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Biomedical subjects

Atul Malhotra

Publications and source records attributed to Atul Malhotra.

At least 19 recordsLinked to original sources

Genioglossus premotoneurons and the negative pressure reflex in rats.

Reflex increases in genioglossus (GG) muscle activity in response to negative pharyngeal pressure are important for maintenance of upper airway patency in humans. However, little is known of the central circuitry that mediates this negative pressure reflex (NPR). We used two approaches to determine which GG premotoneurons relay negative pressure-related information to the hypoglossal motor nucleus. First, to identify GG premotoneurons, we injected pseudorabies virus (PRV152) into the GG muscle. We found that medullary GG premotoneurons were concentrated mainly in the reticular formation adjacent to the hypoglossal motor nucleus. Second, in order to determine whether these perihypoglossal neurons were involved in the NPR, we quantified GG EMG responses to negative pressure applied to the isolated upper airway in anaesthetized rats before and after microinjection of muscimol (9 nl; 0.25 mM), a GABA-A receptor agonist, into the perihypoglossal premotor field. Pressures as low as -4 cm H(2)O increased inspiratory phase-related GG activity. The NPR was abolished following bilateral injections of muscimol into the perihypoglossal premotor field at and up to 500 mum rostral to the obex. Muscimol in this location also increased the amplitude of basal, unstimulated phasic GG activity. By contrast, inhibition of neurons caudal to the obex decreased phasic GG activity but had no impact on the NPR. These results suggest that perihypoglossal GG premotoneurons near the obex mediate the NPR and those caudal to the obex are important mediators of respiratory-related GG activity but are not involved in the NPR.

Animals↗

Association between reduced sleep and weight gain in women.

Physiologic studies suggest that sleep restriction has metabolic effects that predispose to weight gain. The authors investigated the association between self-reported usual sleep duration and subsequent weight gain in the Nurses' Health Study. The 68,183 women who reported habitual sleep duration in 1986 were followed for 16 years. In analyses adjusted for age and body mass index, women sleeping 5 hours or less gained 1.14 kg (95% confidence interval (CI): 0.49, 1.79) more than did those sleeping 7 hours over 16 years, and women sleeping 6 hours gained 0.71 kg (95% CI: 0.41, 1.00) more. The relative risks of a 15-kg weight gain were 1.32 (95% CI: 1.19, 1.47) and 1.12 (95% CI: 1.06, 1.19) for those sleeping 5 and 6 hours, respectively. The relative risks for incident obesity (body mass index: >30 kg/m(2)) were 1.15 (95% CI: 1.04, 1.26) and 1.06 (95% CI: 1.01, 1.11). These associations remained significant after inclusion of important covariates and were not affected by adjustment for physical activity or dietary consumption. These data suggest that short sleep duration is associated with a modest increase in future weight gain and incident obesity. Further research is needed to understand the mechanisms by which sleep duration may affect weight.

Adult↗

Follow-up assessment of CPAP efficacy in patients with obstructive sleep apnea using an ambulatory device based on peripheral arterial tonometry.

This study aimed to assess the accuracy of a wrist-worn device based on peripheral arterial tonometry (Watch_PAT 100) to detect residual episodes of respiratory disturbance during continuous positive airway pressure (CPAP) therapy. Concurrent polysomnography was used as the reference standard to identify sleep disordered breathing (SDB) events. The study was conducted in three sleep laboratories affiliated with tertiary care academic medical centers. Seventy patients using CPAP to treat obstructive sleep apnea for at least 3 months, following an in-laboratory titration to determine the optimal therapeutic positive airway pressure, participated in this study. Symptoms indicating suboptimal therapy were not required for participation, but self-reported adherence to CPAP therapy was necessary for inclusion. Interventions are not applicable in this study. The accuracy of the PAT-derived respiratory disturbance index (PAT RDI scored by automated algorithm) to detect residual SDB on CPAP was assessed against polysomnography (PSG) using Bland-Altman analysis, receiver-operator characteristic (ROC) curves, and likelihood ratios for increasing (LR+) and decreasing (LR-) the probability of moderate-severe SDB in the study population. Respiratory events on the PSG were quantified using standard criteria for research investigations ("Chicago criteria") to yield a PSG RDI.C. Based on the PSG results, 19% of the participants had moderate-severe SDB (PSG RDI.C>15 events per hour) on their prescribed pressure. For PAT RDI >15 events per hour, the area under the ROC curve was 0.95 (SE 0.03, p < 0.0001, 95% CI 0.89 to 1.00), the LR+ was 8.04 (95% CI 3.64-17.7), and the LR- was 0.17 (95% CI 0.05-0.62). The mean difference between the PAT RDI and PSG RDI.C was three (2SD 14.5) events per hour. Therefore, residual moderate-severe SDB on CPAP was not uncommon in a multicenter population self-reporting adherence to CPAP therapy to treat obstructive sleep apnea. The Watch_PAT device accurately identified participants with moderate-severe SDB while using CPAP in the attended setting of a sleep laboratory.

Adult↗

Mechanical ventilation and air leaks after lung biopsy for acute respiratory distress syndrome.

BACKGROUND: Open lung biopsy in acute respiratory distress syndrome (ARDS) may provide a specific etiology and change clinical management, yet concerns about complications remain. Persistent air leak is the most common postoperative complication. Risk factors in this setting are not known. METHODS: We performed a retrospective analysis of 53 patients who underwent open lung biopsy for clinical ARDS (based on American European Consensus Conference criteria) between 1989 and 2000. RESULTS: Sixteen patients (30.2%) developed an air leak lasting more than 7 days or died with an air leak. Univariate analyses showed no significant correlation with age, gender, sex, corticosteroid use, diabetes, immunocompromised status, or pathologic diagnosis. A lower risk of air leak was associated with lower peak airway pressure and tidal volume, use of pressure-cycled ventilation, and use of an endoscopic stapling device. In multivariate analyses, only peak airway pressure remained a significant predictor. The risk of prolonged air leak was reduced by 42% (95% confidence interval [CI: 17% to 60%]) for every 5 cm H2O reduction in peak airway pressure. CONCLUSIONS: The use of a lung-protective ventilatory strategy that limits peak airway pressures is strongly associated with a reduced risk of postoperative air leak after open lung biopsy in ARDS. Using such a strategy may allow physicians to obtain information from open lung biopsy to make therapeutic decisions without undue harm to ARDS patients.

Adult↗

Genioglossal muscle response to CO2 stimulation during NREM sleep.

STUDY OBJECTIVES: The objective was to evaluate the responsiveness of upper airway muscles to hypercapnia with and without intrapharyngeal negative pressure during non-rapid eye movement (NREM) sleep and wakefulness. DESIGN: We assessed the genioglossal muscle response to CO2 off and on continuous positive airway pressure (CPAP) (to attenuate negative pressure) during stable NREM sleep and wakefulness in the supine position. SETTING: Laboratory of the Sleep Medicine Division, Brigham and Women's Hospital. PATIENTS OR PARTICIPANTS: Eleven normal healthy subjects. INTERVENTIONS: During wakefulness and NREM sleep, we measured genioglossal electromyography (EMG) on and off CPAP at the normal eupneic level and at levels 5 and 10 mm Hg above the awake eupneic level. MEASUREMENTS AND RESULTS: We observed that CO2 could increase upper-airway muscle activity during NREM sleep and wakefulness in the supine position with and without intrapharyngeal negative pressure. The application of nasal CPAP significantly decreased genioglossal EMG at all 3 levels of PETCO2 during NREM sleep (13.0 +/- 4.9% vs. 4.6 +/- 1.6% of maximal EMG, 14.6 +/- 5.6% vs. 7.1 +/- 2.3% of maximal EMG, and 17.3 +/- 6.3% vs. 10.2 +/- 3.1% of maximal EMG, respectively). However, the absence of negative pressure in the upper airway did not significantly affect the slope of the pharyngeal airway dilator muscle response to hypercapnia during NREM sleep (0.72 +/- 0.30% vs. 0.79 +/- 0.27% of maximal EMG per mm Hg PCO2, respectively, off and on CPAP). CONCLUSIONS: We conclude that both chemoreceptive and negative pressure reflex inputs to this upper airway dilator muscle are still active during stable NREM sleep.

Adult↗

Correlates of long sleep duration.

STUDY OBJECTIVE: Sleeping more than 7 to 8 hours per day has been consistently associated with increased mortality. Whether this association is causal and what pathways explain this association are unknown. We sought to identify factors that could potentially explain the association between long sleep and mortality. DESIGN: Cross-sectional epidemiologic survey. PARTICIPANTS: Middle-aged women (n = 60,028) participating in the Nurses Health Study II who reported a habitual sleep duration of 7 hours or more. RESULTS: Multiple sclerosis (odds ratio [OR] = 3.7, 95% confidence interval [3.0-4.5]), antidepressant use (OR = 3.1, [2.9-3.3]), benzodiazepine use (OR = 3.0 [2.6-3.3]), and systemic lupus erythematosus (OR = 2.9, [2.3-3.6]) were the factors most strongly associated with prolonged sleep. Combining these data with prevalence information and a range of plausible associations with mortality, the confounding rate ratio was estimated. This parameter is the ratio of the unadjusted long sleep-mortality rate ratio to the rate ratio adjusted for the factor and measures the extent that the factor can alter the long sleep-mortality association, either through confounding or as a causal intermediate. Based on this parameter, psychiatric and socioeconomic factors have the greatest potential to influence the long sleep-mortality relationship. Assuming each factor doubles mortality risk, the confounding rate ratios for depression, antidepressant use, and unemployment were 1.10, 1.18, and 1.12. Lesser influential factors were benzodiazepine use, poverty, low societal status, sedentary lifestyle, and obesity. CONCLUSION: Depression and low socioeconomic status are strong candidates for producing the statistical association between long sleep and mortality, either as confounders or as causal intermediates. Future causal research on the effects of long sleep should include a detailed assessment of psychiatric disease and socioeconomic status.

Antidepressive Agents↗

Esophageal and transpulmonary pressures in acute respiratory failure.

OBJECTIVE: Pressure inflating the lung during mechanical ventilation is the difference between pressure applied at the airway opening (Pao) and pleural pressure (Ppl). Depending on the chest wall's contribution to respiratory mechanics, a given positive end-expiratory and/or end-inspiratory plateau pressure may be appropriate for one patient but inadequate or potentially injurious for another. Thus, failure to account for chest wall mechanics may affect results in clinical trials of mechanical ventilation strategies in acute respiratory distress syndrome. By measuring esophageal pressure (Pes), we sought to characterize influence of the chest wall on Ppl and transpulmonary pressure (PL) in patients with acute respiratory failure. DESIGN: Prospective observational study. SETTING: Medical and surgical intensive care units at Beth Israel Deaconess Medical Center. PATIENTS: Seventy patients with acute respiratory failure. INTERVENTIONS: Placement of esophageal balloon-catheters. MEASUREMENTS AND MAIN RESULTS: Airway, esophageal, and gastric pressures recorded at end-exhalation and end-inflation Pes averaged 17.5 +/- 5.7 cm H2O at end-expiration and 21.2 +/- 7.7 cm H2O at end-inflation and were not significantly correlated with body mass index or chest wall elastance. Estimated PL was 1.5 +/- 6.3 cm H2O at end-expiration, 21.4 +/- 9.3 cm H2O at end-inflation, and 18.4 +/- 10.2 cm H2O (n = 40) during an end-inspiratory hold (plateau). Although PL at end-expiration was significantly correlated with positive end-expiratory pressure (p < .0001), only 24% of the variance in PL was explained by Pao (R = .243), and 52% was due to variation in Pes. CONCLUSIONS: In patients in acute respiratory failure, elevated esophageal pressures suggest that chest wall mechanical properties often contribute substantially and unpredictably to total respiratory impedance, and therefore Pao may not adequately predict PL or lung distention. Systematic use of esophageal manometry has the potential to improve ventilator management in acute respiratory failure by providing more direct assessment of lung distending pressure.

Analysis of Variance↗

Lung biopsy in ARDS: is it worth the risk?

Progress in the treatment of acute respiratory distress syndrome(ARDS) has been slow, perhaps in part due to the heterogeneity in the biology underlying this syndrome. Open lung biopsy is a feasible approach to define various subcategories of underlying histology. In experienced hands, with careful selection of patients and close attention to details of critical care management,including mechanical ventilator settings, the procedure is safe even in patients with severe disease. However, further work is needed to define which patients, if any, experience a beneficial effect on outcome from this procedure. More research is needed on assessing efficacy of potential therapies within histologically defined subgroups. In the future, various biomarkers may be available to non-invasively classify ARDS patients from the standpoint of responsiveness to various therapies, such as glucocorticoids.

Biopsy↗

The impact of endotracheal suctioning on gas exchange and hemodynamics during lung-protective ventilation in acute respiratory distress syndrome.

OBJECTIVE: To evaluate the respiratory and hemodynamic effects of open suctioning (OS) versus closed suctioning (CS) during pressure-control (PC) and volume-control (VC) ventilation, using a lung-protective ventilation strategy in an animal model of acute respiratory distress syndrome (ARDS). SETTING: Animal laboratory in a university hospital. DESIGN: Randomized cross-over evaluation. ANIMALS: Eight female Dorset sheep. INTERVENTIONS: Lung lavage was used to simulate ARDS. We applied VC and PC mechanical ventilation with a tidal volume of 6 mL/kg and positive end-expiratory pressure (PEEP), adjusted based on a table of PEEP versus fraction of inspired oxygen (FIO2). Suctioning was performed for 10 s with a suction pressure of -100 mm Hg, during both OS and CS. OS and CS were randomly performed with each animal. Hemodynamics and arterial blood gases were recorded before, during, and after endotracheal suctioning. RESULTS: The PaO2/FIO2 ratios before suctioning were similar in all groups, as were the PEEP and FIO2. PaO2/FIO2 was lower after OS than after CS/VC or CS/PC. There was no post-suctioning difference in oxygenation between CS/VC and CS/PC. PaCO2 recorded 10 min after suctioning was greater than the presuctioning value, in all groups. Intrapulmonary shunt fraction increased between baseline and 10 min post-suctioning with OS and CS/VC, but did not significantly increase with CS/PC. There were no significant changes in hemodynamics pre-suctioning versus post-suctioning with OS, CS/VC, or CS/PC. CONCLUSION: PaO2/FIO2) was better maintained during CS with both VC and PC modes during lung-protective ventilation for ARDS, as compared with OS, and shunt fraction post-suctioning changed least with PC.

Animals↗

Profile of neonates admitted in pediatric ICU and validation of Score for Neonatal Acute Physiology (SNAP).

A retrospective study was conducted in the Pediatric Intensive Care Unit (PICU) of a tertiary care hospital in northern India to profile neonatal admissions and to assess the validity of the Score for Neonatal Acute Physiology (SNAP) in predicting the outcome in terms of mortality and length of hospital stay (LOS). Neonatal sepsis (51%) and birth asphyxia (11.2%) were the commonest indications for admission. Thirty-seven (38.1%) of the neonates died. The mean SNAP score in babies who died was 18.8 +/- 9.8 and 10.1 +/- 6.4 in survivors (P<0.001). There was no correlation between SNAP score and mean length of stay in hospital (P=0.5). We conclude that SNAP correlates well with mortality in neonates admitted to the PICU.

Hospital Mortality↗

Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is two to three times more common in men as in women. The mechanisms leading to this difference are currently unclear but could include gender differences in respiratory stability [loop gain (LG)] or upper airway collapsibility [pharyngeal critical closing pressure (Pcrit)]. The aim of this study was to compare LG and Pcrit between men and women with OSA to determine whether the factors contributing to apnea are similar between genders. The first group of 11 men and 11 women were matched for OSA severity (mean +/- SE apnea-hypopnea index = 43.8 +/- 6.1 and 44.1 +/- 6.6 events/h). The second group of 12 men and 12 women were matched for body mass index (BMI; 31.6 +/- 1.9 and 31.3 +/- 1.8 kg/m2, respectively). All measurements were made during stable supine non-rapid eye movement sleep. LG was determined using a proportional assist ventilator. Pcrit was measured by progressively dropping the continuous positive airway pressure level for three to five breaths until airway collapse. Apnea-hypopnea index-matched women had a higher BMI than men (38.0 +/- 2.4 vs. 30.0 +/- 1.9 kg/m2; P = 0.03), but LG and Pcrit were similar between men and women (LG: 0.37 +/- 0.02 and 0.37 +/- 0.02, respectively, P = 0.92; Pcrit: 0.35 +/- 0.62 and -0.18 +/- 0.87, respectively, P = 0.63). In the BMI-matched subgroup, women had less severe OSA during non-rapid eye movement sleep (30.9 +/- 7.4 vs. 52.5 +/- 8.1 events/h; P = 0.04) and lower Pcrit (-2.01 +/- 0.62 vs. 1.16 +/- 0.83 cmH2O; P = 0.005). However, LG was not significantly different between genders (0.38 +/- 0.02 vs. 0.33 +/- 0.03; P = 0.14). These results suggest that women may be protected from developing OSA by having a less collapsible upper airway for any given degree of obesity.

Adult↗

Computational simulation of human upper airway collapse using a pressure-/state-dependent model of genioglossal muscle contraction under laminar flow conditions.

A three-element, pressure- and state (sleep and wake) -dependent contraction model of the genioglossal muscle was developed based on the microstructure of skeletal muscle and the cross-bridge theory. This model establishes a direct connection between the contractile forces generated in muscle fibers and the measured electromyogram signals during various upper airway conditions. This effectively avoids the difficulty of determining muscle shortening velocity during complex pharyngeal conditions when modeling the muscle's contractile behaviors. The activation of the genioglossal muscle under different conditions was then simulated. A sensitivity analysis was performed to determine the effects of varying each modeled parameter on the muscle's contractile behaviors. This muscle contraction model was then incorporated into our anatomically correct, two-dimensional computational model of the pharyngeal airway to perform a finite-element analysis of air flow, tissue deformation, and airway collapse. The model-predicted muscle deformations are consistent with previous observations regarding upper airway behavior in normal subjects.

Airway Obstruction↗

Lung volume and continuous positive airway pressure requirements in obstructive sleep apnea.

Previous studies have demonstrated that lung volume during wakefulness influences upper airway size and resistance, particularly in patients with sleep apnea. We sought to determine the influence of lung volume on the level of continuous positive airway pressure (CPAP) required to prevent flow limitation during non-REM sleep in subjects with sleep apnea. Seventeen subjects (apnea-hypopnea index, 42.6 +/- 6.2 [SEM]) were studied during stable non-REM sleep in a rigid head-out shell equipped with a positive/negative pressure attachment for manipulation of extrathoracic pressure. An epiglottic pressure catheter plus a mask/pneumotachometer were used to assess flow limitation. When lung volume was increased by 1,035 +/- 22 ml, the CPAP level could be decreased from 11.9 +/- 0.7 to 4.8 +/- 0.7 cm H(2)O (p < 0.001) without flow limitation. The decreased CPAP at the same negative extrathoracic pressure yielded a final lung volume increase of 421 +/- 36 ml above the initial value. Conversely, when lung volume was reduced by 732 +/- 74 ml (n = 8), the CPAP level had to be increased from 11.9 +/- 0.7 to 17.1 +/- 1.0 cm H(2)O (p < 0.001) to prevent flow limitation, with a final lung volume decrease of 567 +/- 78 ml. These results demonstrate that relatively small changes in lung volume have an important effect on the upper airway in subjects with sleep apnea during non-REM sleep.

Adult↗

The effect of sleep onset on upper airway muscle activity in patients with sleep apnoea versus controls.

Pharyngeal dilator muscles are important in the pathophysiology of obstructive sleep apnoea syndrome (OSA). We have previously shown that during wakefulness, the activity of both the genioglossus (GGEMG) and tensor palatini (TPEMG) is greater in patients with OSA compared with controls. Further, EMG activity decreases at sleep onset, and the decrement is greater in apnoea patients than in healthy controls. In addition, it is known that the prevalence of OSA is greater in middle-aged compared with younger men. Thus, we had two goals in this study. First we compared upper airway muscle activity between young and middle-aged healthy men compared with men with OSA. We also explored the mechanisms responsible for the decrement in muscle activity at sleep onset in these groups. We investigated muscle activity, ventilation , and upper airway resistance (UAR) during wakefulness and sleep onset (transition from alpha to EEG activity) in all three groups. Measurements were obtained during basal breathing (BB) and nasal continuous positive airway pressure (CPAP) was applied to reduce negative pressure-mediated muscle activation). We found that during wakefulness there was a gradation of GGEMG and UAR (younger < older < OSA) and that muscle activity was reduced by the application of nasal CPAP (to a greater degree in the OSA patients). Although CPAP eliminated differences in UAR during wakefulness and sleep, GGEMG remained greater in the OSA patients. During sleep onset, a greater initial fall in GGEMG was seen in the OSA patients followed by subsequent muscle recruitment in the third to fifth breaths following the alpha to transition. On the CPAP night, and GGEMG still fell further in the OSA patients compared with control subjects. CPAP prevented the rise in UAR at sleep onset along with the associated recruitment in GGEMG. Differences in TPEMG among the groups were not significant. These data suggest that the middle-aged men had upper airway function midway between that of young normal men and the abnormal airway of those with OSA. Furthermore it suggests that the initial sleep onset reduction in upper airway muscle activity is due to loss of a 'wakefulness' stimulus, rather than to loss of responsiveness to negative pressure, and that this wakefulness stimulus may be greater in the OSA patient than in healthy controls.

Adolescent↗

Disorders of sleep: an overview.

Only recently has the medical profession focused on the importance of sleep and health. There are increasing numbers of studies linking sleep disorders with neurobehavioral and cardiovascular morbidity and possibly mortality. Although sleep disorders are diverse and affect a substantial number of patients, they are often misdiagnosed or underdiagnosed. Common presenting symptoms to physicians include hypersomnia and insomnia. A systematic workup helps to diagnose the underlying cause.

Cardiovascular Diseases↗