Diaphragmatic electromyography in infants: an overview of possible clinical applications.

Preterm infants often experience breathing instability and a hampered lung function. Therefore, these infants receive cardiorespiratory monitoring and respiratory support. However, the current respiratory monitoring technique may be unreliable for especially obstructive apnea detection and classification and it does not provide insight in breathing effort. The latter makes the selection of the adequate mode and level of respiratory support difficult. Electromyography of the diaphragm (dEMG) has the potential of monitoring heart rate (HR) and respiratory rate (RR), and it provides additional information on breathing effort. This review summarizes the available evidence on the clinical potential of dEMG to provide cardiorespiratory monitoring, to synchronize patient-ventilator interaction, and to optimize the mode and level of respiratory support in the individual newborn infant. We also try to identify gaps in knowledge and future developments needed to ensure widespread implementation in clinical practice. IMPACT: Preterm infants require cardiorespiratory monitoring and respiratory support due to breathing instability and a hampered lung function. The current respiratory monitoring technique may provide unreliable measurements and does not provide insight in breathing effort, which makes the selection of the optimal respiratory support settings difficult. Measuring diaphragm activity could improve cardiorespiratory monitoring by providing insight in breathing effort and could potentially have an important role in individualizing respiratory support in newborn infants.

Effort and work-of-breathing parameters strongly correlate with increased resistance in an animal model.

BACKGROUND: Effort of Breathing (EOB) calculations may be a reliable alternative to Work of Breathing (WOB) calculations in which Respiratory Inductance Plethysmography (RIP) replaces spirometry. We sought to compare EOB and WOB measurements in a nonhuman primate model of increasing extrathoracic inspiratory resistance simulating upper airway obstruction (UAO). METHODS: RIP, spirometry, and esophageal manometry were measured in spontaneously breathing, intubated Rhesus monkeys utilizing 11 calibrated resistors randomly applied for 2-min. EOB was calculated breath-by-breath as Pressure Rate Product (PRP) and Pressure Time Product (PTP). WOB was calculated from the Pressure-Volume curve based on spirometry (WOBSPIR) or RIP flow (WOBRIP). RESULTS: WOB, PRP and PTP showed similar linear increases when exposed to higher levels of resistive loads. When comparing WOBSPIR to WOBRIP, a similar strong correlation was seen for both signals as resistance increased and there were no statistically significant differences. CONCLUSION: EOB and WOB parameters utilizing esophageal manometry and RIP, independent of spirometry, showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. This allows several potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. IMPACT: EOB and WOB parameters showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. There was a strong correlation between spirometry-based WOB versus RIP-based WOB. To date, it has remained untested as to whether EOB is a reliable alternative for WOB and if RIP can replace spirometry in these measurements. Our results enable additional potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. Where spirometry is not available, there is no need to apply a facemask post extubation to a spontaneously breathing, non-intubated infant to make objective EOB measurements.

Effects of Community-based Exercise Prehabilitation for Patients Scheduled for Colorectal Surgery With High Risk for Postoperative Complications: Results of a Randomized Clinical Trial.

OBJECTIVE: To assess the effects of a 3-week community-based exercise program on 30-day postoperative complications in high-risk patients scheduled for elective colorectal resection for (pre)malignancy. SUMMARY BACKGROUND DATA: Patients with a low preoperative aerobic fitness undergoing colorectal surgery have an increased risk of postoperative complications. It remains, however, to be demonstrated whether prehabilitation in these patients reduces postoperative complications. METHODS: This 2-center, prospective, single-blinded randomized clinical trial was carried out in 2 large teaching hospitals in the Netherlands. Patients (≥60 years) with colorectal (pre)malignancy scheduled for elective colorectal resection and with a score ≤7 metabolic equivalents on the veterans-specific activity questionnaire were randomly assigned to the prehabilitation group or the usual care group by using block-stratified randomization. An oxygen uptake at the ventilatory anaerobic threshold <11 mL/kg/min at the baseline cardiopulmonary exercise test was the final inclusion criterion. Inclusion was based on a power analysis. Patients in the prehabilitation group participated in a personalized 3-week (3 sessions per week, nine sessions in total) supervised exercise program given in community physical therapy practices before colorectal resection. Patients in the reference group received usual care. The primary outcome was the number of patients with one or more complications within 30 days of surgery, graded according to the Clavien-Dindo classification. Data were analyzed on an intention-to-treat basis. RESULTS: Between February 2014 and December 2018, 57 patients [30 males and 27 females; mean age 73.6 years (standard deviation 6.1), range 61-88 years] were randomized to either prehabilitation (n = 28) or usual care (n = 29). The rate of postoperative complications was lower in the prehabilitation group (n = 12, 42.9%) than in the usual care group (n = 21, 72.4%, relative risk 0.59, 95% confidence interval 0.37-0.96, P = 0.024). CONCLUSIONS: Exercise prehabilitation reduced postoperative complications in high-risk patients scheduled to undergo elective colon resection for (pre)malignancy. Prehabilitation should be considered as usual care in high-risk patients scheduled for elective colon, and probably also rectal, surgery.

Allergen provocation tests in respiratory research: building on 50†years of experience.

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.

Diaphragm Activity Pre and Post Extubation in Ventilated Critically Ill Infants and Children Measured With Transcutaneous Electromyography.

OBJECTIVES: Swift extubation is important to prevent detrimental effects of invasive mechanical ventilation but carries the risk of extubation failure. Accurate tools to assess extubation readiness are lacking. This study aimed to describe the effect of extubation on diaphragm activity in ventilated infants and children. Our secondary aim was to compare diaphragm activity between failed and successfully extubated patients. DESIGN: Prospective, observational study. SETTING: Single-center tertiary neonatal ICU and PICU. PATIENTS: Infants and children receiving invasive mechanical ventilation longer than 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Diaphragm activity was measured with transcutaneous electromyography, from 15 minutes before extubation till 180 minutes thereafter. Peak and tonic activity, inspiratory amplitude, inspiratory area under the curve, and respiratory rate were calculated from the diaphragm activity waveform. One hundred forty-seven infants and children were included (median postnatal age, 1.9; interquartile range, 0.9-6.7 wk). Twenty patients (13.6%) failed extubation within 72 hours. Diaphragm activity increased rapidly after extubation and remained higher throughout the measurement period. Pre extubation, peak (end-inspiratory) diaphragm activity and tonic (end-inspiratory) diaphragm activity were significantly higher in failure, compared with success cases (5.6 vs 7.0 µV; p = 0.04 and 2.8 vs 4.1 µV; p = 0.04, respectively). Receiver operator curve analysis showed the highest area under the curve for tonic (end-inspiratory) diaphragm activity (0.65), with a tonic (end-inspiratory) diaphragm activity greater than 3.4 µV having a combined sensitivity and specificity of 55% and 77%, respectively, to predict extubation outcome. After extubation, diaphragm activity remained higher in patients failing extubation. CONCLUSIONS: Diaphragm activity rapidly increased after extubation. Patients failing extubation had a higher level of diaphragm activity, both pre and post extubation. The predictive value of the diaphragm activity variables alone was limited. Future studies are warranted to assess the additional value of electromyography of the diaphragm in combined extubation readiness assessment.

Validation of the oxygen desaturation index in the diagnostic workup of obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) is common, and diagnosis requires expensive and laborious testing to assess the apnea hypopnea index (AHI). We performed an analysis to explore the relationship between the oxygen desaturation index (ODI) as measured with pulse oximetry and the AHI in our large portable monitoring (PM) database to find an optimal cutoff value for the ODI in order to be able to exclude AHI ≥ 5 on PM. METHODS: Three thousand four hundred thirteen PM recordings were randomly divided into a training set (N = 2281) and a test set (N = 1132). The optimal cutoff for the ODI to exclude an AHI ≥ 5 on PM was determined in the training set and subsequently validated in the test set. RESULTS: Area under the curve of the ODI to exclude an AHI ≥ 5 on PM was 0.997 in the training set and 0.996 in the test set. In the training set, the optimal cutoff to predict an AHI < 5 was an ODI < 5. Using this cutoff in the test set provided a sensitivity of 97.7%, a specificity of 97.0%, a positive predictive value of 99.2%, and a negative predictive value of 91.4%. CONCLUSION: An ODI < 5 predicts an AHI < 5 with high sensitivity and specificity when measured simultaneously using the same oximeter during PM recording.

ERS technical standard on bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing.

Recently, this international task force reported the general considerations for bronchial challenge testing and the performance of the methacholine challenge test, a "direct" airway challenge test. Here, the task force provides an updated description of the pathophysiology and the methods to conduct indirect challenge tests. Because indirect challenge tests trigger airway narrowing through the activation of endogenous pathways that are involved in asthma, indirect challenge tests tend to be specific for asthma and reveal much about the biology of asthma, but may be less sensitive than direct tests for the detection of airway hyperresponsiveness. We provide recommendations for the conduct and interpretation of hyperpnoea challenge tests such as dry air exercise challenge and eucapnic voluntary hyperpnoea that provide a single strong stimulus for airway narrowing. This technical standard expands the recommendations to additional indirect tests such as hypertonic saline, mannitol and adenosine challenge that are incremental tests, but still retain characteristics of other indirect challenges. Assessment of airway hyperresponsiveness, with direct and indirect tests, are valuable tools to understand and to monitor airway function and to characterise the underlying asthma phenotype to guide therapy. The tests should be interpreted within the context of the clinical features of asthma.

Clinical and inflammatory phenotyping by breathomics in chronic airway diseases irrespective of the diagnostic label.

Asthma and chronic obstructive pulmonary disease (COPD) are complex and overlapping diseases that include inflammatory phenotypes. Novel anti-eosinophilic/anti-neutrophilic strategies demand rapid inflammatory phenotyping, which might be accessible from exhaled breath.Our objective was to capture clinical/inflammatory phenotypes in patients with chronic airway disease using an electronic nose (eNose) in a training and validation set.This was a multicentre cross-sectional study in which exhaled breath from asthma and COPD patients (n=435; training n=321 and validation n=114) was analysed using eNose technology. Data analysis involved signal processing and statistics based on principal component analysis followed by unsupervised cluster analysis and supervised linear regression.Clustering based on eNose resulted in five significant combined asthma and COPD clusters that differed regarding ethnicity (p=0.01), systemic eosinophilia (p=0.02) and neutrophilia (p=0.03), body mass index (p=0.04), exhaled nitric oxide fraction (p<0.01), atopy (p<0.01) and exacerbation rate (p<0.01). Significant regression models were found for the prediction of eosinophilic (R2=0.581) and neutrophilic (R2=0.409) blood counts based on eNose. Similar clusters and regression results were obtained in the validation set.Phenotyping a combined sample of asthma and COPD patients using eNose provides validated clusters that are not determined by diagnosis, but rather by clinical/inflammatory characteristics. eNose identified systemic neutrophilia and/or eosinophilia in a dose-dependent manner.

A humidifier in the invasive mode during noninvasive respiratory support could increase condensation and thereby impair airway patency.

AIM: Humidifying noninvasively ventilated preterm infants is critical to prevent dehydration of respiratory mucosa, but over-humidification can result in impaired airway patency and lung mechanics. This neonatal bench study investigated the humidity delivered using invasive and noninvasive humidification modes during nasal continuous positive airway pressure. METHODS: The study was conducted at the neonatal intensive care unit of Emma Children's Hospital, the Netherlands, in March 2014. A mannequin was connected to a CareFusion Infant Flow SiPAP system, combined with a Fisher & Paykel MR850 humidifier and a Carefusion Infant Flow LP Generator. We measured the temperature, relative humidity and absolute humidity at the humidification chamber's expiratory port and at the patient's mask. RESULTS: The absolute humidity at the mask was 35-40 mg H2 O/L at 38-39°C (relative humidity 74-80%) for the invasive mode of the humidifier and 23-27 mg H2 O/L at 34-35°C (relative humidity 63-70%) for the noninvasive mode. The absolute humidities exceeded the recommended values for the invasive mode of the humidifier, but not the noninvasive mode, and could be associated with increased condensation. CONCLUSION: The absolute humidity delivered by the humidifier in invasive mode could be associated with increased condensation, which has been associated with airway impairment.

ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests.

This international task force report updates general considerations for bronchial challenge testing and the performance of the methacholine challenge test. There are notable changes from prior recommendations in order to accommodate newer delivery devices. Rather than basing the test result upon a methacholine concentration (provocative concentration (PC20) causing a 20% fall in forced expiratory volume in 1 s (FEV1)), the new recommendations base the result upon the delivered dose of methacholine causing a 20% fall in FEV1 (provocative dose (PD20)). This end-point allows comparable results from different devices or protocols, thus any suitable nebuliser or dosimeter may be used, so long as the delivery characteristics are known. Inhalation may be by tidal breathing using a breath-actuated or continuous nebuliser for 1 min (or more), or by a dosimeter with a suitable breath count. Tests requiring maximal inhalations to total lung capacity are not recommended because the bronchoprotective effect of a deep breath reduces the sensitivity of the test.

Effect of Minimally Invasive Surfactant Therapy on Lung Volume and Ventilation in Preterm Infants.

OBJECTIVE: To assess the changes in (regional) lung volume and gas exchange during minimally invasive surfactant therapy (MIST) in preterm infants with respiratory distress syndrome. STUDY DESIGN: In this prospective observational study, infants requiring a fraction of inspired oxygen (FiO2) ≥ 0.30 during nasal continuous positive airway pressure of 6 cmH2O were eligible for MIST. Surfactant (160-240 mg/kg) was administered in supine position in 1-3 minutes via an umbilical catheter placed 2 cm below the vocal cords. Changes in end-expiratory lung volume (EELV), tidal volume, and its distribution were recorded continuously with electrical impedance tomography before and up to 60 minutes after MIST. Changes in transcutaneous oxygen saturation (SpO2) and partial carbon dioxide pressure, FiO2, respiratory rate, and minute ventilation were recorded. RESULTS: A total of 16 preterm infants were included. One patient did not finish study protocol because of severe apnea 10 minutes after MIST. In the remaining infants (gestational age 29.8 ± 2.8 weeks, body weight 1545 ± 481 g) EELV showed a rapid and sustained increase, starting in the dependent lung regions, followed by the nondependent regions approximately 5 minutes later. Oxygenation, expressed as the SpO2/FiO2 ratio, increased from 233 (IQR 206-257) to 418 (IQR 356-446) after 60 minutes (P < .001). This change was significantly correlated with the change in EELV (ρ = 0.70, P < .01). Tidal volume and minute volume decreased significantly after MIST, but transcutaneous partial carbon dioxide pressure was comparable with pre-MIST values. Ventilation distribution remained unchanged. CONCLUSIONS: MIST results in a rapid and homogeneous increase in EELV, which is associated with an improvement in oxygenation.

The Effect of Caffeine on Diaphragmatic Activity and Tidal Volume in Preterm Infants.

OBJECTIVE: To determine the effect of caffeine on diaphragmatic activity, tidal volume (Vt), and end-expiratory lung volume (EELV) in preterm infants. STUDY DESIGN: Using transcutaneous electromyography of the diaphragm (dEMG), we measured diaphragmatic activity from 30 minutes before (baseline) to 3 hours after administration of an intravenous caffeine-base loading dose in 30 spontaneously breathing preterm infants (mean gestational age, 29.1 ± 1.3 weeks), most of whom were on noninvasive respiratory support. Diaphragmatic activity was expressed as the percentage change in dEMG amplitude, area under the curve, respiratory rate, and inspiratory and expiratory times. Using respiratory inductive plethysmography, we measured changes in Vt and EELV from baseline. These outcome variables were calculated at 8 fixed time points after caffeine administration (5, 15, 30, 60, 90, 120, 150, and 180 minutes) and compared with baseline. RESULTS: Caffeine administration resulted in rapid (within 5 minutes) increases in dEMG amplitude (median, 43%; IQR, 24%-63%; P < .001) and area under the curve (median, 28%; IQR, 14%-48%; P < .001). Vt also increased by a median of 30% (IQR, 7%-48%), and this change was significantly correlated with the change in dEMG amplitude (r = 0.67; P < .001). These effects were relatively stable until 120 minutes after caffeine administration. Caffeine did not consistently impact EELV, respiratory rate, or inspiratory and expiratory times. CONCLUSION: Caffeine treatment results in a rapid and sustained increase in diaphragmatic activity and Vt in preterm infants.

Changes in lung volume and ventilation following transition from invasive to noninvasive respiratory support and prone positioning in preterm infants.

BACKGROUND: To minimize secondary lung injury, ventilated preterm infants are extubated as soon as possible. To maximize extubation success, they are often placed in prone position. The effect of extubation and subsequent prone positioning on lung volumes is currently unknown. METHODS: Changes in end-expiratory lung volume (ΔEELV), tidal volume (VT), and ventilation distribution were monitored during transition from endotracheal to nasal continuous positive airway pressure and following prone positioning using electrical impedance tomography. In addition, the continuous distending pressure (CDP) and oxygen need (FiO2) were recorded. RESULTS: Twenty preterm infants (GA 28.7 ± 1.7 wk) were included. Following extubation, the CDP decreased from 7.9 ± 0.5 to 6.0 ± 0.2 cmH2O, while the FiO2 remained stable. Both ΔEELV and VT increased significantly (P < 0.05) after extubation, without changing ventilation distribution. Prone positioning resulted in a further increase in ΔEELV (P < 0.01) and a decrease in respiratory rate. VT remained stable but its distribution clearly shifted toward the ventral lung regions. CONCLUSION: Infants who are transitioned from invasive to noninvasive respiratory support are able to maintain their EELV and increase their VT. Prone positioning increases EELV and shifts tidal ventilation to the ventral lung regions. The latter suggests that infants should preferably be placed in prone position after extubation.

Cross-sectional changes in lung volume measured by electrical impedance tomography are representative for the whole lung in ventilated preterm infants.

OBJECTIVE: Electrical impedance tomography measures lung volume in a cross-sectional slice of the lung. Whether these cross-sectional volume changes are representative of the whole lung has only been investigated in adults, showing conflicting results. This study aimed to compare cross-sectional and whole lung volume changes using electrical impedance tomography and respiratory inductive plethysmography. DESIGN: A prospective, single-center, observational, nonrandomized study. SETTING: The study was conducted in a neonatal ICU in the Netherlands. PATIENTS: High-frequency ventilated preterm infants with respiratory distress syndrome. INTERVENTIONS: Cross-sectional and whole lung volume changes were continuously and simultaneously measured by, respectively, electrical impedance tomography and respiratory inductive plethysmography during a stepwise recruitment procedure. End-expiratory lung volume changes were assessed by mapping the inflation and deflation limbs using both the pressure/impedance and pressure/inductance pairs and characterized by calculating the inflection points. In addition, oscillatory tidal volume changes were assessed at each pressure step. MEASUREMENTS AND MAIN RESULTS: Twenty-three infants were included in the study. Of these, eight infants had to be excluded because the quality of the registration was insufficient for analysis (two electrical impedance tomography and six respiratory inductive plethysmography). In the remaining 15 infants (gestational age 28.0 ± 2.6 wk; birth weight 1,027 ± 514 g), end-expiratory lung volume changes measured by electrical impedance tomography were significantly correlated to respiratory inductive plethysmography measurements in 12 patients (mean r = 0.93 ± 0.05). This was also true for the upper inflection point on the inflation (r = 0.91, p < 0.01) and deflation limb (r = 0.83, p < 0.01). In 13 patients, impedance and inductance data also correlated significantly on oscillatory tidal volume/pressure relationships (mean r = 0.81 ± 0.18). CONCLUSIONS: This study shows that cross-sectional lung volume changes measured by electrical impedance tomography are representative for the whole lung and that this concept also applies to newborn infants.

Inhaled allergen bronchoprovocation tests.

The allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly TH2 cell-driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications.

Effect of nasal continuous and biphasic positive airway pressure on lung volume in preterm infants.

OBJECTIVE: To monitor regional changes in end-expiratory lung volume (EELV), tidal volumes, and their ventilation distribution during different levels of nasal continuous positive airway pressure (nCPAP) and nasal biphasic positive airway pressure (BiPAP) in stable preterm infants. STUDY DESIGN: By using electrical impedance tomography and respiratory inductive plethysmography, we measured changes in EELV and tidal volumes in 22 preterm infants (gestational age 29.7 ± 1.5 weeks) during 3 nCPAP levels (2, 4, and 6 cmH2O) and unsynchronized BiPAP (nCPAP = 6 cmH2O; pressure amplitude = 3 cmH2O; frequency = 50/min; inspiration time = 0.5 seconds) at 10-minute intervals. We assessed the distribution of these volumes in ventral and dorsal chest regions by using electrical impedance tomography. RESULTS: EELV increased with increasing nCPAP with no difference between the ventral and dorsal lung regions. Tidal volume also increased, and a decrease in phase angle and respiratory rate was noted by respiratory induction plethysmography. At the regional level, electrical impedance tomography data showed a more dorsally oriented ventilation distribution. BiPAP resulted in a small increase in EELV but without changes in tidal volume or its regional distribution. CONCLUSION: Increasing nCPAP in the range of 2 to 6 cmH2O results in a homogeneous increase in EELV and an increase in tidal volume in preterm infants with a more physiologic ventilation distribution. Unsynchronized BiPAP does not improve tidal volume compared with nCPAP.

Influence of neonatal endotracheal tube dimensions on oscillometry-acquired reactance: a bench study.

Objective.To examine the influence of the endotracheal tube (ETT) on respiratory reactance (Xrs) measured with the forced oscillation technique (FOT) and develop a correction method for it.Approach.In a bench study, the reactance of ETTs (Xtube) with different dimensions was measured on a breathing test lung in various respiratory settings.Main results.Xtubecan be accurately predicted by a fitted formula, with an R2of 0.97, with negligible effects due to changes in respiratory pattern and lung volume.Significance.The developed formula offers the ability to measure ETT-independent Xrsvalues of patients, improving the potential of FOT for lung function testing in mechanically ventilated newborns.