Airway Tone Research Articles

Can short-term heart rate variability be used to monitor fentanyl-midazolam induced changes in ANS preceding respiratory depression?

Opioids have an occasional but high-risk side effect of respiratory depression. The detection of critical respiratory depression usually occurs after the event. Earlier detection would be beneficial in preventing increased morbidity and mortality of 0.01 % patients receiving analgesic opioids. Airway patency during inspiration requires vagal modulation. Regulation of the cardiovascular and respiratory centres may be coupled with a central mechanism that is indirectly measurable with heart rate variability (HRV). While opioids tend to increase parasympathetic tone, a decrease in airway stability could be due to a decrease in respiratory parasympathetic activity. Sympathetic arousal generated by apneic events may separately be recognised with short-term HRV. This pilot observational study examined the dynamic sympathovagal changes during fentanyl-midazolam induced respiratory depression on 10 subjects scheduled for minor surgery. A selection of HRV indices, able to work over sub-minute periods on non-stationary signals, were applied including a range of less common indices. Three analyses tested the effects: post-fentanyl, preceding the first central depression, and preceding obstruction of the upper airway. Statistical significance was assessed with overlap of bootstrap percentile confidence intervals for the median. A decrease in total variability, Lomb Total using the Lomb-Scargle method, is a positive finding for short-term HRV use in this study. No significant change before critical respiratory events was observed in traditional, spectral power, respiratory or other indices. One index, PolVar20, indicated a burst of sympathetic activity preceding respiratory depression similar to sleep apnoea arousals that restore airway patency. Before its usefulness in early detection of airway tone can be determined, PolVar20 requires further work: a statistical method for highly skewed distributions, auto adjustment for baseline variability, and detecting a range of sympathetic responses to apnea.

Eczema and race as combined determinants for differential response to step-up asthma therapy

Eczema and race as combined determinants for differential response to step-up asthma therapy

P87 Role of hydrogen sulfide as an oxygen sensor in human airways

Previous studies have shown that H 2 S can act as an oxygen sensor in the vasculature. To date the role of H 2 S as an oxygen sensor in human airways has not been investigated. The aim of this study was to compare the effects of H 2 S and hypoxia on airway tone in isolated human bronchi. Human bronchial rings were obtained at resection for cancer and mounted in organ baths to measure isometric tension. The effects of H 2 S on resting tension and active tension to methacholine were determined by cumulative addition of NaHS. The effects of hypoxia on resting and active tension were determined by changing the aerating gas to 95% N 2 : 5% CO 2 .The effect of H 2 S synthesis inhibitors, DL-Propargylglycine (PPG) and Hydroxylamine (HA), on the effect of hypoxia was investigated. NaHS caused a dose dependent (0.1–1 mM) relaxation of human bronchi ( n = 14) from resting and active tension. Hypoxia also caused a relaxation from resting and active tension and the magnitude of relaxation to hypoxia was comparable to the maximum relaxation to NaHS. PPG ( n = 3) and HA ( n = 4) had no effect on the hypoxic relaxation. It has been shown for the first time that H 2 S causes a dose dependent relaxation of human bronchi. Similarities in the effect of H 2 S and hypoxia suggest that H 2 S could act as an O 2 sensor in human airways. However, H 2 S synthesis inhibitors did not inhibit the effects of hypoxia and the role of H 2 S as an O 2 sensor is in need of further investigation.

The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease

Muscarinic receptor antagonists and β-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and β-adrenoceptors are physiological antagonists for smooth muscle tone in airways and bladder. Muscarinic agonism may attenuate β-adrenoceptor-mediated relaxation more than other contractile stimuli. Chronic treatment with one drug class may regulate expression of the target receptor but also that of the opposing receptor. Prejunctional β2-adrenoceptors can enhance neuronal acetylcholine release. Moreover, at least in the airways, muscarinic receptors and β-adrenoceptors are expressed in different locations, indicating that only a combined modulation of both systems may cause dilatation along the entire bronchial tree. While all of these factors contribute to a rationale for a combination of muscarinic receptor antagonists and β-adrenoceptor agonists, the full value of such combination as compared to monotherapy can only be determined in clinical studies.

Before and after radiographs and CBCT scans show an opening of the airway at the base of the tongue which presumably improved airway tone.

Before and after radiographs and CBCT scans show an opening of the airway at the base of the tongue which presumably improved airway tone.

Neurobiologic Mechanisms of Sleep and Wakefulness

Neurobiologic Mechanisms of Sleep and Wakefulness

Does drug-induced emphysema exist?

Pulmonary physicians are well aware of drug-induced acute and chronic pulmonary toxicities; inhaled or systemically administered drugs can affect airway tone and cause cough, dyspnoea due to airspace disease, diffuse alveolar damage, pulmonary capillaritis or interstitial lung fibrosis, to name a few presentations and tissue manifestations. Well-studied drugs that cause pulmonary toxicity include methotrexate [1], bleomycin [2] and amiodarone [3], all of which can cause interstitial lung disease, platinum compounds which can generate pulmonary hypersensitivity reactions [4], or propylthiouracil which can cause anti-neutrophil cytoplasmic antibody positive vasculitis and nonspecific interstitial pneumonitis [5, 6]. Over the years a catalogue of drug-induced pulmonary toxicities has been assembled [7] and, more recently, drug-induced respiratory disease in patients with haematological disorders [8] and toxicity related to the systemic treatment of nonsmall cell lung cancer [9] have been reviewed. In contrast, repeated PubMed research of the literature did not uncover a single clinical report of drug-induced emphysema. This circumstance begs the question whether drugs do not cause toxicities that result in alveolar–capillary cell changes and emphysematous lung parenchyma destruction in humans, or whether drug-induced emphysema is simply not reported. Herein, we attempt to approach this topic with the appropriate caution, beginning with the statement that on theoretical ground, and based on data derived from animal studies, there ought to be drugs that cause emphysema in susceptible patients. It has been acknowledged that not all of the patients that develop emphysema are smokers; the estimate is that ∼15% of emphysema patients are nonsmokers [10]. Yet pathogenetic mechanisms that can explain emphysema in these patients are lacking after rare associations, like anorexia [11], cadmium exposure [12] or playing a wind instrument, have been ruled …

Hydrogen sulphide‐induced relaxation of porcine peripheral bronchioles

Hydrogen sulphide (H2S) is an endogenous gasotransmitter. Although it has been shown to elicit responses in vascular and other smooth muscle preparations, a role for endogenously produced H2S in mediating airway tone has yet to be demonstrated. Therefore, the aim of this study was to determine whether H2S is produced within the airways and to determine the functional effect on airway tone. Small peripheral airways (<5 mm in diameter) from porcine lungs were set up in isolated tissue baths, pre-contracted with the muscarinic agonist carbachol, and then exposed to either the H2S donor sodium hydrosulphide (NaHS), or the precursor L-cysteine. H2S production from L-cysteine or 3-mercaptopyruvate in tissue homogenates was measured by the methylene blue assay. Expression of the H2S-synthesizing enzymes cystathionine β-synthase (CBS), cystathionine γ lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MST) were measured by Western blotting. NaHS caused a large relaxation of the airways, which was inhibited partially by pre-contraction with KCl or exposure to tetraethylammonium, but not glibenclamide, paxilline or 4-aminopyridine. L-cysteine also caused a relaxation of the airways which was inhibited by the CBS inhibitor aminooxyacetic acid. Tissue homogenates from airways exposed to L-cysteine or 3-mercaptopyruvate in vitro showed a significant production of H2S. Western blotting demonstrated immunoreactivity to CBS, CSE and 3-MST enzymes in the airways. These data demonstrate that H2S can be produced endogenously within porcine airways causing relaxation. The mechanism of relaxation depends, in part, on K(+) channel activity.

Pharmacological Characterization of GSK573719 (Umeclidinium): A Novel, Long-Acting, Inhaled Antagonist of the Muscarinic Cholinergic Receptors for Treatment of Pulmonary Diseases

Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 μg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 μg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.

Relationship of Airway Hyperresponsiveness and RGS2 Expression in Smokers

G-protein coupled receptors and their downstream regulators, especially regulator of G-protein signaling -2 (RGS-2), appear to be important in controlling airway tone. We have found that RGS-2 knock-out mice have spontaneous airway hyperresponsiveness (AHR). Human peripheral blood mononuclear cells (PBMC) from asthmatics express less RGS2 and the expression is correlated to the degree of AHR. Since smoking causes AHR we examined whether PBMCs from smokers with AHR also have decreased RGS2 expression.

Are tetraplegic handbikers going to disappear from team relay in para-cycling?

Are tetraplegic handbikers going to disappear from team relay in para-cycling?

Neuronal Modulation of Airway and Vascular Tone and Their Influence on Nonspecific Airways Responsiveness in Asthma

The autonomic nervous system provides both cholinergic and noncholinergic neural inputs to end organs within the airways, which includes the airway and vascular smooth muscle. Heightened responsiveness of the airways to bronchoconstrictive agents is a hallmark feature of reactive airways diseases. The mechanisms underpinning airways hyperreactivity still largely remain unresolved. In this paper we summarize the substantial body of evidence that implicates dysfunction of the autonomic nerves that innervate smooth muscle in the airways and associated vasculature as a prominent cause of airways hyperresponsiveness in asthma.

Future bronchodilator therapy: a bitter pill to swallow?

Maintenance of airway tone, prevention of airway obstruction, and acute relief from bronchospasm are key targets of asthma therapy. This role is currently performed by β-agonists. However, chronic use of β-agonists to treat asthma is associated with desensitization of β-agonist signaling and a resultant loss of bronchodilator effect, worsening of airway hyperreactivity, and increased incidence of asthma-related morbidity and mortality. There have been several attempts to identify novel non-β-agonist bronchodilators including ATP-sensitive potassium channel (K(ATP)) agonists such as cromakalim and its active enantiomer BRL-38227 and the cGMP activators atrial natriuretic peptide (ANP) and BAY 41-22722. However, these either have not made it to clinical trial, required high doses, had little effect in patients, or had a high incidence of side effects. Recent data suggests that a novel bronchodilator target exists, the bitter taste receptor TAS2R. Two recent studies [An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, Panettieri RA Jr, Liggett SB. Am J Physiol Lung Cell Mol Physiol 303: L304-L311, 2012; Pulkkinen V, Manson ML, Säfholm J, Adner M, Dahlén SE. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00205.2012.] provide new understanding of the signaling pathways utilized by TAS2Rs to mediate their bronchodilatory effects and how TAS2R-mediated bronchodilation is affected by β-agonist signaling desensitization. As our understanding of TAS2Rs and their agonists increases, they move closer to a viable therapeutic option; however, further definition is still required and questions remain to be answered. This editorial focus discusses these studies within the context of existing literature and raises questions and challenges for the future development of bitter (better?) therapies for asthma.

Treatment with Gabapentin Associated with Resolution of Apnea in Two Infants with Neurologic Impairment

Infants with neurologic impairment (NI) as a result of injury to the central nervous system have a significant rate of pain. Problems associated with pain in children with NI include increased tone. This secondary hypertonia may contribute to apnea as a result of alterations in airway tone and chest wall movement. Infants are at greatest risk given their smaller airways, lower functional residual capacity, and the high rate of unrecognized pain at this age. We report two cases of infants with NI, identified to have significant improvement in apnea following empiric treatment with gabapentin for presumed central pain and/or visceral hyperalgesia. This correlation between pain and apnea, with resolution in apnea following effective treatment of these presumed sources, has not been previously reported in the literature. Infants with NI and apnea should have careful pain assessment and treatment, when considering other causes and interventions for apnea.

New insights from the measurement of loop gain in obstructive sleep apnoea

One of the purposes of modelling the control of breathing is to improve our understanding of how the system works, so new effective therapies can be developed. Current therapies, e.g. surgery, continuous positive airway pressure (CPAP) and dental devices for obstructive sleep apnoea (OSA), are often uncomfortable and sometimes poorly tolerated. In a recent issue of The Journal of Physiology, Edwards et al. (2012) report the results of an interesting experiment in which they used acetazolamide to reduce the severity of OSA, in a group of 12 volunteers who were known to be compliant users of CPAP therapy. They used the modelling concept of ‘loop gain’ to explain the benefits of acetazolamide. The concept of ‘loop gain’ is used to quantify the internal amplification of a system (Grodins et al. 1967). It is a dimensionless value of the propensity of a system governed by feedback loops to develop unstable behaviour. Respiration is such a system (Strohl et al. 2007). The gain can be influenced by control of variables relating to hypercapnic and hypoxic ventilatory responses (controller gain), or the ability to eliminate CO2 and the size of oxygen stores (plant gain) (Younes 1989). Circulation time has an effect on the interaction between ventilation and controller gain. Upper airway factors (e.g. resistance) have effects on the interaction between controller gain and ventilation (Younes 1989). The presence of sleep reduces controller gain relative to wakefulness, and more importantly upper airway tone, particularly in rapid eye movement sleep (REM) (see Fig. 1). The higher the loop gain, the potentially more unstable the respiratory control system becomes. A high loop gain promotes recurrent apnoeas as a response to an initial disturbances, such as a sigh, because it is over compensated, while a low loop gain dampens subsequent oscillations in breathing. Although the early modelling was done for central sleep apnoea (Cherniack 1981), the principles have more recently also been applied to obstructive sleep apnoea (White 2005). A very simplified diagram of the control of breathing during sleep, showing the relationship between ventilation and the two gains in the feedback system Sleep state has important effects on upper airway tone and the controller output. See Younes (1989) for more detail. In the experiments under discussion, the subjects underwent repeated drops in CPAP pressure during Stage 2 non-REM sleep to induce prolonged hypopnoeas and then the CPAP pressure was returned to normal, which was associated with an overshoot of ventilation. Loop gain was calculated by dividing ‘the response’ (the overshoot in ventilation after CPAP pressure was restored) by ‘the stimulus’ (the difference between ventilation during the induced hypopnoea and the calculated zero ventilation) which the authors used as a surrogate for the physiological stimuli to ventilation, (alterations in blood gas tensions in the brain and carotid bodies, increases in pleural pressure and other factors). The acetazolamide was given 500 mg BID for 1 week without placebo control and the subjects underwent two nights’ study in a sleep laboratory, one night without CPAP and on other they underwent a complicated experiment to measure loop gain. Edwards et al. found an approximate 50% reduction in the apnoea–hypopnoea index (AHI) with acetazolamide therapy compared to control night, and this was associated with an approximate 40% reduction in loop gain. Parameters of upper airway function were not significantly changed. Oral acetazolamide administration typically causes a metabolic acidosis. In these experiments, on the non-CPAP night it caused an increase in resting ventilation due to an increase in tidal volume and a fall in serum bicarbonate and end tidal , with an associated increase in arterial saturation. There was an increase in serum urea and creatinine values to suggest some degree of dehydration, but this is unlikely to be important. The authors state that the acetazolamide acted predominantly via lowering plant gain, because the measured changes in end tidal gas values, saturation and bicarbonate are more likely to represent changes in plant gain than controller gain. Nevertheless, the article provides new insights into the control of breathing in patients with OSA and provides a stimulus for future therapeutic strategies that modify gain rather than the upper airway. Unfortunately acetazolamide in high dosage is poorly tolerated in long term usage. So, some challenges remain: firstly, to confirm their findings with direct assessment of controller gain; subsequently to develop other drugs that are better tolerated, to either complement or replace the sometimes uncomfortable current therapies for OSA.

Reply

Editor, We sincerely thank Xue et al.1 for the careful reading of our article2 and their valuable comments. We recall that the primary purposes of this study were the feasibility of awake fibreoptic intubation and patient tolerability of this type of procedure. On the first point, we fully agree with the reservation of Xue et al. about hydroxyzine premedication which is no longer routinely used in our patients. As for midazolam, it had not seemed appropriate at the time of the study because of its deleterious effects on airway tone and on patients’ memory of the intubation (patients’ tolerability of the procedure was one of the points tested in the study). Because of the high variability of responses among patients and the depressant effect of the drug on the tone of airway muscles, we still reject its use for predicted difficult intubation in awake patients. Regarding the second point, we have also abandoned the routine use of atropine and scopolamine given as antisialagogue agents. However, most of the patients actually suffer from a lack of secretions due to previous cancer treatments (surgery, radiation therapy) and glycopyrrolate is not available for clinical use in France. Administration of atropine or scopolamine is sometimes required to diminish secretions and facilitate intubation. Information on the duration of upper airway preparation would certainly be helpful, but this point did not seem essential to us, as this preparation step can be performed outside the operating room, thereby avoiding delays in the turnover of patients. However, we agree that the quality of airway preparation is essential to the success of the procedure. Finally, we confirm that independent investigators evaluated patients’ perception and recall of the procedure. In total, 84–91% of our patients rated their global perception of awake intubation as good, even when the procedure did not meet all the criteria for success. We believe that this point should be distinguished from anaesthesia awareness, as this occurs when a patient under general anaesthesia becomes aware of events during invasive surgery, but without discomfort or pain. Indeed, patients in our study were fully informed of the procedure and of their potential reactions. They were in constant vocal contact with the operator and provided clear answers to the operator's questions until the end of the intubation and induction of general anaesthesia by propofol. They were fully aware beforehand of the necessity to maintain spontaneous breathing, even if the procedure carried a risk of transient discomfort. Almost all patients were willing to undergo the same procedure in the future if medically indicated.

301 Effect of Ascorbic Acid on Aiway Hyperresponsiveness in Bronchial Asthma

IntroductionAscorbic acid has been reported to have a role in the decrease of airway responsiveness in animal models. This data has been based on the regulation of airway tone and modulation of airway reactivity by ascorbic acid. Human studies show that ascorbic acid has a protective effect against the increase in bronchial responsiveness induced by ozone, and nitrogendioxide. We hypothesized that ascorbic acid may attenuate bronchial hyperresponsiveness in bronchial asthma.MethodsWe studied 15 mild asthma patients and 13 healthy non smoker controls. These patients were measured plasma ascorbic acid levels with 2, 4-DNPH (dinitrophenyhydrazine) method and checked methacholine challenge with Chi method before and 1 hour after ascorbic acid intake (3 gm). To assess chronic effect of ascorbic acid on airway responsiveness, these participants were checked again plasm ascorbic acid and methacholine challenge after daily intake of ascorbic acid (1 gm) for 2 weeks.ResultsThere were no significant differences in plasma ascorbic acid levels in asthma patients and controls. Bronchial hyperresponsiveness was decreased after ascorbic acid intake (3 gm) in asthma patients, but not statistacally significant. This decrease was persisted with daily 1 g of ascorbic acid intake for 2 weeks. PC20FEV1 were not correlated to plasma ascorbic acid levels in asthma patients.ConclusionsIn mild bronchial asthma, Airway hyperresponsiveness may be ameliorated by ascorbic acid supplementations. But further studies are necessary to address the question of the effectiveness of ascorbic acid in bronchial asthma.

563 Measurement of Long-acting Natriuretic Peptide (Lanp) in Exacerbation of Asthma

BackgroundEvidence exists that atrial natriuretic peptide (ANP) is a regulator of smooth muscle airway tone and is a potent bronchodilator and immune modulator in animals. Objective: Long-acting natriuretic peptide (LANP), encoded by the same gene and derived from the same pro-hormone as ANP, was measured in patients with acute asthma exacerbation pre- and post-treatment with systemic or inhaled glucocorticosteroids.MethodsMeasurement of LANP was obtained from plasma samples in 15 subjects with acute asthma exacerbation, by an enzyme immunoassay technique. A repeat measurement of LANP was obtained 5 to 7 and 10 to 14 days after initiation of treatment.ResultsNo significant differences were found compared to baseline in plasma LANP level after treatment of the asthma exacerbation (P = 0.8904). The average LANP values were 2.12 higher in the oral glucocorticosteroid group versus the inhaled glucocorticosteroid group, (P = 0.0608). There was no significant difference in LANP levels between male and females (P = 0.5743), with antibiotic use (P = 0.9437), or with age (P = 0.6384).ConclusionsPlasma LANP level did not differ before and after treatment for an asthma exacerbation. Measuring plasma LANP pro-hormone was not helpful in assessing treatment outcome of asthma exacerbation.

Histamine And Endogenously Produced Spasmogenic Prostaglandins Increase The Strength Of Airway Smooth Muscle

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma and could be due to increased force-generating capacity (strength) of airway smooth muscle (ASM). We have recently shown that increasing ASM-tone with acetylcholine increases muscle strength over time, a process dubbed “force adaptation”. We hypothesize that the increased airway tone observed in asthmatics due to the release of inflammation-derived spasmogens contributes to AHR by fostering force adaptation. Here we sought to determine whether force adaptation occurs in response to: 1) the inflammatory spasmogen histamine; and 2) the intrinsic tone that prevailed in some ovine ASM preparations due to the endogenous production of spasmogenic prostanglandins.

Anesthetic Management of Myasthenia Gravis: COPD and Asthma Patient

Abstract Introduction Conduction of general anesthesia and perioperative management of the patients with compromised lung functions and myasthenia gravis, presented for major abdominal surgery, pos...