Individual patient improvements in walking distance and breathlessness severity were observed post-LLSRT intervention. http://bit.ly/30xYpWI.

The influence of posture on parasternal intercostal muscle activity in healthy young adults.

OBJECTIVE: Parasternal intercostal muscle electromyography (EMGpara) has been used as an index of respiratory load in health and disease. While reference values are available, such data have been obtained with subjects in the seated position only. The objective of the current study was to determine the influence of posture on measurements of EMGpara. APPROACH: Fifty-one healthy adult participants underwent measurement of EMGpara, respiratory flow and volume in the seated, reclined at 45°, and supine positions. Resting peak EMGpara activity per breath was determined and expressed both as the raw signal and normalised to that obtained during a maximum inspiratory effort (EMGpara%max). Neural respiratory drive index (NRDI, the product of EMGpara%max and respiratory rate) and neuroventilatory efficiency (NVE, tidal volume divided by EMGpara) were also calculated. MAIN RESULTS: No significant differences were observed in raw EMGpara, EMGpara%max, NRDI, NVE or tidal volume from the seated to reclined or supine positions. Respiratory rate and minute ventilation were significantly lower in the supine position compared to seated (p  = 0.0043 and 0.0266 respectively). Poor agreement was observed between raw EMGpara and EMGpara%max, likely due to submaximal efforts or cross-talk from adjacent musculature during the maximal manoeuvres. Agreement was notably poorer in the supine posture. SIGNIFICANCE: Posture does not have a significant effect on EMGpara activity, suggesting that measurements can be made in the reclined or supine position if required or requested by the participant. Normalising the EMGpara signal to a maximal respiratory effort may give unreliable estimates of respiratory load.

Work of breathing during HHHFNC and synchronised NIPPV following extubation.

Our aim was to compare the work of breathing (WOB) during synchronised nasal intermittent positive pressure ventilation (SNIPPV) and heated humidified high flow nasal cannula (HHHFNC) when used as post-extubation support in preterm infants. A randomised crossover study was undertaken of nine infants with a median gestational age of 27 (range 24-31) weeks and post-natal age of 7 (range 2-50) days. Infants were randomised to either SNIPPV or HHHFNC immediately following extubation. They were studied for 2 h on one mode and then switched to the other modality and studied for a further 2-h period. The work of breathing, assessed by measuring the pressure time product of the diaphragm (PTPdi), and thoracoabdominal asynchrony (TAA) were determined at the end of each 2-h period. The infants' inspired oxygen requirement, oxygen saturation, heart rate and respiratory rate were also recorded. The median PTPdi was lower on SNIPPV than on HHHFNC (232 (range 130-352) versus 365 (range 136-449) cmH2O s/min, p = 0.0077), and there was less thoracoabdominal asynchrony (13.4 (range 8.5-41.6) versus 36.1 (range 4.3-50.4) degrees, p = 0.038).Conclusion: In prematurely born infants, SNIPPV compared to HHHFNC post-extubation reduced the work of breathing and thoracoabdominal asynchrony. What is Known: • The work of breathing and extubation failure are not significantly different in prematurely-born infants supported by HHHFNC or nCPAP. • SNIPPV reduces inspiratory effort and increases tidal volume and carbon dioxide exchange compared to nCPAP in prematurely born infants. What is New: • SNIPPV, as compared to HHHFNC, reduced the work of breathing in prematurely-born infants studied post-extubation. • SNIPPV, as compared to HHHFNC, reduced thoracoabdominal asynchrony in prematurely born infants studied post-extubation.

Surface mechanomyography and electromyography provide non-invasive indices of inspiratory muscle force and activation in healthy subjects.

The current gold standard assessment of human inspiratory muscle function involves using invasive measures of transdiaphragmatic pressure (Pdi) or crural diaphragm electromyography (oesEMGdi). Mechanomyography is a non-invasive measure of muscle vibration associated with muscle contraction. Surface electromyogram and mechanomyogram, recorded transcutaneously using sensors placed over the lower intercostal spaces (sEMGlic and sMMGlic respectively), have been proposed to provide non-invasive indices of inspiratory muscle activation, but have not been directly compared to gold standard Pdi and oesEMGdi measures during voluntary respiratory manoeuvres. To validate the non-invasive techniques, the relationships between Pdi and sMMGlic, and between oesEMGdi and sEMGlic were measured simultaneously in 12 healthy subjects during an incremental inspiratory threshold loading protocol. Myographic signals were analysed using fixed sample entropy (fSampEn), which is less influenced by cardiac artefacts than conventional root mean square. Strong correlations were observed between: mean Pdi and mean fSampEn |sMMGlic| (left, 0.76; right, 0.81), the time-integrals of the Pdi and fSampEn |sMMGlic| (left, 0.78; right, 0.83), and mean fSampEn oesEMGdi and mean fSampEn sEMGlic (left, 0.84; right, 0.83). These findings suggest that sMMGlic and sEMGlic could provide useful non-invasive alternatives to Pdi and oesEMGdi for the assessment of inspiratory muscle function in health and disease.

Assessment of Inspiratory Muscle Activation using Surface Diaphragm Mechanomyography and Crural Diaphragm Electromyography.

The relationship between surface diaphragm mechanomyography (sMMGdi), as a noninvasive measure of inspiratory muscle mechanical activation, and crural diaphragm electromyography (oesEMGdi), as the invasive gold standard measure of diaphragm electrical activation, had not previously been examined. To investigate this relationship, oesEMGdi and sMMGdi were measured simultaneously in 6 healthy subjects during an incremental inspiratory threshold loading protocol, and analyzed using fixed sample entropy (fSampEn). A positive curvilinear relationship was observed between mean fSampEn sMMGdi and oesEMGdi (r = 0.67). Accordingly, an increasing electromechanical ratio was also observed with increasing inspiratory load. These findings suggest that sMMGdi could provide useful noninvasive measures of inspiratory muscle mechanical activation.

Predicting healthcare outcomes in prematurely born infants using cluster analysis.

AIMS: Prematurely born infants are at high risk of respiratory morbidity following neonatal unit discharge, though prediction of outcomes is challenging. We have tested the hypothesis that cluster analysis would identify discrete groups of prematurely born infants with differing respiratory outcomes during infancy. METHODS: A total of 168 infants (median (IQR) gestational age 33 (31-34) weeks) were recruited in the neonatal period from consecutive births in a tertiary neonatal unit. The baseline characteristics of the infants were used to classify them into hierarchical agglomerative clusters. Rates of viral lower respiratory tract infections (LRTIs) were recorded for 151 infants in the first year after birth. RESULTS: Infants could be classified according to birth weight and duration of neonatal invasive mechanical ventilation (MV) into three clusters. Cluster one (MV ≤5 days) had few LRTIs. Clusters two and three (both MV ≥6 days, but BW ≥or <882 g respectively), had significantly higher LRTI rates. Cluster two had a higher proportion of infants experiencing respiratory syncytial virus LRTIs (P = 0.01) and cluster three a higher proportion of rhinovirus LRTIs (P < 0.001) CONCLUSIONS: Readily available clinical data allowed classification of prematurely born infants into one of three distinct groups with differing subsequent respiratory morbidity in infancy.

The effect of caffeine on the ventilatory response to hypercarbia in preterm infants.

BackgroundWe tested the hypotheses that caffeine therapy would increase the ventilatory response to hypercarbia in infants above the effect of maturation and those with a weaker ventilatory response to hypercarbia would be more likely to subsequently develop apnea that required treatment.MethodsInfants born at less than 34 weeks of gestation underwent a steady-state hypercarbic challenge using 0, 2, and 4% carbon dioxide soon after birth that was repeated at weekly intervals. The results of the initial study were compared between infants who did or did not subsequently develop apnea requiring treatment with caffeine.ResultsTwenty-six infants born at a median gestation of 32 (range 31-33) weeks were assessed. Caffeine administration was associated with an increase in CO2 sensitivity, and the mean increase was 15.3 (95% CI: 1-30) ml/kg/min/% CO2. Fourteen infants subsequently developed apnea treated with caffeine. After controlling for gestational age and birth weight, they had significantly lower carbon dioxide sensitivity at their initial study compared with those who did not require treatment.ConclusionCaffeine administration was associated with an increase in the ventilatory response to hypercarbia. An initial weaker ventilatory response to hypercarbia was associated with the subsequent development of apnea requiring treatment with caffeine.