Comparison of Intravenous Lignocaine and Esmolol in Attenuating Hemodynamic Response and Cough Reflex during Extubation in Hypertensive Patients under General Anaesthesia

Tracheal extubation carries higher complication rates compared to intubation during general anaesthesia (GA). Thus, various drugs are used to attenuate hemodynamic responses and cough reflex during extubation. We investigated if intravenous (IV) lignocaine and esmolol, given prior extubation, was able to achieve that in hypertensive patients under GA. In this prospective, double-blinded, randomised controlled study, 68 hypertensive patients on treatment undergoing GA were analysed. Group L received IV lignocaine 1 mg/kg while Group E received IV esmolol 1.5 mg/kg, 2 minutes before extubation. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were recorded at the following interval: before study drug administration (T-0), prior extubation (T-1), 1 minute (T-2), 3 minutes (T-3), 5 minutes (T-4) and 10 minutes (T-5) post-extubation. Group L showed significantly increase in HR at T-2 while SBP and MAP increased significantly from T-1 until T-5. Group E showed a significant reduction in HR at T-1 up to T-5 and significantly lower HR at T-1 and T-2 compared to Group L. Group E showed stable SBP, DBP and MAP at all intervals. In conclusion, IV esmolol at 1.5 mg/kg was able to attenuate the hemodynamic response more pronounced when compared to IV lignocaine at 1 mg/kg from extubation stress in patients with hypertension on treatment. Both lignocaine and esmolol were equally effective in suppressing cough reflex during extubation.

Predicting feeding-tube dependence in patients following endotracheal extubation: a two-item swallowing screen

Background To meet the surging demands for intubation and invasive ventilation as more COVID-19 patients begin their recovery, clinicians are challenged to find an ultra-brief and minimally invasive screen for postextubation dysphagia predicting feeding-tube dependence persisting for 72 h after extubation. Methods This study examined the predictive validity of a two-item swallowing screen on feeding-tube dependence over 72 h in patients following endotracheal extubation. Intensive-care-unit (ICU) patients (≥ 20 years) successfully extubated after ≥ 48 h endotracheal intubation were screened by trained nurses using the swallowing screen (comprising oral stereognosis and cough-reflex tests) 24 h postextubation. Feeding-tube dependence persisting for 72 h postextubation was abstracted from the medical record by an independent rater. To verify the results and cross-check whether the screen predicted penetration and/or aspiration during fiberoptic endoscopic evaluation of swallowing (FEES), participants agreeing to receive FEES were analyzed within 30 min of screening. Results The results showed that 95/123 participants (77.2%) failed the screen, which predicted ICU patients’ prolonged (> 72 h) feeding-tube dependence, yielding sensitivity of 0.83, specificity of 0.35, and accuracy of 0.68. Failed-screen participants had 2.96-fold higher odds of feeding-tube dependence (95% CI, 1.13–7.76). For the 38 participants receiving FEES, the swallowing screen had 0.89 sensitivity to detect feeding-tube dependence and 0.86 sensitivity to predict penetration/aspiration, although specificity had room for improvement (0.36 and 0.21, respectively). Conclusion This ultra-brief swallowing screen is sufficiently sensitive to identify high-risk patients for feeding-tube dependence persisting over 72 h after extubation. Once identified, a further assessment and care are indicated to ensure the prompt return of patients’ oral feeding. Trial registration NCT03284892, registered on September 15, 2017.

Chronic cough in postmenopausal women and its associations to climacteric symptoms

BackgroundPostmenopausal women often have chronic cough, which is likely caused by hormonal changes affecting lung function and the mucous membrane of the airways, causing hypersensitivity of the cough reflex. Therefore, postmenopausal hormonal changes could play a key role in the association between increased cough and menopause. The aim of this study is to evaluate the relation of chronic cough and postmenopausal symptoms.MethodsWe performed a questionnaire-based cohort study in generally healthy postmenopausal women (age 45–65 years). Women with cough of known origin were excluded. Comorbidities, medication and baseline data were collected. The Menopause Rating Scale II (MRS II) was combined with the Leicester Cough Questionnaire (LCQ). Groups were divided in chronic cough versus non-coughing participants, chronic cough was defined as symptoms over 8 weeks. We performed correlations and logistic regression for predicting cough based on postmenopausal symptoms.ResultsSixty-six of 200 women (33%) reported mild to heavier symptoms of chronic cough over 8 weeks. No significant differences in baseline data (age, BMI, onset of menopause, years since menopause, concomitant diseases, and medication) were found between coughing and non-coughing women. The MRS II showed higher menopausal symptoms in patients with cough, with significant differences in 2 of the 3 MRS-domains (urogenital (p < 0.001) and somato-vegetative (p < 0.001)). Climacteric symptoms correlated strongly with parameters of cough (p<0.001). On the basis of the MRS total score (p<0.001) and the somato-vegetative and urogenital domains (p<0,05), the prediction for respiratory complaints could be shown.DiscussionChronic cough was significantly associated with menopausal symptoms. Therefore chronic cough as a possible climacteric symptom and its underlying mechanisms should be further explored.

Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels

Background Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E2 (PGE2), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE2 can sensitize the cough reflex via central actions and, if so, via which mechanisms. Methods All drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS). Results We show that both PGE2 and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS. Conclusion Collectively, our findings show that PGE2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1,TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE2 plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or NaVv 1.8 channels may represent novel antitussive molecular targets. Graphical Abstract

Follow Your Nose: A Key Clue to Understanding and Treating COVID-19

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.

Cough. The place of herbal medicine in treatment

Cough is one of the auxiliary mechanisms for cleaning the airways from mucus, foreign particles, microorganisms. The physiological cough reflex allows the mechanism of airway cleansing, provided that mucociliary clearance works sufficiently. However, sometimes the cough loses its protective function, becomes persistent, and impairs the quality of life of the patient. In this regard, in the treatment of cough, attention is paid to both secretomotor and secretolytic therapy. Medicinal plants are among the drugs with such properties. Numerous group of drugs containing herbal components has a reflex action, which allows coping most effectively with cough in the initial stages of diseases accompanied by respiratory symptoms. The most common among them and widely used are plantain leaf, coltsfoot leaf, thermopsis herb, ipecacuanha root, marshmallow root, licorice root, anise fruit, thyme (thyme) herb extract, ivy leaf extract. A well-known drug, the active ingredient of which is ivy leaf extract. Its mechanism of action consists in increasing the production of surfactant and increasing the number of β2-adrenoreceptors on the surface of alveolar cells of the bronchial tree, to which ivy active substance α-hederin is attached, which has a bronchospasmodic and expectorant action. Numerous clinical studies have proven a high efficacy and safety of the product based on ivy leaf extract, which allows us to recommend it as the drug of choice for symptomatic cough therapy in both children and adults during acute respiratory infections.

Cough in Idiopathic Pulmonary Fibrosis

Chronic cough is experienced by most patients with idiopathic pulmonary fibrosis (IPF). It is often the first symptom and is associated with reduced quality of life, increased rates of depression and anxiety, more severe physiological impairment, and disease progression. Although not fully understood, recent gains in understanding the pathophysiology of chronic cough in IPF have been made. The pathophysiology is likely multifactorial and includes alterations in mucous production and clearance, architectural distortion, and increased cough reflex sensitivity, suggesting a role for targeted therapies and multidisciplinary treatment. Modifiable comorbidities can also induce cough in patients with IPF. There is a renewed emphasis on measuring cough in IPF, with clinical trials of novel and repurposed therapies for chronic cough emerging in this population. This review provides an update on the clinical characteristics, pathophysiology, and measurement of chronic cough in patients with IPF and summarizes recent developments in non-pharmacological and pharmacological therapies.

Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough

BackgroundThe purinoceptor subtype P2X3 has been shown to have significant involvement in the cough reflex; the heterotrimer version of the purinoceptor (P2X2/3) has been implicated in taste disturbance. The most advanced clinical candidate antagonist gefapixant has low selectivity among P2X3 receptors and induced taste disturbance, whereas newly developed sivopixant has high selectivity towards P2X3versus P2X2/3.MethodsIn a phase 2a, randomised, double-blind, placebo-controlled, crossover, multicentre study, adult patients with refractory or unexplained chronic cough received oral sivopixant 150 mg or placebo once daily for 2 weeks, followed by a 2–3-week washout period, and then crossed over to placebo or sivopixant for 2 weeks. Efficacy and safety of sivopixant were evaluated.ResultsOf 31 randomised patients, 15 in the sivopixant-first group and 15 in the placebo-first group completed the study. After 2 weeks’ treatment, the placebo-adjusted ratios of the average hourly number of coughs to baseline during daytime (primary endpoint) and over 24 h (secondary endpoint) were −31.6% (p=0.0546) and −30.9% (p=0.0386), respectively. Sivopixant also improved health-related quality of life. Treatment-related adverse events occurred in 12.9% and 3.2% of patients during sivopixant and placebo administration, respectively. Mild taste disturbance occurred in two patients (6.5%) during sivopixant administration.ConclusionsSivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough.