Cough - History Cough Acute Subacute ChronicLess than 3Less than 3 3 to 8 weeks 3 to 8 weeks More than More than weeks weeks 3 weeks 3 weeks Richard Irwin, NEJM, Volume 343, Dec 7, 2000
Cough - Acute• Most common causes – Common cold [viral] – Acute bacterial sinusitis – Pertussis – Exacerbation of COPD – Allergic rhinitis – Rhinitis secondary to environmental irritants
Cough – Viral Infection• Upper respiratory viral infections are the most common cause of cough – 83% within first 48 hours – 26% on day 14• Arises from the stimulation of the cough reflex in upper airway by postnasal drip and/or clearing of the throat
Cough – Viral Infection• Signs and symptoms include: rhinorrhea, sneezing, nasal obstruction, post nasal drip, irritation of the throat, +/- fever and normal chest exam – Diagnostic testing is not indicated in a immunocompetent patient as there is a very low yield — over 97% of CXR are normal
Cough - Acute• Remember: – Think bacterial bronchitis & use antibiotics if exacerbation of COPD with worsening SOB or wheezing is present – Cough and vomiting is suggestive of Bordetella pertussis – Bacterial sinusitis can present like a viral rhinitis but use antibiotics only two of the following are present: • Maxillary toothache • Purulent nasal discharge, discolored nasal discharge • Abnormal transillumination of any sinus
Cough - Acute• In elderly, classic signs and symptoms may be minimal, so consider – Pneumonia – CHF – Asthma – Aspiration
Cough - Subacute• Most common etiologies 1. Post-infectious cough • Begins with respiratory tract infection • NOT pneumonia • Ultimately resolves without treatment • Results from PND or clearing of throat • With or without bronchial hyper-responsiveness 1. Bacterial sinusitis 2. Asthma
Postinfectious Cough - Treatment• Begin with treatment similar to the common cold• If wheezing – use bronchodilators – This does not make the diagnosis of asthma• If not resolved in one week • Nasal decongestant for 5 days • Antibiotics till total disappearance of cough
Chronic Cough• In immunocompetent patients, 95% caused by – Postnasal drip – Asthma – Gastroesophageal reflux – Chronic bronchitis due to cigarette smoking – Bronchiectasis – Use of angiotensin-converting enzymes inhibitors
Evaluation of Chronic Cough• History – Character of cough, quality of the sound and the timing of cough (except the absence during sleep) have not shown to be useful• Physical – Oropharyngeal mucous or cobblestone appearance suggests postnasal-drip syndrome – “silent” postnasal-drip syndrome
Evaluation of Chronic Cough• Heartburn and regurgitation suggest Gastroesophageal reflux disease – “silent”GERD in up to 75% of patients • Irwin,Chest 1993;104:1511-1517• Wheezing suggests asthma – “silent”asthma (cough variant asthma) in up to 57% of cases • Irwin, Am Rev Respir Dis 1981;123:413-417
Evaluation of Chronic Cough• Where to start – CXR: normal is consistent with PND, GERD, asthma, chronic bronchitis. • Unlikely : bronchogenic carcinoma, sarcoid, TB and bronchiectasis – Since PND syndromes are most common--- start there • Sinusitis or rhinitis of the following varieties: nonallergic, allergic, postinfectious, vasomotor, drug-induced and environmental-irritant induced
Chronic Cough - PND• PND is by far the most common cause of chronic cough• Since the signs and symptoms are nonspecific, the definitive diagnosis cannot be made by History and Physical examination alone• Therapy – 1st generation antihistamine + a decongestant
Therapy• Remember – “The newer-generation H1 antagonist do not appear to be effective when cough induced by postnasal drip is not mediated by histamine” • Irwin, Consensus Report of the American College of Chest Physicians. Chest 1998;114:suppl:133S-181S.
Chronic Cough – Asthma• Cough can be the only symptom of asthma in up to 57% of patients—cough- variant asthma• +/- airflow obstruction on PFT’s• Therapy – If severe, PO steroids followed by inhaled steroids for 6-8 weeks with β2 agonist – If mild, inhaled steroids with β2 agonists
Chronic Cough -- GERD• When GERD is cause of chronic cough, up to 75% of patients have no GI symptoms• Empiric therapy can if tried if – GI complaints compatible with GERD or – No GI complaints with normal CXR, no ACEI, patients who do not smoke and in whom PND and asthma have been eliminated.• Improvement may take 2-3 months to begin• MEAN TIME TO RECOVERY IS 161-179 DAYS.
Chronic Cough -- ACEI• Class effect of drug; not drug related• Incidence of 0.2 to 33%; – True incidence ≈ 10%• Cough may appear within a few hours up to months after taking the first dose – Pathogenesis seems be an accumulation of inflammatory mediators: bradykinin, substance P and/or prostaglandins.• Therapy – STOP ACEI – Other therapies include oral sulindac, ASA, indomethacin and even oral iron.
Treatment of cough• Cough is a useful physiological mechanism that serves to clear the respiratory passages of foreign material and excess secretions. – It should not be suppressed indiscriminately.• There are, however, many situations in which cough does not serve any useful purpose – Instead it only annoys the patient or prevents rest and sleep.• Cough may be – i) Un productive (dry) cough OR
Treatment of cough• It is suggested that irritation of the bronchial mucosa causes bronchoconstriction:• This, stimulates cough receptors. – ( which probably represent a specialized type of stretch receptor) located in the tracheobronchial passages.
Treatment of Cough• Antitussives (cough centre suppressants)• Antihistamines• Bronchodilators• Pharyngeal Demulcents• Expectorants, Mucokinetics & Mucolytics
Antitussives (cough centre suppressants)• Drugs suppress cough & produces symptomatic relief• MOA – Mainly suppress cough centre in medulla (both central & peripheral effects) • E.g., Opoid drugs (codeine, pholcodeine, noscapine, dextromethorphan) – Opioid = most effective for cough.
Codeine• Codeine= prodrug ⇒ metabolized to morphine – It is an alkaloid found in Opium poppy plant• Has less addiction + resp. centre depressant action – Has useful antitussive action at low doses (<15 mg)• Produce drowsiness, thickening of sputum &• constipation
Noscapine & Pholcodeine• Related to papaverine• Do not have addictive, analgesic & constipating properties• Do not interfere with mucocilliary movement – Noscapine (15 mg) & – pholcodeine (10 mg)=syrup
Dextromethorphan• Available in syrup, tablets, spray forms• MOA – NMDA receptor antagonist• Uses – Cough suppressant, temporary relief of cough caused by minor throat & bronchial irritation (accompanies with flu & cold), pain relief• Adverse Effects – Nausea, vomiting, drowsiness, dizziness, blurred vision.
Antihistamines• Added to antitussives / expectorant formulation – Due to sedative & anticholinergic actions produce relief in cough but lack selectivity for cough centre – No expectorant action =▼secretions (anticholinergic effect)• Suitable for allergic cough (not for asthma) – E.g., Chlorpheniramine, diphenhydramine, promethazine.
Bronchodilators• Bronchospasm or stimulation of pulmonary receptors = induce or aggravate cough + bronchoconstriction• e.g. β2-agonist (salbutamol, terbutaline)• MOA of bronchodilators in cough – ▲surface velocity of air flow during cough→ Clear secretions of airway – Not used routinely for every type of cough but only when bronchoconstriction is present
Pharyngeal demulcents• Soothe the throat (directly & also by promoting salivation) – ▼ afferent impulses from inflamed/irritated pharyngeal mucosa• Provide symptomatic relief in dry cough arising from throat – E.g. lozenges, cough drops, glycerine, liquorice, honey
Mucus Layer• Gel (1 to 2 µm): Gelatinous and sticky (flypaper)• Sol (4 to 8 µm): Watery, Cilia in this layer – Total layer thickness: 5 to 10 µm thick• Surface Epithelial Cells – Pseudostratified ciliated columnar – Surface goblet cells (6,800/mm 2) – Serous cells – Sol layer – Clara cells – Unknown function (enzymes?)• Submucosal Gland – Bronchial Gland
Mucus Layer• Bronchial Gland – Found in submucosa – Found down to terminal bronchioles – Parasympathetic control (Vagus nerve) – Provide the majority of mucus secretion – Total volume 40 times greater than goblet cells
Function of Mucociliary Escalator• Protective function – Remove trapped or inhaled particles and dead or aging cells. – Antimicrobial (enzymes in sol/gel) – Humidification – Insulation (prevents heat and moisture loss) • NOTE: No cilia or mucus in lower airways (respiratory bronchioles on down)• Mucus also protects the epithelium from toxic materials.
Structure and Composition of Mucus• Composition – 95% water • Need for water intake to replenish • Mucus doesn’t easily absorb water once created – 3% protein and carbohydrates – 1% lipids – Less than 0.3% DNA
Structure and Composition of Mucus• Glycoprotein – Large (macro)molecules – Strands of polypeptides (protein) that make up the backbone of the molecule • String of amino acids – Carbohydrate side chains – Chemical bonds “hold” mucus together • Intramolecular: Dipeptide links – Connect amino acids • Intermolecular: Disulfide and Hydrogen bonds – Connect adjacent macromolecules
Mucus Production• Normal person produces 100 mL of mucus per 24 hour period – Most is reabsorbed back in the bronchial mucosa – 10 mL reaches the glottis – Most of this is swallowed• Mucus production increases with lung disease
Diseases that Increase Mucus Production• Chronic Bronchitis• Asthma• Cystic Fibrosis• Acute Bronchitis• Pneumonia• Also some drugs (anticholinergics, antimuscarinics)
Factors that Impair Ciliary Activity• Endotracheal tubes• Temperature extremes• High FiO2 levels• Dust, Fumes, Smoke• Dehydration• Thick Mucus• Infections
Viscosity and Elasticity• Rheology• Viscosity: Property of a liquid that measures the resistance to movement when a force is applied. – Increased viscosity, increased resistance to flow • Olive oil vs. Water• Elasticity: Property of solid whereby a solid changes shape (deforms) when a force is applied. – Ideally, a solid is totally elastic, and returns to its original shape when force is released.• The mucus layer is ideally very elastic and has a very low viscosity.
Hypoviscosity/Wetting Agents: Saline solutions• Normal Saline (.9%) – Isotonic and good diluent for drugs• Half-normal Saline (.45%) – Hypotonic, good diluent, and can be administered via USN• Aerosol solutions tend to increase in tonicity as they go deeper into the lung because of evaporation!
Hypoviscosity/Wetting Agents: Saline solutions (cont.)• Hypertonic Saline (usually 10%) – Wetting agent – Bronchorrhea (draws fluid from mucosa to dilute gel) – May also help break up mucoprotein-DNA bonds in mucus (mucolytic effect!)• Limitations: – Bronchospasm – Hypernatremia
Hypoviscosity/Wetting Agents: Sodium Bicarb• Usually 2 – 7.5% solution• Wetting agent and bronchorrhea• Also alkaline pH breaks up hydrogen bonds• Also breaks up calcium bonds• Like hypertonic saline, it is both a wetting agent and a mucolytic• Can usually NOT be used as a diluent for drugs• Has same side effects as hypertonic saline
Mucociliary Escalator• Mucosal Blanket – Sol layer – Gel layer• Cilia – 200 per cell – 6 µm in length – Beat 1000/min – Move mucus 2 cm/min – Paralyzed by cigarette smoke
Mucus vs. Sputum• Mucus is the total secretion from mucous membranes including the surface goblet cell and the bronchial glands.• Sputum is the expectorated secretions that contains mucus, as well as oropharyngeal and nasopharyngeal secretions (saliva).
Facilitation of Mucus Clearance• Provide adequate hydration – Increase fluid intake orally or IV• Remove causative factors – Smoking, pollution, allergens• Optimize tracheobronchial clearance• Use Mucolytics• Reduce Inflammation
Function of Mucolytics• Weakening of intermolecular forces binding adjacent glycoprotein chains – Disruption of Disulfide Bonds• Alteration of pH to weaken sugar side chains of glycoproteins• Destruction of protein (Proteolysis) contained in the glycoprotein core of proteolytic enzymes – Breaking down of DNA in mucus
Function of Mucolytics• Disruption of Disulfide Bonds – acetylcysteine breaks the bonds by substituting a sulfhydril radical –HS
Function of Mucolytics• Alteration of pH – 2% NaHCO3 solutions are used to increase the pH of mucus by weakening carbohydrate side chains – Can be injected directly into the trachea or aerosolized (2-5 mL)
Function of Mucolytics• Proteolysis – Dornase alfa (Pulmozyme) – Attacks the protein component of the mucus
Hazard of Mucolytics• The problem with all three mucolytics is that they destroy the elasticity of mucus while reducing the viscosity.• Elasticity is crucial for mucociliary transport.• The patient must be able to cough adequately to remove the mucus.
Mucolysis• Mucolysis is the breakdown of mucus.• Mucolysis is needed in diseases in which there is increased mucus production: – Cystic Fibrosis – COPD – Bronchiectasis – Respiratory Infections • Turberculosis
Mucolysis• These diseases result in a marked slowing of mucus transport – Changes in properties of the mucus – Decreased ciliary activity – Both
Dairy Intake• No evidence to support the common belief that drinking milk increases the production of mucus or phlegm and congestion in the respiratory tract• There is a loose cough associated with milk intake
Secretion Management• Increase the depth of the sol layer – Water – Saline – Expectorants• Alter the consistency of the gel layer – Mucolytics• Improve ciliary activity – Sympathomimetic bronchodilators – Corticosteroids
Bland Aerosols• “Dilutes” mucus molecule• Also known as wetting agents – Function may be more of an irritant than a wetter• Types – Sterile & Distilled Water • Humectant • Dense aerosols and asthmatics – Normal (isotonic) Saline – Hypertonic Saline • Increase mucus production – Hypotonic Saline
Cough Suppressants• Vagal stimulation causes a cough.• Irritation of pharynx, larynx, and bronchi lead to a reflex cough impulse.• If the cough is dry and non-productive, it may be desirable to suppress its activity.• Cough suppressants depress the cough center in medulla (?). – Narcotic preparations (codeine) – Non-Narcotic preparations (dextromethorphan)• Caution in patients with thick secretions.
acetylcysteine• Indications – Mucolytic by aerosol or direct instillation into the ET tube. – Given orally to reduce liver injury with acetaminophen (Tylenol) overdose. • Mix with cola or given by NG tube.
Dosage of acetylcysteine• Concentration – 10% or 20%• Dosage – 3-5 mL of a 20% solution TID or QID • Maximum dose 10 mL – 6-10 mL of a 10% solution TID or QID • Maximum dose 20 mL• 1-2 mL of a 10% or 20% for direct instillation
Hazards of acetylcysteine• Bronchospasm – Asthma – may be a problem during an acute asthma attack. • Anecdotal; lack of evidence – If used with asthma, use 10% and mix with a bronchodilator (preferably a short-acting agent).• Increase mucus production – Be prepared to suction a patient who cannot cough or who is intubated.
Hazards of acetylcysteine• Do not mix with antibiotics in the same nebulizer (incompatible).• Nausea & Vomiting – Disagreeable odor (smells like rotten eggs) due to the hydrogen sulfide.• Open vials should be used within 96 hours to prevent contamination.
Expectorants (Bronchomucotropics) • Drugs that increase and aid clearance of respiratory tract secretions • Act peripherally to increase expulsion of mucus from the respiratory tract. – Increase bronchial secretion OR – Decrease its viscosity & facilitate its removal by coughing – Loosen cough ► less tiring & more productive – Hypoviscosity agents (Wetting agents) • Aerosol hypertonic saline – increases secretion volume and/or hydration, may decrease viscosity by diluting the gel layer – Mucolytics
Expectorants• Iodides – Unclear function – SSKI (Saturated Solution of Potassium Iodide)• Guifenesin – At high doses, stimulates bronchial gland secretion – Robitussin
Expectorants (Bronchomucotropics) • Drugs that increase and aid clearance of respiratory tract secretions • Act to stimulate the cholinergic system and ↑ mucus secretion. – Eg. Guaiphenesin - Expectorant drug usually taken by mouth – Available as single & also in combination – MOA=Increase the volume & reduce the viscosity of secretion in trachea & bronchi • Act directly – Ammonium chloride - Gastric irritants = reflexly↑ bronchial secretions + sweating – Sodium citrate &
Expectorants (Bronchomucotropics) • Drugs that increase and aid clearance of respiratory tract secretions – Usually stimulate sol layer production by direct irritation or indirect through vagal stimulation • Increased sol means decreased viscosity! – Smoke is a bronchomucotropic! Unfortunately, it’s irritation stimulates the bronchial submcosal glands AND the goblet cells so mucus production increases as well as viscosity – Spicy food causes increased sol due to vagal stimulation!
N-Acetylcysteine• Given directly into respiratory tract as 10 or 20% solution (hypertonic and alkaline pH)• MOA of acetylcysteine – Opens disulfide bond in mucoproteins of sputum =↓ viscosity (most effective form of mucolysis) – Also breaks mucoprotein bonds and hydrogen bonds• Bronchorrhea
N-Acetylcysteine• Onset of action quick---used 2-8 hourly• Uses – Cystic fibrosis (to ↓viscosity of sputum)• Adverse effects – Nausea, vomiting, bronchospasm in bronchial asthma.
Pulmozyme (Dornase Alpha or DNAse)• Excellent aerosol mucolytic for cystic fibrosis patients• Lyses the DNA bonds in the sputum of cystic fibrosis patients – These patients have a lot of such bonds!
Mucolytic treatment in acute exacerbations :• Mucolytic drugs have a small effect in decreasing acute exacerbations.• Improvement of subjective complaints – Decrease of inflammatory markers – Bacterial eradication – They are not effective on FEV1 decline. – They may have some effects on frequent exacerbators requiring hospitalization BUT no difference on hospitalization length.
Mucoregulators• Agents regulating mucus secretion or interfere with the DNA/F-actin network – Carbocysteine - regulates mucus visco-elasticity. Also antioxidant, anti-inflammatory – Anticholinergics- inhibits cholinergic system which ↑ mucus secretion (M3 res). – Glucocorticoids – decrease airway inflammation and mucus secretion. – Macrolides – ↓ airway inflammation & mucus secretion.
Mucokinetics• Agents used when secretions ↑ in amount and/or viscosity to ↑ the mucociliary transport – Bronchodilators - Improves cough by increasing expiratory flow and increase in secretion expulsion, Also antioxidant, antiinflammatory – Bromhexine – Ambroxol-increases in surfactant production, inhibits chloride channels, Decrease in viscosity of secretions – Surfactant –decreases surface adhesion between mucus and airway.
Bromhexine• MOA of Bromhexine – Synthetic derivative of vasicine (alkaloid= Adhatoda vasica) – Thinning & fragmentation of mucopolysaccaride fibers – ↑ volume & ↓ viscosity of sputum
Ambroxol• Ambroxol Hydrochloride is the active metabolite of Bromhexine & works as – Secretolytic agent used in the treatment of viscid or excessive mucus. – Mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract, – Stimulates synthesis and release of surfactant by type II pneumocytes. Surfactant acts as an anti- glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport.
Ambroxol• Ambroxol allows patients to breathe freely and deeply by: – Promoting mucus clearance, – Facilitating expectoration and – Easing productive cough.• Anti-inflammatory properties of Ambroxol lead to ↓ of redness of the sore throat and thus, ambroxol relieves pain in acute sore throat, with a fast onset of action and a long duration of effect of at least 3 hours.