Caregiver willingness to give TPT to children living with drug-resistant TB patients.

BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) are at high risk of infection and active disease. Evidence of caregiver willingness to give MDR-TB preventive therapy (TPT) to children is limited.METHODS This was a cross-sectional study of HHCs of patients with MDR-TB to assess caregiver willingness to give TPT to children aged <13 years.RESULTS Of 743 adult and adolescent HHCs, 299 reported caring for children aged <13 years of age. The median caregiver age was 35 years (IQR 27-48); 75% were women. Among caregivers, 89% were willing to give children MDR TPT. In unadjusted analyses, increased willingness was associated with TB-related knowledge (OR 5.1, 95% CI 2.3-11.3), belief that one can die of MDR-TB (OR 5.2, 95% CI 1.2-23.4), concern for MDR-TB transmission to child (OR 4.5, 95% CI 1.6-12.4), confidence in properly taking TPT (OR 4.5, 95% CI 1.6-12.6), comfort telling family about TPT (OR 5.5, 95% CI 2.1-14.3), and willingness to take TPT oneself (OR 35.1, 95% CI 11.0-112.8).CONCLUSIONS A high percentage of caregivers living with MDR- or rifampicin-resistant TB patients were willing to give children a hypothetical MDR TPT. These results provide important evidence for the potential uptake of effective MDR TPT when implemented.

Directional Recording of Subthalamic Spectral Power Densities in Parkinson's Disease and the Effect of Steering Deep Brain Stimulation.

BACKGROUND: A new 32-contacts deep brain stimulation (DBS) lead, capable of directionally steering stimulation, was tested intraoperatively. OBJECTIVE: The aim of this pilot study was to perform recordings from the multidirectional contacts and to investigate the effect of directional current steering on the local field potentials (LFPs). METHODS: In eight patients with Parkinson's disease, after standard microelectrode recording and clinical testing, the new lead was temporarily implanted. The 32-channel LFP recordings were measured simultaneously at different depths and directions before and after directional stimulation. RESULTS: The spatial distribution of LFPs power spectral densities across the contact array at baseline marked the borders of the subthalamic nucleus (STN) with a significant increase in beta power and with a mean accuracy of approximately 0.6 mm in four patients.The power in the 18.5-30 Hz frequency band varied across different directions in all patients. In the three cases that showed improvement of rigidity, this was higher when current was steered toward the direction with the highest LFP power in the beta band. Subthalamic LFPs in six patients showed a differential frequency-dependent suppression/enhancement of the oscillatory activity in the 10-45 Hz frequency band after four different 'steering' modes as compared to ring mode, suggesting a higher specificity. CONCLUSIONS: Through a new 32-contact DBS lead it is possible to record simultaneous subthalamic LFPs at different depths and directions, providing confirmation of adequate lead placement and multidirectional spatial-temporal information potentially related to pathological subthalamic electrical activity and to the effect of stimulation. Although further research is needed, this may improve the efficiency of steering stimulation.

Functional neuronal activity and connectivity within the subthalamic nucleus in Parkinson's disease.

OBJECTIVE: Characterization of the functional neuronal activity and connectivity within the subthalamic nucleus (STN) in patients with Parkinson's disease (PD). METHODS: Single units were extracted from micro-electrode recording (MER) of 18 PD patients who underwent STN deep brain stimulation (DBS) surgery. The firing rate and pattern of simultaneously recorded spike trains and their coherence were analyzed. To provide a precise functional assignment of position to the observed activities, for each patient we mapped its classified multichannel STN MERs to a generic atlas representation with a sensorimotor part and a remaining part. RESULTS: Within the sensorimotor part we found significantly higher mean firing rate (P < 0.05) and significantly more burst-like activity (P < 0.05) than within the remaining part. The proportion of significant coherence in the beta band (13-30 Hz) is significantly higher in the sensorimotor part of the STN than elsewhere (P = 0.015). CONCLUSIONS: The STN sensorimotor part distinguishes itself from the remaining part with respect to beta coherence, firing rate and burst-like activity and postoperatively was found as the preferred target area. SIGNIFICANCE: Our firing behavior analysis may help to discriminate the STN sensorimotor part for the placement of the DBS electrode.

From Parkinsonian thalamic activity to restoring thalamic relay using deep brain stimulation: new insights from computational modeling.

We present a computational model of a thalamocortical relay neuron for exploring basal ganglia thalamocortical loop behavior in relation to Parkinson's disease and deep brain stimulation (DBS). Previous microelectrode, single-unit recording studies demonstrated that oscillatory interaction within and between basal ganglia nuclei is very often accompanied by synchronization at Parkinsonian rest tremor frequencies (3-10 Hz). These oscillations have a profound influence on thalamic projections and impair the thalamic relaying of cortical input by generating rebound action potentials. Our model describes convergent inhibitory input received from basal ganglia by the thalamocortical cells based on characteristics of normal activity, and/or low-frequency oscillations (activity associated with Parkinson's disease). In addition to simulated input, we also used microelectrode recordings as inputs for the model. In the resting state, and without additional sensorimotor input, pathological rebound activity is generated for even mild Parkinsonian input. We have found a specific stimulation window of amplitudes and frequencies for periodic input, which corresponds to high-frequency DBS, and which also suppresses rebound activity for mild and even more prominent Parkinsonian input. When low-frequency pathological rebound activity disables the thalamocortical cell's ability to relay excitatory cortical input, a stimulation signal with parameter settings corresponding to our stimulation window can restore the thalamocortical cell's relay functionality.

The pedunculopontine nucleus as an additional target for deep brain stimulation.

The pedunculopontine nucleus has been suggested as a target for DBS. In this paper we propose a single compartment computational model for a PPN Type I cell and compare its dynamic behavior with experimental data. The model shows bursts after a period of hyperpolarization and spontaneous firing at 8 Hz. Bifurcation analysis of the single PPN cell shows bistability of fast and slow spiking solutions for a range of applied currents. A network model for STN, GPe and GPi produces basal ganglia output that is used as input for the PPN cell. The conductances for projections from the STN and the GPi to the PPN are determined from experimental data. The resulting behavior of the PPN cell is studied under normal and Parkinsonian conditions of the basal ganglia network. The effect of high frequency stimulation of the STN is considered as well as the effect of combined high frequency stimulation of the STN and the PPN at various frequencies. The relay properties of the PPN cell demonstrate that the combined high frequency stimulation of STN and low frequency (10 Hz, 25 Hz, 40 Hz) stimulation of PPN hardly improves the effect of exclusive STN stimulation. Moreover, PPN-DBS at low stimulation amplitude has a better effect than at higher stimulation amplitude. The effect of PPN output on the basal ganglia is investigated, in particular the effect of STN-DBS and/or PPN-DBS on the pathological firing pattern of STN and GPe cells. PPN-DBS eliminates the pathological firing pattern of STN and GPe cells, whereas STN-DBS and combined STN-DBS and PPN-DBS eliminate the pathological firing pattern only from STN cells.

Effect of expiratory resistance on gas-exchange and breathing pattern in chronic obstructive pulmonary disease (COPD) patients being weaned from the ventilator.

BACKGROUND: The majority of patients with severe chronic obstructive pulmonary disease (COPD) have flow limitation, which has deleterious side effects. If these patients are mechanically ventilated, this often results in difficult weaning. Spontaneously breathing COPD patients experience a beneficial effect of pursed lip breathing. We investigated whether in intubated COPD patients application of an external resistance could produce the same beneficial effects on breathing pattern and gas-exchange as pursed lip breathing. METHODS: Ten COPD patients with flow limitation were studied during pressure support mechanical ventilation. Two types of expiratory resistances were applied: one fixed level of resistance and one with a resistive pressure decay. Each resistance was applied in 5 patients and the highest level was chosen that did not cause hyperinflation. Blood gas values and breathing pattern with and without resistance were compared. RESULTS: With resistance 1, gas-exchange and breathing pattern did not change significantly; average PCO2 changed from 8.0 to 8.1 kPa, PO2 from 10.2 to 10.3 kPa, tidal volume from 0.380 to 0.420 l, respiratory rate from 25 to 23 bpm and inspiratory:expiratory ratio from 1:1.9 to 1:2.0. With resistance 2, gas-exchange and breathing pattern did not change significantly; average PCO2 changed from 5.8 to 6.0 kPa, PO2 from 11.1 to 12.1 kPa, tidal volume from 0.733 to 0.695 l, respiratory rate from 16 to 18 bpm and inspiratory:expiratory ratio from 1:2.3 to 1:2.9. CONCLUSION: In intubated COPD patients being weaned from the ventilator, application of an external resistance did not have the same beneficial effects as pursed lip breathing.

Detection of flow limitation in mechanically ventilated patients.

OBJECTIVE: In mechanically ventilated patients flow limitation often goes unrecognised. We compared three methods for detection of flow limitation in mechanically ventilated patients: the resistance method, the negative expiratory pressure (NEP) method, and the interrupter method. DESIGN: Prospective study. SETTING: A medical intensive care unit in a university hospital. PATIENTS: Twenty-six patients (20 COPD, six other pathology), mechanically ventilated under sedation. MEASUREMENTS AND RESULTS: Respiratory mechanics were obtained during application of the three methods. For the resistance method, flow limitation was expressed as percentage of expiratory tidal volume, in which flow did not decrease (FLP-R). For the NEP method, flow limitation was expressed as percentage of expiratory tidal volume in which flow did not increase (FLP-NEP). For the interrupter method, flow limitation was expressed as area of spike-overshoot in flow after interruption. In 18 COPD patients, flow limitation was detected by all methods; mean FLP-R 76% (SD 12%), mean FLP-NEP 90% (SD 11%), mean spike area 21 ml (SD 7 ml). In three patients with other pathology, these values were, respectively, 20% (SD 19%), 48% (SD 21%), and 5 ml (SD 4 ml). The three methods were in close agreement. In nine patients the resistance method increased flow and in six patients the NEP method decreased flow compared to the unimpeded breath. CONCLUSIONS: In mechanically ventilated patients, flow limitation can well be detected by the resistance-, NEP-, and interrupter methods. However, the NEP method can overestimate the flow limited portion, while the resistance method can underestimate the flow limited portion. The interrupter method is found to be less practical.

Effect of series of resistance levels on flow limitation in mechanically ventilated COPD patients.

In severe chronic obstructive pulmonary disease (COPD) lung emptying is disturbed by airways compression and expiratory flow limitation. Application of an external resistance has been suggested to counteract airways compression and improve lung emptying. We studied the effect of various resistance levels on lung emptying in mechanically ventilated COPD patients. In 18 patients an adjustable resistor was applied. The effect on airways compression was assessed by iso-volume pressure--flow curves (IVPF) and by interrupter measurements. Respiratory mechanics during unimpeded expirations were correlated to the results obtained with the resistances. The resistances caused an increase in iso-volume flow at the IVPF-curves in six patients, indicating that airways compression was counteracted. Interrupter measurements showed that overshoots in flow (as measure of flow limitation) were significantly reduced by the resistor. These effects could be predicted on basis of respiratory mechanics during unimpeded expiration. In conclusion, mechanically ventilated COPD patients can be identified in whom application of external resistances counteracts airways compression and reduces flow limitation.

Estimation of respiratory parameters via fuzzy clustering.

The results of monitoring respiratory parameters estimated from flow-pressure-volume measurements can be used to assess patients' pulmonary condition, to detect poor patient-ventilator interaction and consequently to optimize the ventilator settings. A new method is proposed to obtain detailed information about respiratory parameters without interfering with the expiration. By means of fuzzy clustering, the available data set is partitioned into fuzzy subsets that can be well approximated by linear regression models locally. Parameters of these models are then estimated by least-squares techniques. By analyzing the dependence of these local parameters on the location of the model in the flow-volume-pressure space, information on patients' pulmonary condition can be gained. The effectiveness of the proposed approaches is demonstrated by analyzing the dependence of the expiratory time constant on the volume in patients with chronic obstructive pulmonary disease (COPD) and patients without COPD.

Expiratory time constants in mechanically ventilated patients with and without COPD.

OBJECTIVE: In mechanically ventilated patients, the expiratory time constant provides information about the respiratory mechanics and the actual time needed for complete expiration. As an easy method to determine the time constant, the ratio of exhaled tidal volume to peak expiratory flow has been proposed. This assumes a single compartment model for the whole expiration. Since the latter has to be questioned in patients with chronic obstructive pulmonary disease (COPD), we compared time constants calculated from various parts of expiration and related these to time constants assessed with the interrupter method. DESIGN: Prospective study. SETTING: A medical intensive care unit in a university hospital. PATIENTS: Thirty-eight patients (18 severe COPD, eight mild COPD, 12 other pathologies) were studied during mechanical ventilation under sedation and paralysis. MEASUREMENTS AND RESULTS: Time constants determined from flow-volume curves at 100%, the last 75, 50, and 25% of expired tidal volume, were compared to time constants obtained from interrupter measurements. Furthermore, the time constants were related to the actual time needed for complete expiration and to the patient's pulmonary condition. The time constant determined from the last 75% of the expiratory flow-volume curve (RCfv75) was in closest agreement with the time constant obtained from the interrupter measurement, gave an accurate estimation of the actual time needed for complete expiration, and was discriminative for the severity of COPD. CONCLUSIONS: In mechanically ventilated patients with and without COPD, a time constant can well be calculated from the expiratory flow-volume curve for the last 75% of tidal volume, gives a good estimation of respiratory mechanics, and is easy to obtain at the bedside.

Flow-volume curves as measurement of respiratory mechanics during ventilatory support: the effect of the exhalation valve.

OBJECTIVE: To assess the feasibility of expiratory flow-volume curves as a measurement of respiratory mechanics during ventilatory support: to what extent is the shape of the curve affected by the exhalation valve of the ventilator? DESIGN: Prospective, comparative study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: 28 consecutive patients with various conditions, mechanically ventilated with both the Siemens Servo 900C and 300 ventilators, were studied under sedation and paralysis. INTERVENTIONS: The ventilator circuit was intermittently disconnected from the ventilator at end-inspiration in order to obtain flow-volume curves with and without the exhalation valve in place. MEASUREMENTS AND RESULTS: Peak flow (PEF) and the slope of the flow-volume curve during the last 50 % of expired volume (SF50) were obtained both with and without the exhalation valve in place. The exhalation valve caused a significant reduction in peak flow of 0.3 l/s (from 1.27 to 0.97 l/s) with the Siemens Servo 900 C ventilator and of 0.42 l/s (from 1.36 to 0.94 l/s) with the Siemens Servo 300 ventilator (p < 0.001). The SF50 was not affected. CONCLUSION: In mechanically ventilated patients, the exhalation valve causes a significant reduction in peak flow, but does not affect the SF50. This study further suggests that the second part of the expiratory flow-volume curve can be used to estimate patients' respiratory mechanics during ventilatory support.

Agreement between spirometry and tracheal auscultation in assessing bronchial responsiveness in asthmatic children.

We have recently found that changes in lung sounds correspond well with a 20% fall in the forced expiratory volume in 1 s (FEV1) after methacholine challenge in asthmatic children. Up to now, little was known about the agreement between a 20% fall in FEV1 and a change in lung sounds after repeated bronchial challenge. In this study we investigated the agreement between the total cumulative histamine dose causing a fall in FEV1 of 20% or more (PD20) and the detection of a change in lung sounds (PDlung sounds) after two bronchial challenges on different occasions in asthmatic children. Fifteen asthmatic children (nine boys), mean age 10.8 years (range 9-15), were studied. All performed two histamine challenge tests on 2 days, with a 24 h to 1 week interval. Lung sounds were recorded over the trachea for 1 min and stored on tape. Lung sounds were analysed directly and also scored from the tape-recording by a blinded second investigator. Wheeze, cough, and an increase in respiratory rate were assessed. The relationship between PD20 and PDlung sounds was calculated by Bland and Altman's measurement of agreement. Eleven children had a positive challenge test (PD20 < or = 16.0 mg ml-1) on both test days; four had a positive challenge on one test day. In 24 out of 26 positive challenges, wheeze, cough, prolonged expiration and/or increased respiratory rate were detected one dose-step before, or at the dose-step of histamine that induced a fall in FEV1 of 20% or more. In two challenges, PD20 was not detected by a change in lung sounds. In four out of four negative challenges (PD20 > 16.0 mg ml-1) no change in lung sounds could be detected. Good agreement between the logarithm of PD20 and the logarithm of PDlung sounds was found on both test days. The mean difference was 0.04 and the limits of agreement (d +/- 2 SD of the differences) were 0.04 +/- 0.41. A good agreement was found between the total cumulative histamine dose causing a fall in FEV1 of 20% or more and the detection of a change in lung sounds after two bronchial challenges on different occasions in asthmatic children.

Expiratory flow-volume curves in mechanically ventilated patients with chronic obstructive pulmonary disease.

BACKGROUND: Forced expiratory flow-volume curves are commonly used to assess the degree of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). In mechanically ventilated subjects, expiratory airways obstruction can only be estimated from relaxed expirations. The aim of this study was to quantify the degree of airways obstruction from relaxed expiratory flow-volume curves in mechanically ventilated patients with COPD. METHODS: As measure of airflow obstruction, the effective time constant during the last 50% of expired volume (tau) was calculated. For bedside monitoring, tau was recalculated as the slope of the flow during the last 50% of expired volume (SF50). In order to study reproducibility, the variables were calculated from consecutive breaths and at different levels of end-expiratory lung volume (EEV). The SF50 and the tau-were correlated with the forced expiratory volume in 1 s (FEV1) measured prior to the start of ventilatory support. RESULTS: Twenty-seven patients were studied with a FEV1 expressed as percentage predicted of 31 +/- 12% (mean +/- SD). The SF50 amounted to 19 +/- 10 degrees. A positive linear correlation was established between SF50 and the FEV1, (%pred), (r = 0.90, P < 0.0001). The tau showed an exponential relationship with FEV1 (%pred), (r2 = 0.78). From 5 consecutive breaths the mean variation coefficient of SF50 was 5 +/- 2%. Changes of delta EEV from 0.05 to 1.00 L did not affect the SF50-values. In 12 patients, mechanically ventilated for respiratory diseases other than COPD, mean tau and SF50 were significantly different from the COPD-patients (P < 0.0001). CONCLUSIONS: This study indicates that relaxed expiratory flow-volume curves can be used to assess airflow obstruction in mechanically ventilated patients with COPD. This information can be used to adapt ventilatory settings.

Respiratory muscle activity in the assessment of bronchial responsiveness in asthmatic children.

We investigated whether an increase in transcutaneous electromyographic (EMG) activity of the diaphragm and intercostal muscles corresponds with the concentration of histamine that induces a 20% fall in the forced expiratory volume in one second (FEV1; PC20). Eleven asthmatic children (mean age 11.9 yr) were studied after they were given histamine challenge. EMG activity at PC20 or at the highest histamine concentration was compared with activity at baseline by calculating the ratio of the mean peak-to-peak excursion at the highest histamine dose to that at baseline [EMG activity ratio (EMGAR)]. In all children reaching PC20, an increase in diaphragmatic and intercostal EMGAR was observed. No increase was found at the dose step before PC20 was reached. In six challenges, no fall in FEV1 was induced, and no increase in EMGAR was seen. In two challenges, no fall in FEV1 was induced, but increase in diaphragmatic or intercostal EMGAR was observed. Increase in the electrical activity of the diaphragm and intercostal muscles in asthmatic children corresponds closely to a 20% fall in FEV1 induced by histamine challenge.

Use of tracheal auscultation for the assessment of bronchial responsiveness in asthmatic children.

BACKGROUND: It can be difficult to assess bronchial responsiveness in children because of their inability to perform spirometric tests reliably. In bronchial challenges lung sounds could be used to detect the required 20% fall in the forced expiratory volume in one second (FEV1). A study was undertaken to determine whether a change in lung sounds corresponded with a 20% fall in FEV1 after methacholine challenge, and whether the occurrence of wheeze was the most important change. METHODS: Fifteen children with asthma (eight boys) of mean age 10.8 years (range 8-15) were studied. All had normal chest auscultation before the methacholine challenge test. Lung sounds were recorded over the trachea for one minute and stored on tape. They were analysed directly and also scored blindly from the tape recording by a second investigator. Wheeze, cough, increase in respiratory rate, and prolonged expiration were assessed. RESULTS: The total cumulative methacholine dose causing a fall in FEV1 of 20% or more (PD20) was detected in 12 children by a change in lung sounds - in four by wheeze and in eight by cough, increased respiratory rate, and/or prolonged expiration. In two subjects altered lung sounds were detectable one dose step before PD20 was reached. In three cases in whom no fall in FEV1 occurred, no change in lung sounds could be detected at the highest methacholine dose. CONCLUSION: Changes in lung sounds correspond well with a 20% fall in FEV1 after methacholine challenge. Wheeze is an insensitive indicator for assessing bronchial responsiveness. Cough, increase in respiratory rate, and prolonged expiration occurs more frequently.

Overberg Research Projects. XI. First stage larval reduction test to assess anthelmintic efficacy ante mortem in sheep.

Two field trials, one with suckling Merino ewe lambs and the other with yearling Dohne Merino rams, are described. In these the anthelmintic efficacy of febantel (a benzimidazole), ivermectin, levamisole and morantel are compared, using the 1st stage larval reduction test. The mean natural log (+1 for zero values) of the post treatment larval counts of the treated groups was compared with that of the untreated controls and the percentage reduction used to assess anthelmintic efficacy. Febantel was only 87.4% effective against Teladorsagia in suckling lambs but the other anthelmintics were more than 99% effective against this genus. Efficacy against Haemonchus and Trichostrongylus ranged from 93.2%-100% for all 4 compounds. In the rams all compounds were 100% effective against Trichostrongylus, with the exception of morantel which was only 87.5% effective. None of the compounds were effective against Teladorsagia, particularly morantel, animals treated with which having more larvae than the controls. The interpretation of anthelmintic efficacy; the advantages of the first stage larval reduction test, compared with the faecal egg count reduction test; and the importance of incubating cultures at 30 degrees C for 24 h, in order to harvest first stage larvae, are discussed.