Cardiovascular risk and mortality in end-stage renal disease patients undergoing dialysis: sleep study, pulmonary function, respiratory mechanics, upper airway collapsibility, autonomic nervous activity, depression, anxiety, stress and quality of life: a prospective, double blind, randomized controlled clinical trial

Background: Chronic kidney disease (CKD) is one of the most serious public health problems. The increasing prevalence of CKD in developed and developing countries has led to a global epidemic. The hypothesis proposed is that patients undergoing dialysis would experience a marked negative influence on physiological variables of sleep and autonomic nervous system activity, compromising quality of life.Methods/Design: A prospective, consecutive, double blind, randomized controlled clinical trial is proposed to address the effect of dialysis on sleep, pulmonary function, respiratory mechanics, upper airway collapsibility, autonomic nervous activity, depression, anxiety, stress and quality of life in patients with CKD. The measurement protocol will include body weight (kg); height (cm); body mass index calculated as weight/height(2); circumferences (cm) of the neck, waist, and hip; heart and respiratory rates; blood pressures; Mallampati index; tonsil index; heart rate variability; maximum ventilatory pressures; negative expiratory pressure test, and polysomnography (sleep study), as well as the administration of specific questionnaires addressing sleep apnea, excessive daytime sleepiness, depression, anxiety, stress, and quality of life.Discussion: CKD is a major public health problem worldwide, and its incidence has increased in part by the increased life expectancy and increasing number of cases of diabetes mellitus and hypertension. Sleep disorders are common in patients with renal insufficiency. Our hypothesis is that the weather weight gain due to volume overload observed during interdialytic period will influence the degree of collapsibility of the upper airway due to narrowing and predispose to upper airway occlusion during sleep, and to investigate the negative influences of haemodialysis in the physiological variables of sleep, and autonomic nervous system, and respiratory mechanics and thereby compromise the quality of life of patients.

Ivabradine: Just another New Pharmacological Option for Heart Rate Control?

Ivabradine (IVB) is a heart rate lowering agent that acts via selective inhibition of the pacemaker funny current in sinoatrial nodal P cells, thus, reducing heart rate at rest and during exercise with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction. IVB exerts no effect on external respiratory function parameters and it may also play a role in patients with concurrent chronic obstructive pulmonary disease. This property constitutes an important advantage over β-blockers. IVB acts by reducing the heart rate in a mechanism different from β-blockers, calcium channel blockers or late sodium channel blockers, three commonly prescribed antianginal drugs. As clinical trials have shown, it is remarkably well-tolerated and offers an alternative for patients who cannot take β-blockers. The combination of IVB and atenolol at commonly used doses in patients with chronic stable angina produced additional efficacy with no untoward effect on safety or tolerability. Additionally, side effects are rare and largely limited to a luminous phenomenon or phosphenes. This sensation is thought to be due to a block of Ih in the retina, a current very similar to cardiac If channels. IVB is contraindicated in patients with sick sinus syndrome or sinus node dysfunction and in patients taking hepatic inhibitors of Cytochrome P450 family 3, subfamily A, polypeptide 4 (abbreviated CYP3A4), with exception of omeprazole or lansoprazole. This review briefly summarizes the main studies regarding this drug.

Chronic obstructive pulmonary disease and heart rate variability: a literature update

Background: The literature indicates that chronic obstructive pulmonary disease (COPD) affects cardiac autonomic control. In this study, we conducted a literature review in order to investigate the heart rate variability (HRV) in COPD subjects. Methods: A search was performed in Medline database, using the link between the keywords: “autonomic nervous system”, “cardiovascular system”, “COPD” and “heart rate variability”. Results: The search resulted in a total of 40 references. Amongst these references, the first exclusion resulted in the barring of 29 titles and abstracts, which were not clearly related to the purpose of review. This resulted in a total of 11 articles that were then read and utilized in the review. The selected studies indicated that there is significant reduction of HRV in patients with COPD, characterized by reduction of indices that assess parasympathetic activity in addition to dealing with the global autonomic modulation. We also established that supervised exercise can reduce these harmful effects in COPD patients. Also, it was reported that the use of non-invasive ventilation in these patients may contribute to the improvement of respiratory symptoms, with no impairing, and may even induce positive responses in cardiac autonomic regulation. Conclusion: The studies indicate a need for further investigations to guide future therapies to improve the treatment of cardiovascular system in the respiratory diseases.

Age and gender influence the cardiorespiratory function and metabolic rate of broiler chicks during normocapnia and hypercapnia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities

It is well known that breathing introduces rhythmical oscillations in the heart rate and arterial pressure levels. Sympathetic oscillations coupled to the respiratory activity have been suggested as an important homeostatic mechanism optimizing tissue perfusion and blood gas uptake/delivery. This respiratory-sympathetic coupling is strengthened in conditions of blood gas challenges (hypoxia and hypercapnia) as a result of the synchronized activation of brainstem respiratory and sympathetic neurons, culminating with the emergence of entrained cardiovascular and respiratory reflex responses. Studies have proposed that the ventrolateral region of the medulla oblongata is a major site of synaptic interaction between respiratory and sympathetic neurons. However, other brainstem regions also play a relevant role in the patterning of respiratory and sympathetic motor outputs. Recent findings suggest that the neurons of the nucleus of the solitary tract (NTS), in the dorsal medulla, are essential for the processing and coordination of respiratory and sympathetic responses to hypoxia. The NTS is the first synaptic station of the cardiorespiratory afferent inputs, including peripheral chemoreceptors, baroreceptors and pulmonary stretch receptors. The synaptic profile of the NTS neurons receiving the excitatory drive from afferent inputs is complex and involves distinct neurotransmitters, including glutamate, ATP and acetylcholine. In the present review we discuss the role of the NTS circuitry in coordinating sympathetic and respiratory reflex responses. We also analyze the neuroplasticity of NTS neurons and their contribution for the development of cardiorespiratory dysfunctions, as observed in neurogenic hypertension, obstructive sleep apnea and metabolic disorders.

Maternal protein restriction increases respiratory and sympathetic activities and sensitizes peripheral chemoreflex in male rat offspring

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Comparison between noninvasive mechanical ventilation and standard oxygen therapy in children up to 3 years old with respiratory failure after extubation: a pilot prospective randomized clinical study

Objectives: The effectiveness of noninvasive positive-pressure ventilation in preventing reintubation due to respiratory failure in children remains uncertain. A pilot study was designed to evaluate the frequency of extubation failure, develop a randomization approach, and analyze the feasibility of a powered randomized trial to compare noninvasive positive-pressure ventilation and standard oxygen therapy post extubation for preventing reintubation within 48 hours in children with respiratory failure.Design: Prospective pilot study.Setting: PICU at a university-affiliated hospital.Patients: Children aged between 28 days and 3 years undergoing invasive mechanical ventilation for greater than or equal to 48 hours with respiratory failure after programmed extubation.Interventions: Patients were prospectively enrolled and randomly assigned into noninvasive positive-pressure ventilation group and inhaled oxygen group after programmed extubation from May 2012 to May 2013.Measurements and Main Results: Length of stay in PICU and hospital, oxygenation index, blood gas before and after tracheal extubation, failure and reason for tracheal extubation, complications, mechanical ventilation variables before tracheal extubation, arterial blood gas, and respiratory and heart rates before and 1 hour after tracheal extubation were analyzed. One hundred eight patients were included (noninvasive positive-pressure ventilation group, n = 55 and inhaled oxygen group, n = 53), with 66 exclusions. Groups did not significantly differ for gender, age, disease severity, Pediatric Risk of Mortality at admission, tracheal intubation, and mechanical ventilation indications. There was no statistically significant difference in reintubation rate (noninvasive positive-pressure ventilation group, 9.1%; inhaled oxygen group, 11.3%; p > 0.05) and length of stay (days) in PICU (noninvasive positive-pressure ventilation group, 3 [116]; inhaled oxygen group, 2 [1-25]; p > 0.05) or hospital (noninvasive positive-pressure ventilation group, 19 [7-141]; inhaled oxygen group, 17 [8-80]).Conclusions: The study indicates that a larger randomized trial comparing noninvasive positive-pressure ventilation and standard oxygen therapy in children with respiratory failure is feasible, providing a basis for a future trial in this setting. No differences were seen between groups. The number of excluded patients was high.

Coupling of respiratory and sympathetic activities in rats submitted to chronic intermittent hypoxia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Can geometric indices of heart rate variability predict improvement in autonomic modulation after resistance training in chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is associated with autonomic dysfunctions that can be evaluated through heart rate variability (HRV). Resistance training promotes improvement in autonomic modulation; however, studies that evaluate this scenario using geometric indices, which include nonlinear evaluation, thus providing more accurate information for physiological interpretation of HRV, are unknown. This study aimed to investigate the influence of resistance training on autonomic modulation, using geometric indices of HRV, and peripheral muscle strength in individuals with COPD. Fourteen volunteers with COPD were submitted to resistance training consisting of 24 sessions lasting 60 min each, with a frequency of three times a week. The intensity was determined as 60% of one maximum repetition and was progressively increased until 80% for the upper and lower limbs. The HRV and dynamometry were performed at two moments, the beginning and the end of the experimental protocol. Significant increases were observed in the RRtri (4·81 ± 1·60 versus 6·55 ± 2·69, P = 0·033), TINN (65·36 ± 35·49 versus 101·07 ± 63·34, P = 0·028), SD1 (7·48 ± 3·17 versus 11·04 ± 6·45, P = 0·038) and SD2 (22·30 ± 8·56 versus 32·92 ± 18·78, P = 0·022) indices after the resistance training. Visual analysis of the Poincare plot demonstrated greater dispersion beat-to-beat and in the long-term interval between consecutive heart beats. Regarding muscle strength, there was a significant increase in the shoulder abduction and knee flexion. In conclusion, geometric indices of HRV can predict improvement in autonomic modulation after resistance training in individuals with COPD; improvement in peripheral muscle strength in patients with COPD was also observed.

Ventilator-induced lung injury and acute respiratory distress syndrome: a basic science review

Acute respiratory distress syndrome is the most severe manifestation of acute lung injury and it is associated with high mortality rate. Despite better understanding of ARDS pathophysiology, its mechanism is still unclear. Mechanical ventilation is the main ARDS supportive treatment. However, mechanical ventilation is a non-physiologic process and complications are associated with its application. Mechanical ventilation may induce lung injury, referred to as ventilator-induced lung injury. Frequently, VILI is related to macroscopic injuries associated with alveolar rupture. The present article is a review of the literature on ventilator-induced lung injury in acute respiratory distress syndrome. Animal and human studies were reviewed. We mainly selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications.

KCNQ Channels Determine Serotonergic Modulation of Ventral Surface Chemoreceptors and Respiratory Drive

Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to CO2/H+ changes. Their activity is also sensitive to neuromodulatory inputs from multiple respiratory centers, and thus they serve as a key nexus of respiratory control. However, molecular mechanisms that control their activity and susceptibility to neuromodulation are unknown. Here, we show in vitro and in vivo that KCNQ channels are critical determinants of RTN neural activity. In particular, we find that pharmacological block of KCNQ channels (XE991, 10 mu M) increased basal activity and CO2 responsiveness of RTN neurons in rat brain slices, whereas KCNQ channel activation (retigabine, 2-40 mu M) silenced these neurons. Interestingly, we also find that KCNQ and apamin-sensitive SK channels act synergistically to regulate firing rate of RTN chemoreceptors; simultaneous blockade of both channels led to a increase in CO2 responsiveness. Furthermore, we also show that KCNQ channels but not SK channels are downstream effectors of serotonin modulation of RTN activity in vitro. In contrast, inhibition of KCNQ channel did not prevent modulation of RTN activity by Substance P or thyrotropin-releasing hormone, previously identified neuromodulators of RTN chemoreception. Importantly, we also show that KCNQ channels are critical for RTN activity in vivo. Inhibition of KCNQ channels lowered the CO2 threshold for phrenic nerve discharge in anesthetized rats and decreased the ventilatory response to serotonin in awake and anesthetized animals. Given that serotonergic dysfunction may contribute to respiratory failure, our findings suggest KCNQ channels as a new therapeutic avenue for respiratory complications associated with multiple neurological disorders.

High Rates of Detection of Respiratory Viruses in Tonsillar Tissues from Children with Chronic Adenotonsillar Disease

Chronic tonsillar diseases are an important health problem, leading to large numbers of surgical procedures worldwide. Little is known about pathogenesis of these diseases. In order to investigate the role of respiratory viruses in chronic adenotonsillar diseases, we developed a cross-sectional study to determine the rates of viral detections of common respiratory viruses detected by TaqMan real time PCR (qPCR) in nasopharyngeal secretions, tonsillar tissues and peripheral blood from 121 children with chronic tonsillar diseases, without symptoms of acute respiratory infections. At least one respiratory virus was detected in 97.5% of patients. The viral co-infection rate was 69.5%. The most frequently detected viruses were human adenovirus in 47.1%, human enterovirus in 40.5%, human rhinovirus in 38%, human bocavirus in 29.8%, human metapneumovirus in 17.4% and human respiratory syncytial virus in 15.7%. Results of qPCR varied widely between sample sites: human adenovirus, human bocavirus and human enterovirus were predominantly detected in tissues, while human rhinovirus was more frequently detected in secretions. Rates of virus detection were remarkably high in tonsil tissues: over 85% in adenoids and close to 70% in palatine tonsils. In addition, overall virus detection rates were higher in more hypertrophic than in smaller adenoids (p = 0.05), and in the particular case of human enteroviruses, they were detected more frequently (p = 0.05) in larger palatine tonsils than in smaller ones. While persistence/latency of DNA viruses in tonsillar tissues has been documented, such is not the case of RNA viruses. Respiratory viruses are highly prevalent in adenoids and palatine tonsils of patients with chronic tonsillar diseases, and persistence of these viruses in tonsils may stimulate chronic inflammation and play a role in the pathogenesis of these diseases.

Improvement in ARDS experimental model installation: Low mortality rate and maintenance of hemodynamic stability

Introduction: Many experimental models using lung lavage have been developed for the study of acute respiratory distress syndrome (ARDS). The original technique has been modified by many authors, resulting in difficulties with reproducibility. There is insufficient detail on the lung injury models used, including hemodynamic stability during animal preparation and drawbacks encountered such as mortality. The authors studied the effects of the pulmonary recruitment and the use of fixed tidal volume (Vt) or fixed inspiratory pressure in the experimental ARDS model installation. Methods: Adult rabbits were submitted to repeated lung lavages with 30 ml/kg warm saline until the ARDS definition (PaO2/FiO(2) <= 100) was reached. The animals were divided into three groups, according to the technique used for mechanical ventilation: 1) fixed Vt of 10 ml/kg; 2) fixed inspiratory pressure (IP) with a tidal volume of 10 ml/kg prior to the first lung lavage; and 3) fixed Vt of 10 ml/kg with pulmonary recruitment before the first lavage. Results: The use of alveolar recruitment maneuvers, and the use of a fixed Vt or IP between the lung lavages did not change the number of lung lavages necessary to obtain the experimental model of ARDS or the hemodynamic stability of the animals during the procedure. A trend was observed toward an increased mortality rate with the recruitment maneuver and with the use of a fixed IP. Discussion: There were no differences between the three study groups, with no disadvantage in method of lung recruitment, either fixed tidal volume or fixed inspiratory pressure, regarding the number of lung lavages necessary to obtain the ARDS animal model. Furthermore, the three different procedures resulted in good hemodynamic stability of the animals, and low mortality rate. (C) 2012 Elsevier Inc. All rights reserved.

Age-Related Maximum Heart Rate Among Ischemic and Nonischemic Heart Failure Patients Receiving beta-Blockade Therapy

Background: Equations to predict maximum heart rate (HRmax) in heart failure (HF) patients receiving beta-adrenergic blocking (BB) agents do not consider the cause of HF. We determined equations to predict HRmax in patients with ischemic and nonischemic HF receiving BB therapy. Methods and Results: Using treadmill cardiopulmonary exercise testing, we studied HF patients receiving BB therapy being considered for transplantation from 1999 to 2010. Exclusions were pacemaker and/or implantable defibrillator, left ventricle ejection fraction (LVEF) >50%, peak respiratory exchange ratio (RER) <1.00, and Chagas disease. We used linear regression equations to predict HRmax based on age in ischemic and nonischemic patients. We analyzed 278 patients, aged 47 +/- 10 years, with ischemic (n = 75) and nonischemic (n = 203) HF. LVEF was 30.8 +/- 9.4% and 28.6 +/- 8.2% (P = .04), peak VO2 16.9 +/- 4.7 and 16.9 +/- 5.2 mL kg(-1) min(-1) (P = NS), and the HRmax 130.8 +/- 23.3 and 125.3 +/- 25.3 beats/min (P = .051) in ischemic and nonischemic patients, respectively. We devised the equation HRmax = 168 - 0.76 x age (R-2 = 0.095; P = .007) for ischemic HF patients, but there was no significant relationship between age and HRmax in nonischemic HF patients (R-2 = 0.006; P = NS). Conclusions: Our study suggests that equations to estimate HRmax should consider the cause of HF. (J Cardiac Fail 2012;18:831-836)

Severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors

Abstract Background Lower respiratory tract infection (LRTI) is a major cause of pediatric morbidity and mortality, especially among non-affluent communities. In this study we determine the impact of respiratory viruses and how viral co-detections/infections can affect clinical LRTI severity in children in a hospital setting. Methods Patients younger than 3 years of age admitted to a tertiary hospital in Brazil during the months of high prevalence of respiratory viruses had samples collected from nasopharyngeal aspiration. These samples were tested for 13 different respiratory viruses through real-time PCR (rt-PCR). Patients were followed during hospitalization, and clinical data and population characteristics were collected during that period and at discharge to evaluate severity markers, especially length of hospital stay and oxygen use. Univariate regression analyses identified potential risk factors and multivariate logistic regressions were used to determine the impact of specific viral detections as well as viral co-detections in relation to clinical outcomes. Results We analyzed 260 episodes of LRTI with a viral detection rate of 85% (n = 222). Co-detection was observed in 65% of all virus-positive episodes. The most prevalent virus was Respiratory Syncytial Virus (RSV) (54%), followed by Human Metapneumovirus (hMPV) (32%) and Human Rhinovirus (HRV) (21%). In the multivariate models, infants with co-detection of HRV + RSV stayed 4.5 extra days (p = 0.004), when compared to infants without the co-detection. The same trends were observed for the outcome of days of supplemental oxygen use. Conclusions Although RSV remains as the main cause of LRTI in infants our study indicates an increase in the length of hospital stay and oxygen use in infants with HRV detected by RT-PCR compared to those without HRV. Moreover, one can speculate that when HRV is detected simultaneously with RSV there is an additive effect that may be reflected in more severe clinical outcome. Also, our study identified a significant number of children infected by recently identified viruses, such as hMPV and Human Bocavirus (HBov), and this is a novel finding for poor communities from developing countries.