Pediatric Simulation of Intrinsic PEEP and Patient-Ventilator Trigger Asynchrony During Mechanical Ventilation.

BACKGROUND: Intrinsic PEEP during mechanical ventilation occurs when there is insufficient time for expiration to functional residual capacity before the next inspiration, resulting in air trapping. Increased expiratory resistance (RE), too rapid of a patient or ventilator breathing rate, or a longer inspiratory to expiratory time ratio (TI/TE) can all be causes of intrinsic PEEP. Intrinsic PEEP can result in increased work of breathing and patient-ventilator asynchrony (PVA) during patient-triggered breaths. We hypothesized that the difference between intrinsic PEEP and ventilator PEEP acts as an inspiratory load resulting in trigger asynchrony that needs to be overcome by increased respiratory muscle pressure (Pmus). METHODS: Using a Servo lung model (ASL 5000) and LTV 1200 ventilator in pressure control mode, we developed a passive model demonstrating how elevated RE increases intrinsic PEEP above ventilator PEEP. We also developed an active model investigating the effects of RE and intrinsic PEEP on trigger asynchrony (expressed as percentage of patient-initiated breaths that failed to trigger). We then studied if trigger asynchrony could be reduced by increased Pmus. RESULTS: Intrinsic PEEP increased significantly with increasing RE (r = 0.97, P = .006). Multivariate logistic regression analysis showed that both RE and negative Pmus levels affect trigger asynchrony (P < .001). CONCLUSIONS: A passive lung model describes the development of increasing intrinsic PEEP with increasing RE at a given ventilator breathing rate. An active lung model shows how this can lead to trigger asynchrony since the Pmus needed to trigger a breath is greater with increased RE, as the inspiratory muscles must overcome intrinsic PEEP. This model will lend itself to the study of intrinsic PEEP engendered by a higher ventilator breathing rate, as well as higher TI/TE, and will be useful in ventilator simulation scenarios of PVA. The model also suggests that increasing ventilator PEEP to match intrinsic PEEP can improve trigger asynchrony through a reduction in RE.

Identifying Clinical and Research Priorities in Sickle Cell Lung Disease. An Official American Thoracic Society Workshop Report.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality.Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus.Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation.Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

Input oscillometry and the forced oscillation technique for assessing lung function in preschool children with asthma.

Preschool children with asthma present a challenge in lung function testing, as they cannot readily cooperate with spirometry. The forced oscillation technique (FOT) measures passive pressures and flows delivered by a loudspeaker to a facemask, at frequencies much higher than those occurring physiologically. This in turn allows for rapid collection of data from a spontaneously breathing child in a timespan of seconds. However, at very rapid oscillatory flow rates, the mechanical properties opposing flows into and out of the respiratory system (collectively termed the respiratory system impedance, and comprised of elastic, resistive and inertial components) are very different from at normal breathing frequencies, with elastic properties being less important and inertial properties being more important. An understanding of how the respiratory system behaves at high frequencies is essential to understanding the physiological basis of this technique. This article presents a way to understand these oscillatory mechanics of the respiratory system. It then describes studies of the FOT in normal preschool children and in children with asthma. The technique can also measure the separate contributions of the central and peripheral airways, as well as assess for changes after bronchodilator administration. The FOT holds promise for the objective measurement of lung function in children who are too young to reliably perform spirometry.

Bronchodilator responsiveness assessed by forced oscillometry and multiple breath washout techniques in preschool children.

IMPORTANCE: The forced oscillation (FOT) and multiple breath washout (MBW) techniques are passive tests of lung function, and are reliable for preschool-age children. There has not been comparison testing to determine which test could more accurately differentiate between healthy controls and poorly controlled asthmatics, or differentiate a response to bronchodilator administration. OBJECTIVE: To determine whether the MBW and/or FOT could differentiate between healthy controls and poorly controlled asthmatics, and whether the two tests could detect a response to bronchodilator administration. METHODS: Twenty-eight healthy controls and 23 poorly controlled asthmatics 3-6 years of age participated. All subjects were administered the MBW followed by the FOT. A bronchodilator was then administered and testing was repeated. Wilcoxon Rank Sum tests were used to compare the difference between healthy controls and poorly controlled asthmatics. Wilcoxon Signed Rank tests were used to compare the pre- and post-bronchodilator values. RESULTS: Neither MBW nor FOT differentiated healthy controls from poorly controlled asthmatics (pre-bronchodilator data); both groups had similar baseline gas mixing and airway mechanics. There was no improvement in any MBW outcomes post-bronchodilator administration. FOT detected a significant and similar degree of improvement in the airway mechanics in both groups. INTERPRETATION: Neither MBW nor FOT differentiated between poorly controlled asthmatics (when well) and healthy controls. MBW did not detect a significant bronchodilator response in either subject group, whereas FOT detected a similar degree of bronchodilator responsiveness in both groups. This discrepancy may reflect differential changes in airway mechanics and gas mixing properties in response to bronchodilators.

Presumed Pseudotumor Cerebri Syndrome After Withdrawal of Inhaled Glucocorticoids.

Pseudotumor cerebri syndrome (PTCS) is characterized by increased intracranial pressure with normal brain parenchyma and cerebrospinal fluid constituents. PTCS after withdrawal of systemic corticosteroids also has been described in children. In contrast, to our knowledge, PTCS after withdrawal of inhaled glucocorticoids has not previously been described. Here we report the case of an 8-year and 6-month-old girl who developed signs and symptoms consistent with PTCS after withdrawal of inhaled glucocorticoids. The patient had excellent adherence to inhaled glucocorticoid therapy for ∼1 year before presentation, after which the therapy was stopped for concern related to poor growth. The withdrawal of inhaled glucocorticoids was associated with the development of severe headaches and diplopia, and further clinical examination led to the patient's diagnosis of likely PTCS. Although its occurrence is likely rare, clinicians caring for the many children receiving inhaled glucocorticoid therapy should be aware of the potential for PTCS after abrupt withdrawal of such treatment, and consider ophthalmology evaluation if patients report suggestive symptoms, such as headaches or vision changes in this context.

Airway Resistance in Children with Obstructive Sleep Apnea Syndrome.

STUDY OBJECTIVES: Enlarged tonsils and adenoids, the main cause of obstructive sleep apnea syndrome (OSAS) in children, results in upper airway (UA) loading. This contributes to the imbalance between structural and neuromotor factors ultimately leading to UA collapse during sleep. However, it is unknown whether this UA loading can cause elevated airway resistance (AR) during wakefulness. We hypothesized that children with OSAS have elevated AR compared to controls and that this improves after OSAS treatment. METHODS: Case control study performed at an academic hospital. Children with OSAS and nonsnoring healthy controls underwent baseline polysomnography and spirometry, and AR measurement by body plethysmography while breathing via an orofacial mask. Children with OSAS repeated the previously mentioned tests after adenotonsillectomy. RESULTS: 31 OSAS participants (mean age ± SD = 9.7 ± 3.0 y, obstructive apnea-hypopnea index (OAHI) median [range] = 14.9 [2-58.7] events/h, body mass index [BMI] z = 1.5 ± 1) and 31 controls (age = 10.5 ± 2.5 y, P = 0.24; OAHI = 0.4 [0-1.4], P < 0.001; BMI z = 0.9 ± 1, P = 0.01) were tested. OSAS AR at baseline was 3.9 [1.5-10.3] cmH2O/L/sec and controls 2.8 [1.4 - 6.2] (P = 0.027). Both groups had similar spirometry results. 20 patients with OSAS were tested 6.4 ± 6.6 mo after adenotonsillectomy. OAHI decreased from 15.2 [2.1-58.7] to 0.5 [0 - 5.1] events/h postoperatively (P < 0.001), and AR decreased from 4.3 [1.5 - 10.3] to 2.8 [1.7 - 4.7] cmH2O/L/sec (P = 0.009). CONCLUSIONS: Children with OSAS have elevated AR that decreases after treatment. This is likely because of upper airway loading secondary to adenotonsillar hypertrophy and may contribute to the increased frequency of respiratory diseases in untreated children with OSAS.

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin.

Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.

Hypoxemia in sickle cell disease: significance and management.

Hypoxemia is common in SCD and likely exacerbates SCD vasculopathy. Pulse oximeter correlation with arterial oxygen tension in patients with SCD may at times be poor and arterial blood gas confirmation is required in hypoxic patients. Supplemental oxygen should be administered for the correction of hypoxemia, which if untreated creates a risk of multi-organ failure. Transfusion and hydroxyurea can improve oxygen delivery to tissues and organs. The role of supplemental oxygen therapy in preventing or reversing SCD vasculopathy is controversial. Nitric oxide therapy for VOC pain has not fulfilled promise to date. On the other hand, lung distension (CPAP, incentive spirometry, PEP therapy) are promising treatments requiring further study.

Gene network analysis in a pediatric cohort identifies novel lung function genes.

Lung function is a heritable trait and serves as an important clinical predictor of morbidity and mortality for pulmonary conditions in adults, however, despite its importance, no studies have focused on uncovering pediatric-specific loci influencing lung function. To identify novel genetic determinants of pediatric lung function, we conducted a genome-wide association study (GWAS) of four pulmonary function traits, including FVC, FEV1, FEV1/FVC and FEF25-75% in 1556 children. Further, we carried out gene network analyses for each trait including all SNPs with a P-value of <1.0 × 10(-3) from the individual GWAS. The GWAS identified SNPs with notable trends towards association with the pulmonary function measures, including the previously described INTS12 locus association with FEV1 (pmeta=1.41 × 10(-7)). The gene network analyses identified 34 networks of genes associated with pulmonary function variables in Caucasians. Of those, the glycoprotein gene network reached genome-wide significance for all four variables. P-value range pmeta=6.29 × 10(-4) - 2.80 × 10(-8) on meta-analysis. In this study, we report on specific pathways that are significantly associated with pediatric lung function at genome-wide significance. In addition, we report the first loci associated with lung function in both pediatric Caucasian and African American populations.

Respiratory muscle force and lung volume changes in a population of children with sickle cell disease.

Sickle cell disease (SCD) is a disorder known to impact the respiratory system. We sought to identify respiratory muscle force and lung volume relationships in a paediatric SCD population. Thirty-four SCD-SS subjects underwent pulmonary function testing. Height, weight, age, and gender-adjusted percent predicted maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) values were compared to spirometry and lung volumes. Statistical analyses were performed using Pearson's correlation coefficient and paired two-tailed t-test. The mean ± standard deviation (SD) MIP and MEP was 69·6 ± 31·6 cm H2 O and 66·9 ± 22·9 cm H2 O, respectively, and mean ± SD percent predicted MIP (101·3 ± 45·9) exceeded MEP (72·1 ± 26·0) (P = 0·002). MIP correlated with forced vital capacity (FVC; r = 0·51, P = 0·001) and TLC (r = 0·54, P < 0·0001). MEP also correlated with FVC (r = 0·43, P = 0·011) and total lung capacity (TLC; r = 0·42, P = 0·013). Pearson's correlation coefficient testing yielded relationships between MIP and MEP (r = 0·64, P < 0·0001). SCD-SS patients showed correlations between respiratory muscle force and lung volume, and reduced percent predicted expiratory muscle force compared to inspiratory muscle force. Respiratory muscle strength may affect lung volumes in these patients, and expiratory muscles may be more susceptible than the diaphragm to SCD-induced vaso-occlusive damage.

Non-invasive measurements of carboxyhemoglobin and methemoglobin in children with sickle cell disease.

Assessment of oxyhemoglobin saturation in patients with sickle cell disease (SCD) is vital for prompt recognition of hypoxemia. The accuracy of pulse oximeter measurements of blood oxygenation in SCD patients is variable, partially due to carboxyhemoglobin (COHb) and methemoglobin (MetHb), which decrease the oxygen content of blood. This study evaluated the accuracy and reliability of a non-invasive pulse co-oximeter in measuring COHb and MetHb percentages (SpCO and SpMet) in children with SCD. We hypothesized that measurements of COHb and MetHb by non-invasive pulse co-oximetry agree within acceptable clinical accuracy with those made by invasive whole blood co-oximetry. Fifty children with SCD-SS underwent pulse co-oximetry and blood co-oximetry while breathing room air. Non-invasive COHb and MetHb readings were compared to the corresponding blood measurements. The pulse co-oximeter bias was 0.1% for COHb and -0.22% for MetHb. The precision of the measured SpCO was ± 2.1% within a COHb range of 0.4-6.1%, and the precision of the measured SpMet was ± 0.33% within a MetHb range of 0.1-1.1%. Non-invasive pulse co-oximetry was useful in measuring COHb and MetHb levels in children with SCD. Although the non-invasive technique slightly overestimated the invasive COHb measurements and slightly underestimated the invasive MetHb measurements, there was close agreement between the two methods.

Upper airway lymphoid tissue size in children with sickle cell disease.

BACKGROUND: The prevalence of obstructive sleep apnea syndrome (OSAS) is higher in children with sickle cell disease (SCD) as compared with the general pediatric population. It has been speculated that overgrowth of the adenoid and tonsils is an important contributor. METHODS: The current study used MRI to evaluate such an association. We studied 36 subjects with SCD (aged 6.9 ± 4.3 years) and 36 control subjects (aged 6.6 ± 3.4 years). RESULTS: Compared with control subjects, children with SCD had a significantly smaller upper airway (2.8 ± 1.2 cm(3) vs 3.7 ± 1.6 cm(3), P < .01), and significantly larger adenoid (8.4 ± 4.1 cm(3) vs 6.0 ± 2.2 cm(3), P < .01), tonsils (7.0 ± 4.3 cm(3) vs 5.1 ± 1.9 cm(3), P < .01), retropharyngeal nodes (3.0 ± 1.9 cm(3) vs 2.2 ± 0.9 cm(3), P < .05), and deep cervical nodes (15.7 ± 5.7 cm(3) vs 12.7 ± 4.0 cm(3), P < .05). Polysomnography showed that 19.4% (seven of 36) of children with SCD had OSAS compared with 0% (zero of 20) of control subjects (P < .05) and that in children with SCD the apnea-hypopnea index correlated positively with upper airway lymphoid tissues size (r = 0.57, P < 001). In addition, children with SCD had lower arterial oxygen saturation nadir (84.3% ± 12.3% vs 91.2% ± 4.2%, P < .05), increased peak end-tidal CO(2) (53.4 ± 8.5 mm Hg vs 42.3 ± 5.3 mm Hg, P < .001), and increased arousals (13.7 ± 4.7 events/h vs 10.8 ± 3.8 events/h, P < .05). CONCLUSIONS: Children with SCD have reduced upper airway size due to overgrowth of the surrounding lymphoid tissues, which may explain their predisposition to OSAS.

Upper airway genioglossal activity in children with sickle cell disease.

STUDY OBJECTIVES: The prevalence of obstructive sleep apnea syndrome (OSAS) in sickle cell disease (SCD) has been reported to be higher than that in the general pediatric population. However, not all subjects with SCD develop OSAS. We hypothesized that SCD patients with OSAS have a blunted neuromuscular response to subatmospheric pressure loads during sleep, making them more likely to develop upper airway collapse. DESIGN: Subjects with SCD with and without OSAS underwent pressure-flow measurements during sleep using intraoral surface electrodes to measure genioglossal EMG (EMGgg). Two techniques were applied to decrease the nasal pressure (P(N)) to subatmospheric levels, resulting in an activated and relatively hypotonic upper airway. The area under the curve of the inspiratory EMGgg moving time average was analyzed. EMGgg activity was expressed as a percentage of baseline. Changes in EMGgg in response to decrements in nasal pressure were expressed as the slope of the EMGgg vs. nasal pressure (slope of EMGgg-P(N)). SETTING: Sleep laboratory. PARTICIPANTS: 4 children with SCD and OSAS and 18 children with SCD but without OSAS. RESULTS: THE MAJOR FINDINGS OF THIS STUDY WERE: (1) using the activated but not the hypotonic technique, the slope of EMGgg-P(N) was more negative in SCD controls than SCD OSAS; (2) the slope of EMGgg-P(N) was significantly lower using the activated technique compared to the hypotonic technique in SCD controls only; (3) similarly, the critical closing pressure, Pcrit, was more negative using the activated technique than the hypotonic technique in SCD controls but not in SCD OSAS. CONCLUSION: This preliminary study has shown that children with SCD but without OSAS have more prominent upper airway reflexes than children with SCD and OSAS.

Beliefs and barriers to follow-up after an emergency department asthma visit: a randomized trial.

BACKGROUND: Studies in urban emergency departments (EDs) have found poor quality of chronic asthma care and identified beliefs and barriers associated with low rates of follow-up with a primary care provider (PCP). OBJECTIVES: To develop an ED-based intervention including asthma symptom screening, a video addressing beliefs and a mailed reminder; and measure the effect on PCP follow-up and asthma-related outcomes. METHODS: This randomized, controlled trial enrolled children aged 1 to 18 years who were discharged after asthma treatment in an urban pediatric ED. Control subjects received instructions to follow-up with a PCP within 3 to 5 days. In addition, intervention subjects (1) received a letter to take to their PCP if they screened positive for persistent asthma symptoms, (2) viewed a video featuring families and providers discussing the importance of asthma control, and (3) received a mailed reminder to follow-up with a PCP. All subjects were contacted by telephone 1, 3, and 6 months after the ED visit, and follow-up was confirmed by PCP record review. Asthma-related quality of life (AQoL), symptoms, and beliefs about asthma care were assessed by using validated surveys. RESULTS: A total of 433 subjects were randomly assigned, and baseline measures were similar between study groups. After the intervention and before ED discharge, intervention subjects were more likely to endorse beliefs about the benefits of follow-up than controls. However, rates of PCP follow-up during the month after the ED visit (44.5%) were similar to control subjects (43.8%) as were AQoL, medication use, and ED visits. CONCLUSIONS: An ED-based intervention influenced beliefs but did not increase PCP follow-up or asthma-related outcomes.

Pulmonary complications of sickle cell disease in children.

PURPOSE OF REVIEW: Sickle cell disease is one of the most prevalent genetic diseases, affecting 1 in 600 African-Americans. The lung is one of the major organs affected in sickle cell disease and the pulmonary complications of sickle cell disease result in significant morbidity and mortality in children. RECENT FINDINGS: Recent literature has provided evidence supporting the strong association between asthma and airway hyperreactivity and sickle cell disease, as well as a link with acute chest syndrome and vaso-occlusive crisis. Additionally, children with sickle cell disease who have acute chest syndrome episodes have worse pulmonary function than those who have not experienced acute chest syndrome episodes. An increasing amount of literature highlights the link between pulmonary hypertension and sickle cell disease, and multiple mechanisms have been invoked to explain why patients with sickle cell disease are prone to the development of pulmonary hypertension. Previous and current studies have also highlighted the manifestations of sleep disordered breathing in children with sickle cell disease. SUMMARY: The pulmonary complications of sickle cell disease include airway hyperreactivity, acute chest syndrome, chronic sickle lung disease, pulmonary hypertension, and sleep disordered breathing. Further understanding of the interrelationships between these disorders will lead to improved therapies.