Deep or awake removal of laryngeal mask airway in children at risk of respiratory adverse events undergoing tonsillectomy-a randomised controlled trial.

BACKGROUND: Laryngeal mask airways (LMA) are widely used during tonsillectomies. Contrasting evidence exists regarding the timing of the removal and the risk of perioperative respiratory adverse events. We assessed whether the likelihood of perioperative respiratory adverse events is influenced by the timing of LMA removal in children with at least one risk factor for these events. METHODS: Participants (n=290, 0-16 yr) were randomised to have their LMA removed either deep (in theatre by anaesthetist at end-tidal sevoflurane >1 minimum alveolar concentration) or awake (in theatre by anaesthetist or in postanaesthesia care unit by anaesthetist or trained nurse). The primary outcome was the occurrence of perioperative respiratory adverse events over the whole emergence and postanaesthesia care unit phases of anaesthesia. The secondary outcome was the occurrence of perioperative respiratory adverse events over the distinct phases of emergence and postanaesthesia care unit. RESULTS: Data from 283 participants were analysed. PRIMARY OUTCOME: even though a higher occurrence of adverse events was observed in the awake group, no evidence for a difference was found [45% vs 35%, odds ratio (OR): 1.5, 95% confidence interval (CI): 0.9-2.5, P=0.09]. Secondary outcome: there was no evidence for a difference between the groups during emergence [19 (14%) deep vs 25 (18%) awake, OR: 0.74, 95%CI: 0.39-1.42, P=0.37]. However, in the postanaesthesia care unit, children with an awake rather than deep removal experienced significantly more adverse events [55 (39%) vs 37 (26%); OR: 1.85, 95%CI: 1.12-3.07, P=0.02]. CONCLUSION: We found no evidence for a difference in the timing of the LMA removal on the incidence of respiratory adverse events over the whole emergence and postanaesthesia care unit phases. However, in the postanaesthesia care unit solely, awake removal was associated with significantly more respiratory adverse events than deep removal. TRIAL REGISTRATION NUMBER: ACTRN12609000387224 (www.anzctr.org.au).

Premedication with salbutamol prior to surgery does not decrease the risk of perioperative respiratory adverse events in school-aged children.

BACKGROUND: Perioperative respiratory adverse events (PRAE) remain the leading cause of morbidity and mortality in the paediatric population. This double-blinded randomized control trial investigated whether inhaled salbutamol premedication decreased the occurrence of PRAE in children identified as being at high risk of PRAE. METHODS: Children with at least two parentally reported risk factors for PRAE undergoing elective surgery were eligible for recruitment. They were randomized to receive either salbutamol (200 µg) or placebo prior to their surgery and PRAE (bronchospasm, laryngospasm, airway obstruction, desaturation, coughing and stridor) were recorded. RESULTS: Out of 470 children (6-16 yr, 277 males, 59%) recruited, 462 were available for an intention-to-treat analysis. Thirty-two (14%) and 27 (12%) children from the placebo and salbutamol groups experienced PRAE. This difference was not significant [odds ratio (OR): 0.83, 95% confidence interval (CI): 0.48-1.44, P : 0.51]. Oxygen desaturation [14/232 (6%) vs 14/230 (6%), OR: 1.01, 95% CI: 0.47-2.17, P : 0.98] and severe coughing [12/232 (5%) vs 10/230 (4%), OR: 0.83, 95% CI: 0.35-1.97, P : 0.68] were the most common PRAE, but did not significantly differ between the groups. The occurrence of PRAE was slightly lower in children with respiratory symptoms who received salbutamol compared with placebo [16/134 (12%) vs 21/142 (15%), OR: 0.93, 95% CI: 0.38-2.26, P : 0.87], but was not significantly different. CONCLUSIONS: Premedication with salbutamol to children aged between 6 and 16 years and at high risk of PRAE prior to their surgery did not reduce their risk of PRAE. TRIAL REGISTRATION NUMBER: ACTRN12612000626864 ( www.anzctr.org.au ).

Peri-operative adverse respiratory events in children.

Three quarters of all critical incidents and a third of all peri-operative cardiac arrests in paediatric anaesthesia are caused by adverse respiratory events. We screened for risk factors from children's and their families' histories, and assessed the usefulness of common markers of allergic sensitisation of the airway as surrogates for airway inflammation and increased risk for adverse respiratory events. One hundred children aged up to 16 years with two or more risk factors undergoing elective surgery were included in the study. Eosinophil counts, IgE level, specific IgE for D. pteronyssinus, cat epithelia and Gx2 (grass pollen) were measured for each child and adverse respiratory events (bronchospasm, laryngospasm, oxygen desaturation < 95%, severe persistent coughing, airway obstruction and postoperative stridor) were recorded. Twenty-one patients had an adverse respiratory event but allergic markers were poor predictors. Binary logistic regression showed a lack of predictive value of the eosinophil range and adverse respiratory events (p = 0.249). Receiver operating characteristic (ROC) curves for the presence of adverse respiratory events vs level of specific IgE antibody (to Gx2 (AUC 0.614), cat epithelia (0.564) and D. pteronyssinus (0.520)) demonstrated poor predictive values. However, the presence of risk factors was strongly associated with adverse respiratory events (p < 0.001) and a ROC-curve analysis indicated a fair capacity to predict adverse respiratory events (AUC 0.788). There was a significant difference (p = 0.001) between the presence of adverse respiratory events in patients with more than four (p = 0.006), compared with less than four (p = 0.001), risk factors. We conclude that while risk factors taken from the child's (or family) history proved good predictors of adverse respiratory events, immunological markers of allergic sensitisation demonstrated low predictive values. Pre-operative identification of children at high risk for an adverse respiratory event should rely on clinical, rather than immunological, assessment.

Prediction of peri-operative adverse respiratory events in children: the role of exhaled nitric oxide.

Increased levels of exhaled nitric oxide (eNO) may be a more objective predictor in identifying children at higher risk of peri-operative adverse respiratory events than the presence of risk factors such as recent cold or wheeze. Children with either none or ≥ 2 risk factors had eNO measured before surgery and any peri-operative adverse respiratory events were recorded. We found that an elevated eNO level was only predictive of adverse respiratory events in children with ≥ 2 risk factors (OR 2.96 (95% CI 1.48-5.93), p = 0.002). The presence of risk factors had a better predictive capability than a raised eNO level (OR 3.83 (95% CI 1.85-7.95), p < 0.001). The combination of both predictors did not improve the predictive capability for adverse respiratory events (OR 1.93 (95% CI 1.44-2.59), p < 0.001). We conclude that measuring eNO levels does not lead to improved prediction of adverse respiratory events and that, in routine clinical practice, an accurate history of risk factors remains the most appropriate tool for successfully identifying children at risk of peri-operative adverse respiratory events.

Expiratory flow limitation and breathing strategies in overweight adolescents during submaximal exercise.

OBJECTIVE: To investigate whether ventilatory factors limit exercise in overweight and obese children during a 6-min step test and to compare ventilatory responses during this test with those of healthy weight children. DESIGN: Cross-sectional, prospective comparative study. SUBJECTS: Twenty-six overweight/obese subjects and 25 healthy weight subjects with no known respiratory illness. MEASUREMENTS: Various fatness and fat distribution parameters (using air displacement plethysmography and anthropometry), pulmonary function tests, breath-by-breath gas analysis during exercise, perceived exertion. RESULTS: Young people who are overweight or obese are more likely to experience expiratory flow limitation (expFL) during submaximal exercise compared with their healthy weight peers [OR 7.2 (1.4, 37.3), P=0.019]. Subjects who had lower lung volumes at rest were even more likely to experience exercise-induced expFLs [OR 8.35 (1.4-49.3)]. Both groups displayed similar breathing strategies during submaximal exercise. CONCLUSION: Young people who are overweight/obese are more likely to display expFL during submaximal exercise compared with children of healthy weight . Use of compensatory breathing strategies appeared to enable overweight children to avoid the experience of breathlessness at this intensity of exercise.

Influence of secular trends and sample size on reference equations for lung function tests.

The aim of our study was to determine the contribution of secular trends and sample size to lung function reference equations, and establish the number of local subjects required to validate published reference values. 30 spirometry datasets collected between 1978 and 2009 provided data on healthy, white subjects: 19,291 males and 23,741 females aged 2.5-95 yrs. The best fit for forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC as functions of age, height and sex were derived from the entire dataset using GAMLSS. Mean z-scores were calculated for individual datasets to determine inter-centre differences. This was repeated by subdividing one large dataset (3,683 males and 4,759 females) into 36 smaller subsets (comprising 18-227 individuals) to preclude differences due to population/technique. No secular trends were observed and differences between datasets comprising >1,000 subjects were small (maximum difference in FEV(1) and FVC from overall mean: 0.30- -0.22 z-scores). Subdividing one large dataset into smaller subsets reproduced the above sample size-related differences and revealed that at least 150 males and 150 females would be necessary to validate reference values to avoid spurious differences due to sampling error. Use of local controls to validate reference equations will rarely be practical due to the numbers required. Reference equations derived from large or collated datasets are recommended.

Interleukin 1 beta is localized in the cytoplasmic ground substance but is largely absent from the Golgi apparatus and plasma membranes of stimulated human monocytes.

The subcellular location of IL-1 beta was determined using a postsectioning immunoelectron microscopic method on ultrathin frozen sections of human monocytes stimulated with LPS. This methodology permits access of antibody probes to all sectioned intracellular compartments, and their visualization at high resolution. Staining was performed with a rabbit antibody that specifically recognized amino acids 197-215 in the 33-kD IL-1 beta precursor molecule, followed by affinity-purified goat anti-rabbit IgG conjugated to 10 nm colloidal gold particles. Approximately 90% of the IL-1 beta antigens were localized in the ground substance of the cytoplasm at 4 or 20 h after activation, when both intracellular and extracellular accumulation of IL-1 beta was well underway. No significant IL-1 beta staining was observed on the outer cell membrane, nor within the lumens of the endoplasmic reticulum (ER), the Golgi apparatus, or secretory vesicles. In contrast, lysozyme was localized in the ER and dense secretory granules using these methods. Our results suggest that IL-1 beta is not anchored on the plasma membrane, and that its secretion occurs by a novel mechanism that does not use a secretory leader sequence, nor the classical secretory pathway involving the ER and Golgi apparatus.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study.

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Cytoglobin is upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer.

BACKGROUND: Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancer syndrome of the upper aerodigestive tract. METHODS: Cytoglobin expression and promoter methylation were investigated in sporadic head and neck squamous cell carcinoma (HNSCC) using a cross-section of clinical samples. Additionally, the putative mechanisms of Cygb expression in cancer were explored by subjecting HNSCC cell lines to hypoxic culture conditions and 5-aza-2-deoxycitidine treatment. RESULTS: In clinically derived HNSCC samples, CYGB mRNA expression showed a striking correlation with tumour hypoxia (measured by HIF1A mRNA expression P=0.013) and consistent associations with histopathological measures of tumour aggression. CYGB expression also showed a marked negative correlation with promoter methylation (P=0.018). In the HNSCC cell lines cultured under hypoxic conditions, a trend of increasing expression of both CYGB and HIF1A with progressive hypoxia was observed. Treatment with 5-aza-2-deoxycitidine dramatically increased CYGB expression in those cell lines with greater baseline promoter methylation. CONCLUSION: We conclude that the CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour's biological aggression.

An urgent need for African spirometry reference equations: the Paediatric and Adult African Spirometry study.

BACKGROUND: The GLI2012 (Global Lung Initiative 2012) has provided the largest data set to date for multi-ethnic spirometry reference equations; however, data on African populations are limited. In pulmonary function testing, diagnosis of lung disorder is based on comparing the individual's lung function to a reference appropriate for sex and ethnicity.METHODS: We conducted a systematic review of studies reporting spirometry results in healthy children and adults in Africa. Data from these studies were collated for Z-scores of forced expiratory volume in 1 sec (zFEV1), forced vital capacity (zFVC) and zFEV1/FVC compared to GLI reference equations.RESULTS: Nine studies, covering a total of 4750 individuals from North, South, East, West and Central Africa (52% were female), were reviewed. Marked differences were noted between individuals from North Africa and sub-Saharan Africa. The Southern zFEV1 (-0.12 ± 0.98), zFVC (-0.15 ± 0.98) and zFEV1/FVC (0.05 ± 0.89), Central zFEV1 (-0.16 ± 0.79), zFVC (-0.09 ± 0.83) and zFEV1/FVC (-0.17 ± 0.71) and East African zFEV1 (0.10 ± 0.88), zFVC (0.16 ± 0.85) and zFEV1/FVC (-0.10 ± 0.95) cohorts had an excellent fit with the GLI-African American. The West African showed a poor fit to all reference equations. The North African group showed the best fit for the GLI Caucasian zFEV1 (-0.12 ± 1.37), zFVC (-0.26 ± 1.36) and zFEV1/FVC (0.25 ± 1.11). The zFEV1/FVC ratios were stable across all the populations.CONCLUSION: Current evidence seems to support the use of GLI2012 reference values in North African and sub-Saharan African populations after taking into account ethnic correction factors.

Forced oscillations in the clinical setting in young children with neonatal lung disease.

The extent of respiratory dysfunction is not well characterised in children with neonatal chronic lung disease (nCLD) too young to perform spirometry. Forced oscillations are easily performed by healthy young children; however, they may be more difficult for those with nCLD. The present study aimed to describe the feasibility of using the forced oscillation technique in children with nCLD in a routine clinical setting and to investigate the influence of neonatal factors on subsequent lung function. Respiratory function tests were attempted in 64 patients with nCLD aged 3.2-6.6 yrs. Respiratory resistance and reactance at 6, 8 and 10 Hz were expressed as z-scores derived from a healthy reference population. The within-test variation and between-test repeatability were also assessed. Technically, satisfactory data were obtained from 77% of children. On grouped data, z-scores for all oscillatory indices were different from zero and related to hospital oxygen administration in the neonatal period. In conclusion, the forced oscillation technique was feasible in preschool children with neonatal chronic lung disease in the clinical outpatient setting. These children had lung function significantly worse than that predicted from healthy children. Respiratory function assessed using forced oscillations appeared to reflect the severity of lung disease during the neonatal period.

Deadspace estimation from CO2 versus molar mass measurements in infants.

BACKGROUND: Estimation of respiratory deadspace is often based on the CO2 expirogram, however presence of the CO2 sensor increases equipment deadspace, which in turn influences breathing pattern and calculation of lung volume. In addition, it is necessary to correct for the delay between the sensor and flow signals. We propose a new method for estimation of effective deadspace using the molar mass (MM) signal from an ultrasonic flowmeter device, which does not require delay correction. We hypothesize that this estimation is correlated with that calculated from the CO2 signal using the Fowler method. METHODS: Breath-by-breath CO2, MM and flow measurements were made in a group of 77 term-born healthy infants. Fowler deadspace (Vd,Fowler) was calculated after correcting for the flow-dependent delay in the CO2 signal. Deadspace estimated from the MM signal (Vd,MM) was defined as the volume passing through the flowhead between start of expiration and the 10% rise point in MM. RESULTS: Correlation (r = 0.456, P < 0.0001) was found between Vd,MM and Vd,Fowler averaged over all measurements, with a mean difference of -1.4% (95% CI -4.1 to 1.3%). Vd,MM ranged from 6.6 to 11.4 ml between subjects, while Vd,Fowler ranged from 5.9 to 12.0 ml. Mean intra-measurement CV over 5-10 breaths was 7.8 +/- 5.6% for Vd,MM and 7.8 +/- 3.7% for Vd,Fowler. Mean intra-subject CV was 6.0 +/- 4.5% for Vd,MM and 8.3 +/- 5.9% for Vd,Fowler. Correcting for the CO2 signal delay resulted in a 12% difference (P = 0.022) in Vd,Fowler. Vd,MM could be obtained more frequently than Vd,Fowler in infants with CLD, with a high variability. CONCLUSIONS: Use of the MM signal provides a feasible estimate of Fowler deadspace without introducing additional equipment deadspace. The simple calculation without need for delay correction makes individual adjustment for deadspace in FRC measurements possible. This is especially important given the relative large range of deadspace seen in this homogeneous group of infants.

Longitudinal monitoring of pediatric cystic fibrosis lung disease using nitrite in exhaled breath condensate.

Cystic fibrosis (CF) lung disease is characterized by airway inflammation and airway infection. Nitrites in exhaled breath condensate (EBC-NO(2)(-)) have been shown to be increased in children and adults with CF compared to healthy controls suggesting its use as a measure of airway inflammation. This longitudinal study aimed to evaluate if repeated measurements of EBC-NO(2)(-) are helpful in monitoring CF lung disease activity in children. Thirty-two children with mild CF lung disease (age 10.6 +/- 3.3 years) were recruited in two study centers. Follow-up visits occurred every 3 months over a period of 1 year with a total of five visits. Each visit included a clinical assessment incorporating a modified Shwachman-Kulczycki (SK) score, spirometry, an oropharyngeal swab, or sputum sample for bacterial analysis and an EBC sample analyzed for NO(2)(-) using a spectrophotometric assay. Furthermore at the first and the last visit a chest radiograph was done and scored (Chrispin-Norman (CN) score). There was no correlation of EBC-NO(2)(-) and parameters of spirometry, SK-score, or CN-score. Furthermore, increased EBC-NO(2)(-) levels did not predict subsequent pulmonary exacerbations. We conclude that repeated measurements of EBC-NO(2)(-) are not helpful in the longitudinal monitoring of mild CF lung disease in children.

Beta-interferon and multiple sclerosis.

Interferon-beta (IFN-beta) is the first therapeutic intervention shown to alter the natural history of multiple sclerosis (MS), a relapsing then progressive inflammatory degenerative disease of the CNS. Since publication of the first randomized placebo-controlled trial of IFN-beta, and subsequent acquisition of US and European product licences for use in relapsing-remitting MS, the hopes and expectations of patients have been elevated greatly only to be dampened as more critical analysis of the trial results, in conjunction with the cost of treatment, led to marked limitations on prescription in several countries. IFN-beta is not a cure. Here we review what is known about the mechanisms of action of IFN-beta in demyelinating disease, and propose a possible model of action of IFN-beta in the treatment of MS.

Lung function in African infants: a pilot study.

BACKGROUND: The burden of childhood respiratory illness is large in low and middle income countries (LMICs). Infant lung function (ILF) testing may provide useful information about lung growth and susceptibility to respiratory disease. However, ILF has not been widely available in LMICs settings where the greatest burden of childhood respiratory disease occurs. AIM: To implement and evaluate a pilot study of ILF testing in a semi-rural setting in South Africa. METHOD: Infant lung function testing was established at a community hospital in South Africa. All measures were done in unsedated infants during sleep. Measurements, made with the infant quietly breathing through a face mask and bacterial filter, included tidal breathing (TBFVL), exhaled nitric oxide (eNO), and sulphur hexafluoride multiple breath washout (MBW) measures using an ultrasonic flow meter and chemoluminescent NO analyzer. RESULTS: Twenty infants, mean age of 7.7 (SD 2.9) weeks were tested; 8 (40%) were Black African and 12 (60%) were mixed race. Five (25%) infants were preterm. There were 19 (95%) successful TBFVL and NO tests and 18 (90%) successful MBW tests. The mean tidal volume was 30.5 ml (SD 5.9), respiratory rate 50.2 breaths per minute (SD 8.7), and eNO 10.4 ppb (SD 7.3). The mean MBW measures were: functional residual capacity 71 ml (SD 13) and the lung clearance index 7.6 (SD 0.5). The intra-subject coefficient of variations (CV) of lung function measures were similar to published normative data for Caucasian European infants. CONCLUSION: In this study we demonstrate that unsedated infant lung function measures of tidal breathing, MBW, and eNO are feasible in a semi-rural African setting with rates comparable to those reported from high income countries.

Recall antigen presentation by gamma-interferon-activated microglia results in T cell activation and propagation of the immune response.

The interaction between microglia and T cells is important in the development of central nervous system inflammation. This may result in full T cell activation, a partial state of activation, anergy or apoptosis of the 'responding' T cell. Here, we demonstrate that neonatal rodent microglia not only fail to initiate a mixed lymphocyte reaction (MLR), but suppress background T cell proliferation. Even after activation with gamma-IFN or following phagocytosis, microglia remain unable to support a MLR. By contrast, gamma-IFN-activated microglia are able to activate memory T cells in a recall assay resulting in cytokine (gamma-IFN) release and modest T cell proliferation. Although the stimulation index is small, functional relevance is demonstrated. Supernatants from the recall assay stimulate gamma-IFN-dependent activation of a STAT (signal transducer and activator of transcription) factor within resting microglia. This demonstrates that memory T cells not only receive sufficient stimulation from the gamma-IFN-activated microglia to proliferate and produce cytokines, but that there is also a reciprocal stimulation of resting microglia. Importantly, this provides evidence that activated microglia have the potential to propagate immune responses in the central nervous system, but are unlikely to initiate a primary response.

beta-Interferon regulates the immunomodulatory activity of neonatal rodent microglia.

beta-interferon (beta-IFN) has both pro and anti-inflammatory properties, the balance of which leads to some suppression of disease activity in multiple sclerosis patients. Here, we examine the immunomodulation of neonatal rodent microglia, the principal CNS accessory cell, by beta-IFN and consider the interaction of beta-IFN and gamma-interferon (gamma-IFN). beta-IFN and gamma-IFN inhibit microglial proliferation. beta-IFN antagonises both gamma-IFN-induced upregulation of class II expression and the ability of gamma-IFN primed cells to mount a respiratory burst. In contrast, beta-IFN upregulates microglial Fc receptor expression and augments tumour necrosis factor alpha secretion from suboptimally stimulated microglia.

Repeated measurements of airway and parenchymal mechanics in rats by using low-frequency oscillations.

For studies investigating the mechanisms underlying the development of allergic conditions such as asthma, noninvasive methodologies for separating airway and parenchymal mechanics in animal models are required. To develop such a method, seven Brown Norway rats were studied on three occasions over a 14-day period. After the baseline measurements, on the third day inhaled methacholine was administered. Once lung function returned to the baseline level, a thoracotomy was performed to compare the lung mechanics in the intact- and open-chest conditions. On each occasion, the rats were anesthetized, paralyzed, and intubated. Small-amplitude oscillations between 0.5 and 21 Hz were applied through a wave tube to obtain respiratory impedance (Zrs). Esophageal pressure was measured to separate Zrs into pulmonary (ZL) and chest wall (Zw) components. A model containing a frequency-independent resistance and inertance and a tissue component, including tissue damping and elastance, was fitted to Zrs, ZL, and Zw spectra. Measurements of Zrs, ZL, or Zw and the model parameters calculated from them did not differ among tests. The number of animals required to show group changes in lung mechanics was significantly lower when animals were measured noninvasively than when the group changes were calculated from open-chest measurements. In conclusion, the method reported in this study can be used to separate airway and lung tissue mechanics noninvasively over a series of tests and can detect pulmonary constrictor responses for the airways and the parenchyma separately.