Posts Tagged ‘pulmonary’


Airway tone and pressures

August 29, 2011

[K&C] Airway tone shows a circadian rhythm which is greatest at 0400 and lowest mid afternoon, hence asthma symptoms often worse early morning. Airways expand as lung volume is increased, and at full inspiration, TLC, they are 30-40% larger in calibre than at full expiration, RV. In COPD the small airways are narrowed and this can be partially compensated by breathing at a larger lung volume. The airways become smaller, and greater in number, towards the periphery. The total cross sectional area of airways increases and the resistance to airflow decreases, until the terminal airways where airflow occurs solely by diffusion. Air pressure increases towards the trachea as resistance increases.

Adrenoceptors on bronchial muscles respond to circulating catecholamines; there is no direct sympathetic innervation.

Between the alveolus and the mouth there is a point where airway pressure equals intrapleural pressure, and airways collapse temporarily, and tend to vibrate. The elastic recoil pressure of the lungs decreases with decreasing volume, so the collapse point moves towards the smaller airways. Where there is pathological loss of recoil pressure, e.g. COPD, the collapse point starts even further upstream and causes expiratory flow limitation. FEV1 is a useful clinical index of this phenomenon. To compensate, these patients often ‘purse their lips’ in order to increase airway pressure so that their peripheral airways do not collapse. On inspiration, the intraplueral pressure is always less than the intraluminal pressure within the intrathoracic airways, so there is no limitation to airflow with increasing effort. Inspiratory flow is limited only by the power of the inspiratory muscles.

In subjects with healthy lungs, maximal flow rates are rarely achieved even during vigorous exercise. In patients with severe COPD, limitation of expiratory flow occurs even during tidal breathing at rest. To increase ventilation these patients have to breathe at higher lung volumes and allow more time for expiration which both reduce the tendency for airway collapse. To compensate they increase flow rates during inspiration, where there is relatively less flow limitation.



August 29, 2011

COPD refers to emphysema, chronic bronchitis, or a combination of the two. These cause severe difficulties in ventilation and in oxygenation of the blood, and are among the major causes of disability and death in the US.

Airway obstruction is not caused by increased smooth muscle contraction in these diseases as it is in asthma. In emphysema the cause of obstruction is destruction and collapse of the smaller airways. Emphysema is characterised by the destruction of the alveolar walls leading to an increase in compliance (compliance = the magnitude of change in lung volume produced by a given change in the transpulmonary pressure). Chronic bronchitis is characterised by excessive mucus production in the bronchi and chronic inflammatory changes in the small airways. Obstruction is caused by accumulation of the mucus in the airways and thickening of the inflamed airways. The same agents that cause emphysema, such as smoking, also cause chronic bronchitis, which is why the two diseases frequently coexist.

[Kumar and Clark]

The global initiative in obstructive lung disease (GOLD) predicts that COPD will become the third most common cause of death and fifth most common cause of disability world-wide by 2020.

The term COPD brings together a variety of syndromes associated with destruction of the lung and airflow obstruction. Chronic asthma, chronic bronchitis, emphysema, pink puffers and blue bloaters. “COPD is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.” (GOLD)

  • Loss of elasticity and alveolar attachments of airways due to emphysema → reduces elastic recoil and airways collapse during expiration.
  • Inflammation and scarring cause the small airways to narrow
  • Mucus secretion blocks airways
  • Combined these lead to hyperinflation of the lung and breathlessness

COPD is caused by long term exposure to toxic particles and gases. In developed countries, cigarette smoking accounts for 90% of cases. Airflow limitation increases with age, and increases more rapidly in smokers. The rate of increase in someone who has quit smoking is the same as that in someone who never smoked, although it may start from a lower level due to the damage of previous smoking. In developing countries, COPD is caused by cigarette smoking and smoke from cooking fuels. Only 10-20% of heavy smokers develop COPD, indicating individual susceptibility. Risk of death for person smoking 30/day is 20x that of a non-smoker. Autopsy studies have shown that substantial numbers of centri-acinar emphysematous spaces are found in the lungs of 50% of British smokers over the age of 60 years and are unrelated to the diagnosis of significant respiratory disease before death. Climate and air pollution have some affect. Urbanisation, social class and occupation may also have an effect on aetiology but difficult to separate from smoking.

In UK, COPD accounts for 7% of all days off work due to sickness. But the number of patients discharged from hospital with this diagnosis has been falling steadily and the death rate has fallen in the last 25 years from 200 to 70 per 100,000 in the UK.


The most consistent pathological finding is hypertrophy and increase in number of the mucus secreting goblet cells of the bronchial tree, evenly distributed throughout the lung but mainly seen in the larger bronchi. In more advanced cases the bronchi themselves are obviously inflamed and pus is seen in the lumen. Microscopically there is infiltration of the bronchi and bronchioles with acute and chronic inflammatory cells and lymphoid follicles in severe disease. In contrast to asthma, the lymphocytic infiltrate is predominantly CD8+. The epithelial layer may become ulcerated and, when the ulcers heal, squamous epithelium may replace the columnar cells. The inflammation is followed by scarring and a remodelling process that thickens the walls and leads to widespread narrowing in the small airways.

The small airways are particularly affected early in the disease, initially without the development of any significant breathlessness. This initial inflammation of the small airways is reversible and accounts for the improvement in airway function if smoking is stopped early. In later stages the inflammation continues even if smoking is stopped.

Further progression of the disease leads to progressive squamous cell metaplasia, and fibrosis of the bronchial walls. The physiological consequence of these changes is the development of airflow limitation. If the airway narrowing is combined with emphysema (causing loss of the elastic recoil of the lung with collapse of small airways during aspiration) the resulting airflow limitation is even more severe.

Emphysema is defined pathologically as dilation and destruction of the lung tissue distal to the terminal bronchiole:

  • Centri-acinar emphysema – damage concentrated around the respiratory bronchioles; extremely common form of emphysema, and when of modest extent it is not normally disabling, but severe Centri-acinar emphysema is associated with substantial airflow limitation.
  • Pan-acinar emphysema – less common, damage appears to involve the whole of the acinus, and in the extreme form the lung becomes a mass of bullae. Severe airflow limitation and Va/Q mismatch occur. This type of emphysema occurs in alpha1-antitrypsin deficiency.
  • Irregular emphysema produces damage and scarring affecting the lung parenchyma patchily without particular regard for acinar structure.

Emphysema leads to expiratory airflow limitation and air trapping. The loss of lung elastic recoil results in an increase in TLC while the loss of alveoli results in decreased gas transfer.

Va/Q mismatch occurs partly because of damage and mucus plugging, and partly because of the rapid expiratory closure of the smaller airways owing to loss of elastic recoil. This leads to a decrease in PaO2 and an increase in the work of respiration.

PaCO2 excretion is not impaired to the same extent and many patients will show low normal PaCO2 values – the “pink puffers” who seek to maintain normal blood gases by increasing their respiratory effort. Other patients fail to maintain their respiratory effort and thus their carbon dioxide levels increase. In the short term, the rise in CO2 leads to stimulation of respiration but in the long term these patients often become insensitive to CO2 and come to depend on hypoxaemia to drive their ventilation. These patients appear less breathless, and because they run low O2 values they start to retain fluid and stimulate the production of erythrocytes (polycythemia). So they become bloated, plethoric and cyanosed. Attempts to abolish hypoxaemia by administering oxygen can make the situation much worse by decreasing respiratory drive in these patients who rely on hypoxia to drive their ventilation.

Loss of 50ml/yr FEV1 in COPD compared to 20mL/yr in healthy people.


Cigarette Smoking

Bronchoalveolar washes have shown that smokers have neutrophil granulocytes present within the lumen of the bronchial tree that are absent in non-smokers. Also, small airways of smokers are infiltrated by granulocytes capable of releasing elastases and proteases, which possibly help to produce emphysema. It is suggested that imbalance between protease and antiprotease activity may produce the damage. Alpha1-antitrypsin is a major serum antiprotease which can be inactivated by cigarette smoke.

The hypertrophy of mucous glands in the larger airways is thought to be a direct response to persistent irritation resulting from the inhalation of cigarette smoke. The smoke has adverse effect on surfactant, favouring overdistension of the lungs.

alpha1-Antitrypsin deficiency

alpha1-antitrypsin inhibitor is produced in liver, secreted into blood and diffuses into the lungs where it acts as antiprotesase that inhibits neutrophil elastase, a proteolytic enzyme capable of destroying alveolar wall connective tissue. There are >75 alleles of the alpha1-antitryptin inhibitor gene, of which 3 main phenotypes. ~1in5000 in UK are homozygous deficient, and those who develop chest disease are usually, but not always, smokers. Hereditary alpha1-antitryptin deficiency accounts for ~2% of emphysema cases.

Clinical Features

Characteristic symptoms are cough with production of sputum, wheeze and breathlessness following many years of smokers cough and frequent chest infections. Can be worsened by, e.g., cold, foggy weather, pollution. With advanced disease, breathlessness becomes severe even after mild exercise such as dressing.

Only sign in mild disease is wheeze throughout the chest. In severe disease patient is tachypnoeic with prolonged expiration, using accessory muscles to breathe, and may show intercostal indrawing on inspiration and pursing of lips on expiration


More than 40 per cent of smokers aged 61-62 and 50 per cent of those aged 76-77 have COPD

Stopping smoking is the only measure that has been conclusively shown to slow further progression of the disease. After stopping smoking, the rate of decline of lung function slows, approaching that in non-smokers. Preventing a exacerbations of COPD is also important, as it has been found that frequent exacerbations are associated with a more rapid decline in lung function. Respiratory infections are a common cause of such exacerbations, so vaccination against influenza and pneumonia may help protect against accelerated decline in lung function. Combinations of inhaled steroids and bronchodilators used in more advanced COPD reduce the frequency and severity of exacerbations and also the risk of death.

In mild COPD (for example, where breathlessness occurs only on exercising), an inhaled short-acting bronchodilator may be sufficient to control the symptoms. If a single bronchodilator is not sufficient, a combination of two types of shortacting bronchodilators may be tried, or a longacting inhaled bronchodilator can be used instead. In more severe cases, guidelines recommend trying a combination of an inhaled long-acting bronchodilator and an inhaled corticosteroid for an initial period of four weeks. If this combination is still not sufficient to provide relief, theophylline, taken by mouth, may be added. However, this can cause unpleasant side-effects and must be closely monitored

Many other therapies can be used to improve the quality of life of people with COPD. Anxiety or depression can be treated by behavioural therapy and medication. Dietary advice can help prevent weight loss and muscle-wasting. Treatment with a mucolytic medicine may ease sputum production. Pulmonary rehabilitation increases exercise tolerance, promoting independence and emotional well-being. Disease flare-ups due to infections such as pneumonia and flu can be prevented by vaccination.

<h2>Infections as complication of COPD</h2>


Patients with COPD often cope badly with respiratory infections, which can be precipitating cause of acute exacerbations. But its not clear if infections affect the progressive airflow limitation. Prompt use of antibiotics and flu jabs are appropriate.













August 25, 2011

Reversible airways obstruction is the characteristic feature of asthma, which is often associated with an atopic disposition. Exposure to allergens, or possibly other environmental determinants, may then result in expression of the condition. Despite the presence of atopy and eosinophilia, neither is absolutely required for asthma without other concurrent risk factors. (Eosinophilia is an increase in peripheral blood eosinophilic leukocytes. Nonpathologic functions of eosinophils and the cationic enzymes of their granules include mediating parasite defense reactions, allergic response, tissue inflammation, and immune modulation.

The most common symptoms of asthma are wheeze and breathlessness. In younger people, cough, especially at night, may the only symptom.

Asthma is characterised by intermittent episodes in which airway smooth muscle contracts strongly, markedly increasing airway resistance. The basic defect in asthma is chronic inflammation of the airways – causes include allergies, viral infections and sensitivity to environmental factors. Underlying inflammation makes the airway smooth muscle hyperresponsive and causes it to contract strongly in response to such things as exercise (especially in cold, dry air), cigarette smoke, environmental pollutants, viruses, allergens, normally released bronchoconstrictor chemicals. Incidence of asthma is increasing, possibly due in part to environmental pollution.

  • WHO estimates that 235 million people currently suffer from asthma. Asthma is the most common chronic disease among children.
  • Children of first generation immigrants have the same incidence of asthma as indigenous children in the overdeveloped world. The risk of developing asthma is about 7 in 100, but risk doubles for each first degree relative with atopy.
  • Asthma is a public health problem not just for high-income countries; it occurs in all countries regardless of the level of development. Most asthma-related deaths occur in low- and lower-middle income countries.
  • Asthma is under-diagnosed and under-treated. It creates substantial burden to individuals and families and often restricts individuals’ activities for a lifetime.
  • Recurrent asthma symptoms frequently cause sleeplessness, daytime fatigue, reduced activity levels and school and work absenteeism. Asthma has a relatively low fatality rate compared to other chronic diseases.

COPD referes to emphysema, chronic bronchitis, or a combination of the two. These cause severe difficulties in ventilation and in oxygenation of the blood, and are major causes of disability and death.

[from Waller et al Medical Pharmacology and Therapeutics]

Asthma and COPD are considered to be distinct entities with clinical overlap. Both are inflammatory disorders of the bronchi. In asthma the underlying problem is a persistent and excessive Th2-dominated immune response and resulting inflammation; this is accompanied by reduced Th1 involvement in the structural and defensive status of tissues. The overall imbalance in T-helper cell types results in persistent inflammation, increased numbers of airways smooth muscle cells, proliferation of blood vessels, epithelial transformation into mucus-secreting cells and increased matrix deposition. Adequate suppression of the inflammation should be the basis of treatment, allowing resolution of the pathological changes. The predominant inflammatory cells are mast cells, eosinophils, and CD4 T-lymphocytes, with fewer macrophages. Important inflammatory mediators are leukotriene D4 (LTD4), histamine, a variety of cytokines including IL-4, IL-5, IL-9, IL-13, eotaxin and RANTES (regulated on activation normal T-cell expressed and secreted), and there is relatively little evidence of oxidative stress.

In asthma, all airways are involved in the inflammatory process, but the degree of fibrosis and mucus secretion are modest, with no parenchymal destruction. (The parenchyma are the functional parts of an organ in the body. This is in contrast to the stroma, which refers to the structural tissue of organs, namely, the connective tissues. E.g. in lungs, parencyma includes alveoli, alveolar ducts, respiratory bronchioles, terminal bronchioles. Early in development the mammalian embryo has three distinct layers: ectoderm (external layer), endoderm (internal layer) and in between those two layers the middle layer or mesoderm. The parenchyma of most organs is of ectodermal (brain, skin) or endodermal origin (lungs, gastrointestinal tract, liver, pancreas). The parenchyma of a few organs (spleen, kidneys, heart) is of mesodermal origin. The stroma of all organs is of mesodermal origin.)

Airway obstruction is not caused by increased smooth muscle contraction in these diseases as it is in asthma. In emphysema the cause of obstruction is destruction and collapse of the smaller airways. Emphysema is characterised by the destruction of the alveolar walls leading to an increase in compliance (compliance = the magnitude of change in lung volume produced by a given change in the transpulmonary pressure – a high degree of compliance indicates a loss of elastic recoil of the lungs). Chronic bronchitis is characterised by excessive mucus production in the bronchi and chronic inflammatory changes in the small airways. Obstruction is caused by accumulation of the mucus in the airways and thickening of the inflamed airways. The same agents that cause emphysema, such as smoking, also cause chronic bronchitis, which is why the two diseases frequently coexist.


 Chronic inflammation of the bronchial mucosa is prominent, with infiltration of activated T-lymphocytes and eosinophils. This leads to the release of several powerful chemical mediators that can damage the epithelial lining of the airways, exposing nerve endings. Many of these mediators are released following activation and degranulation of mast cells in the bronchial tree, which occurs in response to irritants. Some of the mediators act as chemotactic agents for other inflammatory cells, They also produce mucosal oedoma, which narrows the airways and stimulates smooth muscle contraction, leading to bronchoconstriction. Excessive production of mucus can cause further airways obstruction by plugging the bronchiolar lumen

Viral upper respiratory tract infections exacerbate the mucosal inflammatory process, while exposure to allergens, irritants or exercise can cause bronchoconstriction in sensitive airways. Attacks of asthma rapidly follow exposure to a provoking agent. Initial recovery may then be followed some 4-6h later by a late-phase bronchorestrictor response, which can leave the bronchi hyper-reactive to various irritants for several weeks.


Treatments for Asthma

August 25, 2011

<h2>British Guideline on the Management of Asthma</h2>

Aim of oxygen therapy is to maintain SpO2>=92%.

SpO2 = the saturation level of oxygen in hemoglobin; can be determined by noninvasive method of pulse oximetry. ABGs should be taken for patients with SpO2 <92%

ABGs as marker of severityNormal or raised PaCO2 >4.6kPa 35mmHg, Severe hypoxia PaO2 <8kPa, 60mmHg; Low pH (raised PaCO2 indicates near fatal asthma exacerbation)

<h2>Management of Asthma</h2>

Treatment of asthma has two aims: relief of symptoms and reduction of airways inflammation.

First aim of therapy is to reduce the chronic inflammation and airway hyperresponsiveness with anti-inflammatory drugs, particularly inhaled glucocorticoids and leukotrine inhibitors. The second aim is to overcome acute excessive airway smooth muscle contraction with bronchodilator drugs. These relax airway smooth muscle or block the actions of bronchoconstrictors. For example, one class of bronchodilator drugs mimics the normal action of epinephrine on beta-adrenergic (beta 2) receptors. Another class of bronchodilator drugs block muscarinic cholinergic receptors, which have been implicated in bronchoconstriction.

Severe asthma attack:

Inability to complete a sentence, pulse >=110bpm, PEFR <=50% of expected or previous best. Treat by ensuring adequate hydration, 40-60% oxygen by facemask, nebulised beta2-adrenoceptor such as salbutamol, preferably using oxygen. IV hydrocortisone and/or high-dose oral prednisolone

Life-threatening asthma attack:

Silent chest, bradycardia or hypotension, PEFR <=33% of expected or previous best, exhaustion, confusion or coma. Treat as above, plus nebulised ipratropium, IV aminophylline or beta2-adrenoceptor agonist such as salbutamol, IV magnesium sulphate, consider assisted ventilation if there is not rapid clinical improvement.

After recovery from a severe asthma attack, oral corticosteroids should be continued until there are no residual symptoms, especially at night, and the PEFR is at least 80% of the person’s previous best. High doses of these drugs can be stopped abruptly if used for 3 weeks or less, or tapered off if they have been used for a longer period.

Prophylaxis of recurrent attacks

First try to identify and avoid triggers. After initially gaining control of asthma symptoms, long-term treatment is guided by a stepwise treatment plan recommended by the British Thoracic Society / Scottish Intercollegiate Guidelines Network:

Step 1 – mild intermittent ashma – inhaled short acting beta2-adrenoreceptor agonist such as salbutamol, taken as required. For those who are intolerant to this treatment, inhaled ipratropium and oral theophylline are alternative options, but with a higher risk of unwanted effects with the latter.

Step 2 – regular preventer therapy – for adults, a corticosteroid such as beclomethasone is most often used. For children and some adults, an initial trial of cromoglicate or nedocromil can be undertaken, but these agents are generally less effective than inhaled corticosteroid. A leukotriene receptor antagonist could also be tried at this stage.

Step 3 – add-on therapy – in people taking moderately high doses of inhaled corticosteroid, a suitable add-on therapy would be a long-acting beta2-adrenoceptor agonist such as salmeterol. If there is no beneficial response to the beta2-receptor agonist, it should be stopped and the corticosteroid further increased. If control still remains poor, the increased corticosteroid dose together with a long-acting beta2-adrenoceptor agonist should be given. For persistent poor control, sequential add-on therapy with either a leukotriene receptor agonist, a modified-release theophylline formulation or a modified-release oral beta2-adrenoceptor agonist should be tried.

Step 4 – Addition of fourth drug. High-dose inhaled corticosteroid with a short-acting beta2-adrenoceptor agonist as required, and usually an inhaled long-acting beta2-adrenoceptor agonist plus a sequential trial of one or more of the following:

  • leukotriene receptor antagonist
  • oral modified-release thophylline formulation
  • oral modified-release beta2-adrenoceptor agonist

Step 5 – continuous or frequent use of oral prednisolone. This is undertaken in addition to other measures outlined above

For people with resistant disease, especially those requiring oral corticosteroids, the use of immunosuppresive drugs such as ciclosporin or methotrexate has been advocated.


Drug delivery by aerosol spray allows the use of smaller doses and therefore reduces the risk of unwanted side effects. Particles >5micrometres will impact on upper airways and be swallowed. Particles <0.5um will not deposit in the lower respiratory tract and will be exhaled. Optimal size is 1-3um.

About 1/3 users find pressurised metered dose inhalers difficult. Even with optimal coordination, ~70-90% of aerosol is deposited in the oropharynx, then swallowed. Spacers – 750ml, 350ml for young children. Breath activated devices, delivering either aerosol or dry powder, require high airflow and are therefore less efficient than metered-dose inhalers, especially in those with severe airflow limitation. Nebulisers distribute drug from reservoir solution. Jet nebulisers pass air or oxygen through a narrow orifice to such drug solution from a reservoir into a feed tube with fine ligaments. The impact of the solution on these ligaments generates droplets. Ultrasonic jet nebulisers use a piezoelectric crystal vibrating at high frequency – vibrations transmitted through a buffer to the drug solution form a fountain of liquid in the nebulisation chamber. Ultrasonic nebulisers produce a more uniform particle size than do jet nebulisers. Up to 10x the amount of drug is required in a nebuliser to produce the same degree of bronchodilation achieved by a metered dose inhaler. Delivery is more efficient via a mouthpiece than via a mask.

<h2>Symptom-relieving dugs of airflow obstruction.</h2>

Beta2-adrenoceptor agonists, e.g. salbutamol, terbutaline, salmeterol, formoterol

The airways are rich in beta2-adrenoceptors, which are found on bronchial smooth muscle but also on several other cell types. Effects of receptor stimulation include:

  • Bronchodilation via generation of intracellular cyclic adenosine monophosphate (cAMP)
  • inhibition of mediator release from mast cells
  • enhanced mucociliary clearance

Selectivity of an agonist for the beta2-adrenoceptors avoids systemic unwanted effects from stimulation of beta1-adrenoceptors. The selectivity of beta2-adrenoceptors is dose dependent. Inhalation of the drug aids selectivity since it delivers small but effective doses to the airways and minimises systemic exposure. The dose-response relationship for bronchodilation is log-linear, therefore, and tenfold increase in dose is required to double the effect. A metered-dose aerosol inhaler is the most frequently used delivery mechanism, but breath-activated devices and nebuliser solutions are available.

After inhalation, the onset of drug action is rapid, often within 5 minutes, Agents such as salbutamol have an intermediate duration of action (producing bronchodilation for up to about 6h), far longer than the natural adrenoceptor agonists. Their chemical structure prevents neuronal uptake and reduces their affinity for catechol-O-methyl transferase, which metabolises catecholamines.

The long-acting agent salmeterol bronchodilates for up to 12h by virtue of a long lipophilic side-chain on the molecule, which binds to an area adjacent to the active site of the receptor, producing prolonged receptor activation. Formoterol has a prolonged duration of action by entering the lipid bilayer of the cell membrane, from which it is gradually released to stimulate the receptor.

Salbutamol and terbutaline can also be given orally (as conventional or modified-release formulations), or by subcutaneous or intramuscular injections or by IV infusion. However, larger doses are required to deliver and adequate amount to the lungs by any of these routes. This reduces selectivity for beta2-adrenoceptors, and systemic unwanted effects can be troublesome.

Tolerance to pharmacological bronchodilation can occur with beta2-adrenoceptor agonists but not with inhaled antimuscarinic drugs. The Committee on Safety of Medicines has advised that salmeterol and formoterol should not be used for relief of acute asthma and should only be used along with a concurrently administered corticosteroid.

Unwanted effects:

  • Fine skeletal muscle tremor from beta2-adrenoceptor stimulation
  • Tachycardia and arrhythmias result from both beta1 and beta2-adrenoceptor stimulation when high doses of inhaled drug are used, or after oral or parenteral administration.
  • Acute metabolic responses to high-dose beta2-adrenoceptor stimulation include hypokalaemia, hypomagnesaemia and hyperglycemia. They do not persist during long term use.
  • Paradoxical bronchospasm has been reported with inhalation, usually when given for the first time or with a new canister.
  • Headache

Concern has been expressed that regular use of high doses of inhaled beta2-adrenoceptor agonsits may be linked with asthma deaths by precipitation of serious arrhythmias. An alternative possibility is that high doses might allow people to tolerate initial exposure to larger doses of allergens or irritants, which then produce an enhanced late asthmatic response. However it is more likely that the use of high doses is really a reflection of the severity of the underlying asthma.

Anticuscarinic agents, e.g. ipratropium, tiotropium

The antimuscarinic drugs used for bronchodilation are non-selective and bind to all three types of muscarinic receptors in the lung. It remains uncertain whether they also have specific anti-inflammatory effects in addition to their actions on bronchial smooth muscle and mucus secretion. Main use is in COPD, where they are effective. Little use in mild to moderate asthma, but may have a place when added to beta2-adrenoceptor agonists in severe exacerbations of asthma.

Methylxanthines: theophyline, aminophyline

Methylxanthines are a group of naturally occuring substances found in tea, coffee, chocolate and related foodstuffs. Theophylline and its ester derivative aminophylline are the only compounts in clinical use, chemically similar to caffeine. Vasodilator, anti-inflammatory and immunomodulatory actions.

<h2>Anti-inflammatory drugs for airways obstruction</h2>

Corticosteroids e.g. beclamethasone, dipropionate, budesonide, hydrocortisone, fluticasone, propionate, mometasone, prednisolone

Glucocorticoids are the most effective class of drug in the treatment of chronic asthma but are relatively ineffective in COPD. The are recommended as preventer when inhaled beta2-androceptor agonists are used more than once daily. They act to suppress inflammation and the immune response. Powerful glucocorticoids, devoid of significant mineralcorticoid activity, are usually used. (see Steroids)

Intracellular events involved in the anti-inflammatory action

A major event in asthma is probably activation of glucocorticoid receptors that inhibit transcription of genes coding for the cytokines involved in inflammation. Glucocorticoid receptors recruit histone deacetylases to the transcription complex of activated inflammatory genes. The deacetylation of core histones at the transcription complex silence genes that have been activated by inflammatory stimuli. Used long term, corticosteroids reduce airway responsiveness to several bronchoconstrictor mediators and block both the early and late reactions to allergen. Following a delay of 6-12h, several anti-inflammatory actions occur which may be important in ashtma.

Short term anti-inflammatory effects include:

  • Reduced inflammatory cell activation (including macrophages, T-lymphocytes, eosinophils and airway epithelial cells)
  • Decreased IgE synthesis
  • Reduced mucosal oedema and decreased local generation of inflammatory prostaglandins and leukotrienes by inhibition of phospholipase A2
  • Beta-adrenoceptor upregulation, which restores responisveness to beta2-adrenoceptor agonists.

Longterm anti-inflammatory effects include:

  • Reduced T-cell cytokine production and reduced dentritic cell signalling to T-cells
  • Reduced eosinophil deposition in bronchial mucosa (by removing cytokine stimulation, reducing expression or epithelial adhesion molecules and enhancing apoptosis)
  • Reduced mast cell deposition in bronchial mucosa (although the release of mediators from these cells is unaffected)
  • Reversal of the excess epithelial cell shedding and goblet cell hyperplasia found in the bronchial epithelium in asthma.

Inhaled corticosteroids produce some improvement in asthmatic symptoms after 24h and a maximum response after 1-2weeks. Reduction in airway responsiveness to allergens and irritants occurs gradually over several months. Corticosteroids block the late-phase reaction to allergens in asthma. However, many of the chronic structural changes in the airways in asthma are unaffected by corticosteroids.

Pharmacokinetics: Corticosteroids can be used intravenously or orally in severe asthma. However, wherever possible they are given by inhalation of an aerosol or dry powder to minimise systemic unwanted effects. Desirable properties of the inhaled corticosteroid include low rates of absorption across mucosal surfaces (such as the lung, but also including the gut for swallowed drug) and rapid inactivation once absorbed. Beclomethasone dipropionate fulfils the former criterion but is only slowly inactivated once it reaches the systemic circulation. Mudesonide (which is inactivated by extensive first-pass metabolism in the liver if systemically absorbed) and fluticasone (which is very poorly absorbed from the gut) are not given orally and may be prefered if high doses of inhaled drug are needed, or for the treatment of children.

Unwanted effects: amount of swallowed drug can be minimised using a large-volume spacer. Hoarseness and oral candidiasis can occur with inhaled corticosteroids.


Tests for asthma

August 24, 2011

Peak expiratory flow rate (PEFR) is predicted according to tables of normal value for gender and height (e.g. a male of 1.8m would be expected to ave PEFR of 608L/min). Athletes expected to have higher levels; asthmatics lower levels.

Pulse and breathing rates both likely to be high during an asthma attack (normal resting rate for adult 60-100/min pulse and 12/min respirations, but estimates vary 10-20).

Pulse oximetry measures the percentage saturation of haemoglobin with oxygen; in a healthy person normal value is 97-99%, values above 95% are generally considered clinically acceptable, and oxygen therapy aims to maintain saturation of >=92%.

Arterial blood gases are taken from taken from an artery, usually radial, or from arterialised vasodilated ear lobe. Samples need to be analysed quickly; can be stored for up to an hour if chilled to 5C. Predicted PaO2 90-100 mm Hg and PaCO2 31 mm Hg (predicted 36-46mm Hg ), pH predicted 7.35-7.45. Acute changes in PaCO2 result in predictable changes in pH and plasma carbonic acid. This represents the respiratory acid-base change. Although the relation is not completely linear, within clinically relevant ranges it is sufficiently linear to allow the following guideline to estimate the degrees of abnormality resulting from acute changes in PaCO2 :

  • For every increase in PaCO2 of 20 mm Hg (2.6 kPa) above normal the pH falls by 0.1
  • For every decrease of PaCO2 of 10 mm Hg (1.3 kPa) below normal the pH rises by 0.1.

Any change in pH outside these parameters is therefore metabolic in origin.

From ABC of oxygen, Williams, BMJ Clinical Review,

CXR would show if he was experiencing any lung damage, and may assist in checking for pneumothorax in an at-risk patient, e.g. tall and slim, but is unlikely to show much in asthmacase, maybe some hyperinflation as narrowed airways prevent complete expiration. Microscopy is rarely part of routine asthma workup, but asthma has several characteristic findings – bronchial smooth muscle hypertrophy, and eosinophil-derived protein crystalloids (Charcot-Leyden crystals) and mucus (Curchmann spirals) may be seen.


Asthma, allergies, and stress

August 23, 2011


Allergy and other Hypersensitivities

From P. Wood, Ch 13

Excessive production of antibody against harmless antigens can cause disease = hypersensitivity. Type 1 hypersensitivity is allergies; type 2 is caused by cytotoxic antibodies against normal or modified tissue components and type 3 is caused by the deposition of antibody-antigen

Thorax 1998;53:1066-1074 – Review of psychosocial stress and asthma: an integrated biopsychosocial approach, RJ Wright, M Rodriguez, S Cohen

Asthma and allergic disease as chronic inflammatory processes regulated through complicated immune phenomena in which many cells (mast cells, eosinophils, and T lymphocytes) and associated cytokines play a part. Mechanisms of airway inflammation involve a cascade of events that include the release of immunological mediators triggered by both IgE dependent and independent mechanisms. Processes regulated through cytokines of the T helper cell (Th2 phenotype) such as interleukin (IL)-4, IL-5, and IL-13 are thought to promote recruitment of inflammatory cells which may initiate and/or potentiate allergic inflammation and the release of mediators that cause contraction of smooth muscle and influence mucus production. The leukotrienes (LTs), including LTC4, LTD4, and LTE4, are known potent airway constrictors, have been observed to play a part in mucus secretion, and are thought to have an important role in asthma. A substantial body of evidence supports the role of complex neural mechanisms and alterations of autonomic nervous system control in the pathophysiology and symptomatology of asthma. Autonomic nerves can impact airway calibre and function via effects on airway smooth muscle, bronchial vessels, and mucus glands. Hormones and neuropeptides released into the circulation when individuals experience stress are also thought to be involved in regulating both inflammatory and airway responses

In the initial phases, narrowing of the airways in asthma is thought to result primarily from inflammation. Current theory holds that bronchial constriction is due to some combination of vagal input plus inflammation, with the relative importance of these factors being dependent upon genetic and environmental influences.

The relative strength of sympathetic versus parasympathetic control in response to certain forms of stress differs with the individual. Some show a predominantly parasympathetic response and may be particularly susceptible to stress induced bronchoconstriction.

Newborn immune response is Th2 dominated, and Th1 memory cells develop 3-6 months after birth. Th2 dominated immune response later in life associated with atopy. It has been speculated that stress triggers hormones in the early months of life which may influence Th2 cell predominance.

<H2>Asthma and stress</h2>

Psychological stress has been shown to precipitate asthma attacks and significant worsenings of asthma symptoms.

[Stress and Asthma – Eur Respir J 2003; 22: 574–575, Evaluating the effects of stress on asthma: a paradoxical challenge, M.D. Klinnert]

A paradox wherein the typical physiological reaction to emotional arousal was the opposite of physiological events associated with bronchoconstriction.…emotional arousal is accompanied by sympathetic activation, which is physiologically associated with bronchodilation.

Chronic stress has been used to refer to challenges that have an impact on an individual for a long enough period of time that the body’s physiological reactions have returned to baseline, although they may have instigated rebound or compensatory mechanisms in the process. The period of time referred to by the term “chronic” may be hours, days, weeks or years. Given time, the adjustments made by the body may result in a new homeostatic baseline, such as parasympathetic rebound in the short term or shifts in sympathetic/ parasympathetic balance in the long term, or increases in allostatic load. SANDBERG et al. showed that severe negative life events increased the risk of children’s asthma attacks over subsequent weeks. A distinction between intrinsic and extrinsic (or allergic) asthma; individuals with intrinsic asthma have been reported to be more vulnerable to emotional or stress-induced breathing problems.

[Thorax 1998;53:1066-1074 – Review of psychosocial stress and asthma: an integrated biopsychosocial approach, RJ Wright, M Rodriguez, S Cohen]

Asthmatic subjects frequently have associated underlying psychological distress (depression and anxiety). Development of psychological distress in children has been associated with asthma that is more difficult to manage, requiring higher doses of steroids, more frequent and prolonged admissions to hospital, and greater functional disability. Asthmatics with comorbid psychological symptoms are more often non-compliant. Psychological morbidity has been linked to asthmatic mortality. Mechanisms linking psychological morbidity and asthma morbidity and mortality are complex and remain largely undefined.

Hypothalamic- pituitary-adrenocortical (HPA) axis leads to release of corticosteroids, principally cortisol. Chronic stress may induce a state of hyporesponsiveness of the HPA axis whereby cortisol secretion is attenuated, leading to increased secretion of inflammatory cytokines typically counterregulated by cortisol. Furthermore, a state of stress induced HPA hyporesponsiveness in some research subjects has been associated with other inflammatory disorders. A hyporesponsive HPA axis may explain stress induced exacerbations of asthma in certain subgroups of asthmatics and increased association of asthma with particular psychological states.

Psychological stress activates the HPA axis resulting in the release of cortisol, which has known anti-inflammatory effects. However, other regulatory pituitary (i.e. corticotrophin) and hypothalamic hormones (i.e. CRH and arginine vasopressin (AVP)) of the HPA axis have systemic immunopotentiating and proinflammatory effects.

Asthmatic subjects have been characterised by β adrenergic hyporesponsiveness and α-adrenergic and cholinergic hyperresponsiveness. Defects in the function of the autonomic nervous system have also been demonstrated in psychological states including depression, PTSD, and psychomotor agitation.In depression and PTSD, studies of central mediators in the brain also demonstrate parasympathetic hyperresponsiveness and β adrenergic hyporesponsiveness.Whereas increased α adrenergic and cholinergic responsiveness distal from the airway has also been demonstrated in asthmatic patients, a similar imbalance to the autonomic nervous system in the central nervous system among asthmatic populations has not been demonstrated.These data raise the question of common biological pathways.

The strongest suggestion from the current literature is that psychological stress may influence the pathophysiology of asthma by increasing the risk of respiratory infections. Viral respiratory infections damage the airway epithelium causing inflammation. Another mechanism involves the stimulation of virus specific IgE antibody … [and] increasing the release of inflammatory mediators from mast cells and the subsequent cascade of inflammatory events characteristic of asthma


Anatomy and physiology of the lungs

August 23, 2011


From Ward – Respiratory System At a Glance

Regulation of blood pH to 7.35-7.45 is vital for correct functioning of the body. Carriage of CO2 in the blood and its removal in the lungs has an important influence on acid-base status, as around 100 times more acid equivalents are expired every hour in the form of CO2/carbonic acid than are excreted as fixed acids by the kidneys. Buffers bind or release H+ according to the pH: this limits the changes in pH that occur when acid is added. The relationship between the amount of acid equivalent added to a solution containing a buffer and the resultant change in pH is known as the buffer curve. Buffers are most effective when pH is close to their pKa. The most important buffers in blood are haemoglobin and carbonic-acid-bicarbonate.

In a ‘perfect lung’ all alveoli would receive an equal share of alveolar ventilation and the pulmonary capillaries that surround different alveoli would receive an equal share of cardiac output i.e. ventilation and perfusion would be perfectly matched.

Diseased lungs may have marked mismatch between ventilation and perfusion. Some alveoli are relatively overventilated while others are relatively overperfused (the most extreme form of this is shunt where blood flows past alveoli with no gas exchange taking place. Well ventilated alveoli (high PO2 in capillary blood) cannot make up for the oxygen not transferred in the underventilated alveoli with a low PO2 in the capillary blood. This is because there is a maximum amount of oxygen which can combine with haemoglobin (see haemoglobin-oxygen dissociation curve figure 2a). The pulmonary venous blood (mixture of pulmonary capillary blood from all alveoli) will therefore have a lower PO2 than the PO2 in the alveoli (PAO2). Even normal lungs have some degree of ventilation/perfusion mismatch; the upper zones are relatively overventilated while the lower zones are relatively overperfused and underventilated.

<h2>Oxygen carriage by the blood</h2>

Oxygen is carried in the blood in two forms. Most is carried combined with haemoglobin (figure 2b) but there is a very small amount dissolved in the plasma. Each gram of haemoglobin can carry 1.31 ml of oxygen when it is fully saturated. Therefore every litre of blood with a Hb concentration of 15g/dl can carry about 200 mls of oxygen when fully saturated with oxygen (PO2 >100 mmHg). At this PO2 only 3 ml of oxygen will dissolve in every litre of plasma.








Breathing 100% oxygen has only a small difference on teh oxygen content of blood. If the PO2 of oxygen in arterial blood (PAO2) is increased significantly (by breathing 100% oxygen) then a small amount of extra oxygen will dissolve in the plasma (at a rate of 0.003 ml O2/100ml of blood /mmHg PO2) but there will normally be no significant increase in the amount carried by haemoglobin, which is already >95% saturated with oxygen. When considering the adequacy of oxygen delivery to the tissues, three factors need to be taken into account, haemoglobin concentration, cardiac output and oxygenation.

<h2>Oxygen cascade</h2>

Oxygen moves down the pressure or concentration gradient from a relatively high level in air, to the levels in the respiratory tract and then alveolar gas, the arterial blood, capillaries and finally the cell. The PO2 reaches the lowest level (4-20 mmHg) in the mitochondria. This decrease in PO2 from air to the mitochondrion is known as the oxygen cascade and the size of any one step in the cascade may be increased under pathological circumstances and may result in hypoxia (figure 3).

<h2>en delivery</h2>

The quantity of oxygen made available to the body in one minute is known as the oxygen delivery and is equal to the cardiac output x the arterial oxygen content (see previously) ie. 5000ml blood/min x 200 mlO2/1000 ml blood = 1000ml O2/min.

Oxygen delivery (mls O2/min) = Cardiac output (litres/min) x Hb concentration (g/litre) x 1.31 (mls O2/g Hb) x % saturation

Oxygen consumption

Approximately 250 ml of oxygen are used every minute by a conscious resting person (oxygen consumption) and therefore about 25% of the arterial oxygen is used every minute. The haemoglobin in mixed venous blood is about 70% saturated (95% less 25%).

In general there is more oxygen delivered to the cells of the body than they actually use. When oxygen consumption is high (eg. during exercise) the increased oxygen requirement is usually provided by an increased cardiac output – see formula above for how this works. However, a low cardiac output, a low haemoglobin concentration (anaemia) or a low haemoglobin O2 saturation will result in an inadequate delivery of oxygen, unless a compensatory change occurs in one of the other factors. Alternatively, if oxygen delivery falls relative to oxygen consumption the tissues extract more oxygen from the haemoglobin (the saturation of mixed venous blood falls below 70%)(a-b in figure 4). A reduction below point ‘c’ in figure 4 cannot be compensated for by an increased oxygen extraction and results in anaerobic metabolism and lactic acidosis.

<h2>Alveolar structure<2>

From Vander

Typically, a single alveolar wall separates the air in two adjacent alveoli. Most of the air-facing surfaces of the wall are lined by a continuous layer, one cell thick, of flat epithelial cells termed type 1 alveolar cells. Interspersed between these are thicker specialised cells termed type 2 alveolar cells that produce surfactant. The alveolar walls contain capillaries and a very small interstitial space, which consists of interstitial fluid and a loose meshwork of connective tissue. In many places the interstitial space is absent altogether, and the basement membranes of the alveolar-surface epithelium and the capillary-wall endothelium fuse. Thus the blood within an alveolar-wall capillary is separated from the air within the alvoeolus by an extremely thin barrier (0.2micrometer, compared with the 7micrometer diameter of an average red blood cell). Large area and thin barrier allow rapid exchange of large quantities of oxygen and carbon dioxide by perfusion. In some of the alveolar walls, pores permit the flow of air between alveoli, which can be important in obstructive lung disease.

The balance of oxygen entering the body cells and carbon dioxide leaving cells is known as the respiratory quotient (RQ). Its value depends on which nutrients are used for energy – 1 for carbohydrate, 0.7 for fat, 0.8 for protein. On a mixed diet RQ is approximately 0.8, that is 8 molecules of carbon dioxide are produced for every 10 molecules of oxygen consumed.

Normal alveolar gas pressures are PO2 = 105mmHg and PCO2 = 40mmHg