Asthma Holistic Treatments

Asthma Free Forever

Finally, international author, asthma expert Jerry Ericson reveals the secrets to overcoming asthma. Asthma Free Forever reveals a proven success methods and simple step-by-step, easy to follow strategies to achieve the success they have been dreaming of. A well organized and precisely explained all natural asthma recovery methods keeps you out from having on the counter drugs pr from so highly priced medicines prescribed by the doctors, even you need to revolve around the doctor for good results to be shown, there is all consists inside the content of this online health guide and by following it properly and timely you will get treated soon. Along with a wealth of real-life success stories, these strategies can prevent panic, clarify the meaning of symptoms, increase energy levels, and achieve a deeper healing than you ever thought possible. Whether used as a complement to conventional medicine or as a medication reducing alternative, this program empowers people of all ages to live more active, fulfilling lives. Read more here...

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Mortality in asthma patients undergoing mechanical ventilation

Reported mortalities vary considerably from 38 per cent to zero. We have reviewed 511 cases reported over the past three decades and have identified a crude mortality of 11 to 21 per cent, including patients who have suffered brain injury from cardiorespiratory arrest prior to ventilatory support. Exclusion of these latter cases reduces mortality to 16 per cent. Death in asthmatics receiving mechanical ventilation appears to be the result of barotrauma, hypotension, cardiac arrhythmias, or sepsis.

Aminophylline and theophylline

Concomitant drugs (eg, erythromycin or carbamazepine) may increase serum theophylline levels by decreasing drug metabolism. -Aminophylline loading dose 5-6 mg kg total body weight IV over 20-30 min 1 mg kg of aminophylline will raise serum level by 2 mcg mL . -Aminophylline maintenance as continuous IV infusion (based on ideal body weight) 1-6 month 0.5 mg kg hr 6-12 month 0.6-0.75 mg kg hr 1-10 year 1.0 mg kg hr 10-16 year 0.75-0.9 mg kg hr 16 year 0.7 mg kg hr OR -Theophylline PO maintenance -Give theophylline as sustained-release theophylline preparation q8-12h or liquid immediate release q6h. food 50, 75, 100, 125, 200, 300 mg caps q8-12h -Theophylline oral liquid 80 mg 15 mL, 10 mg mL q6-8h. cut in half do not crush q8-12h. -Theophylline Products Cap 100, 200 mg mcg actuation -Triamcinolone (Azmacort) MDI 1-4 puffs bid-qid 100 mcg puff Cromolyn nedocromil -Cromolyn sodium (Intal) MDI 2-4 puffs qid 800 mcg puff or nebulized 20 mg bid-qid 10 mg mL 2...

Asthmaventilatory management Early period

Initially give low VT (5ml kg) breaths at low rate (5-10 min) to assess degree of bronchospasm and air trapping. Slowly increase VT (to 7-8ml kg) increase rate, taking care to avoid significant air trapping and high inspiratory pressures. Low rates with prolonged I E ratio (e.g. 1 1) may be advantageous. Avoid very short expiratory times.Do not strive to achieve normocapnia. 2. Administer muscle relaxants for a minimum 2-4h, until severe bronchospasm has abated and gas exchange improved. Although atracurium may cause histamine release, it does not appear clinically to worsen bronchospasm. 5. If severe bronchospasm persists, consider injecting 1-2ml of 1 10,000 epinephrine down endotracheal tube. Repeat at 5min intervals as necessary.

Obstructive Sleep Apnea And Bronchial Asthma

OSA may represent a trigger for nocturnal acute asthma attacks. Indeed, in patients with concomitant OSA and bronchial asthma, CPAP therapy was demonstrated to be effective also in improving asthma control (75). Bronchial asthma is a chronic inflammatory disease of the airways and is prevalent in the general population. Therapy usually results in a good control of symptoms and airway obstruction in the great majority of patients. However, some patients show frequent and severe exacerbations, with increased morbidity and

Asthma See Also Chapter

Nocturnal worsening of asthma symptoms has been an acknowledged feature of asthma since the fifth century a.d. when Aurelianus Caelius (10) described an increased nocturnal frequency of asthma attacks. Turner Warwick (11) observed that up to 64 of asthmatic patients were awakened with symptoms of asthma at least three nights per week. In a more recent questionnaire-based study, Bellia et al. (12) assessed the frequency of nocturnal asthma symptoms in 1100 patients randomly selected from general medical practices. Up to 24 of patients with the diagnosis of asthma experienced troublesome nocturnal symptoms sometimes, while 15 of patients experienced such symptoms often. Peak expiratory flow rate (PEFR) measurements are widely used to diagnose nocturnal worsening of asthma, which is typically indicated by at least a 15 decrement in PEFR from bedtime to morning awakening. The etiology of the nocturnal worsening of asthma is controversial, and is likely multifactorial. Potential mechanisms...

Cromolyn and Nedocromil

Although cromolyn sodium (Intal) and nedocromil sodium (Tilade) are widely known for their ability to prevent the release of histamine and other inflammatory mediators by mast cells during the early response to antigen challenge, these drugs have a wide variety of inhibitory effects on many cell types, including eosinophils, neutrophils, monocytes, and neurons. Cromolyn sodium and nedocromil sodium are used as pulmonary inhalants in the treatment of asthma. Nasal (Nasalcrom) and ophthalmic (Opticrom) preparations of cromolyn sodium can be used to reduce the symptoms of allergic rhinitis and conjunctivitis. More detailed information on these compounds may be found in Chapter 39.

Pharmacogenetics Of Theophylline

B2-agonists act by increasing the cAMP content of the cell control of cAMP breakdown is by tissue phosphodiesterases. Theophylline has been used in the treatment of asthma and COPD for at least 70 years. Theophylline has both bronchodilator and anti-inflammatory properties. The bronchodilator component of the drug action is thought to be at least in part mediated by phosphodiesterase inhibition in airway smooth muscle cells, leading to elevated cAMP levels and hence smooth muscle relaxation. The phosphodiesterase (PDE) 4D subfamily is thought to be the critical family of phosphodiesterases involved in the hydrolysis of cAMP in airway smooth muscle cells and is probably the main target of theophylline. Polymorphism within the PDE4D gene could potentially influence theophylline efficacy, but to date no specific gene polymorphisms have been associated with theophylline efficacy or adverse effects in asthma. The development of selective PDE4 inhibitors for the treatment of COPD will lead...

Bronchodilator Agents

The bronchodilators are agents that cause expansion of the air passages of the lungs. This allows the patient to breathe more easily and are of value in overcoming acute bronchospasms. They are employed as adjuncts in prophylactic and symptomatic treatment of the individual complications of obstructive pulmonary diseases such as asthma, bronchitis, and emphysema. Most of these agents have been discussed in other lessons of the pharmacology series. b. Bronchodilator Agents (Sympathomimetics). Sympathomimetic bronchodilators act by relaxing contractions of the smooth muscle of the bronchioles. These agents are often referred to as Beta agonists . (1) Albuterol (Proventil , Ventolin ). Albuterol is a short acting beta-agonist or bronchodilator. It is used in the relief and prevention of bronchospasm and in the prevention of exercise-induced bronchospasm. Albuterol is available as an inhalation aerosol, inhalation solution, inhalation capsules, regular and sustained release...

Additional bronchodilators

Ketamine, an intravenous anesthetic with sedative, analgesic, anesthetic, and bronchodilating properties, has been used successfully for the emergency intubation of patients with severe asthma. The usual intubating dose is 1 to 2 mg kg followed by an infusion of 10 to 40 pg kg min to maintain a bronchodilating and sedative effect. Ketamine increases catecholamine levels and directly relaxes bronchial smooth muscle. Anecdotal uncontrolled experience has suggested that magnesium sulfate may offer useful bronchodilator properties but the mechanism is unknown. One possibility is that magnesium inhibits the calcium channels of airway smooth muscle, thus interfering in calcium-mediated smooth muscle contraction. It has been reported that intravenous administration of 1 g magnesium sulfate in the management of acute respiratory failure in a 72-year-old asthmatic produced sufficient improvement to avoid intubation. However, controlled studies have failed to confirm significant bronchodilator...

Methylated xanthines theophylline and aminophylline

Theophylline is inferior to b-agonists as first-line treatment of acute asthmatic attacks, although it may have a synergistic action with b-agonists. It can be combined with ethylenediamine (aminophylline) to become 20 times more soluble than theophylline alone. The mode of action of theophylline is unclear, but it is known to inhibit the enzyme phosphodiesterase to decrease the metabolism of cyclic AMP. The dose necessary for this action is much higher than that used clinically. Theophylline has a direct relaxant effect on bronchial smooth muscle, a mild inotropic effect, and a diuretic effect, and it delays the onset of diaphragmatic muscle fatigue. It is available intravenously (aminophylline) and orally (theophylline) in preparations with different lengths of action. The onset of action by the intravenous route is slower than that of the b-agonists because of the need to deliver it over 20 to 30 min. Side-effects include nausea and vomiting, central nervous system irritability and...

Aminophylline and Theophylline secondline therapy

-Aminophylline load dose 5.6 mg kg total body weight in 100 mL D5W IV over 20min. Maintenance of 0.5-0.6 mg kg ideal body weight h (500 mg in 250 mL D5W) reduce if elderly, heart liver failure (0.2-0.4 mg kg hr). Reduce load 50-75 if taking theophylline (1 mg kg of aminophylline will raise levels 2 mcg mL) OR -Theophylline IV solution loading dose 4.5 mg kg total body weight, then 0.40.5 mg kg ideal body weight hr. -Theophylline (Theo-Dur) PO loading dose of 6 mg kg, then maintenance of 100-400 mg PO bid-tid (3 mg kg q8h) 80 of total daily IV aminophylline in 2-3 doses.

Respiratory disorders Asthma

Asthma affects between 3 and 5 per cent of the population of the United States. The three hallmarks of the disease are airway inflammation, airway hyper-responsiveness, and a partially reversible airway obstruction. (3.9 The diagnosis is based on the presence of episodic dyspnoea and wheezing. Pulmonary function studies may be normal or can show the obstruction. Outpatient treatment is usually instituted with an inhaled b-adrenergic agent. If symptoms continue, an inhaled corticosteroid is added. If symptoms still do not respond, doses of inhaled agents are increased, cromolyn is added, or oral corticosteroids are prescribed. In addition to the psychiatric aspects of asthma symptoms, the treatments may produce significant psychiatric symptomatology. Asthma is one of the classic 'psychosomatic diseases'. Emotional arousal causes changes in airway tone. The severity of an asthma attack is highly correlated with presence of major depressive disorder, panic attacks, and level of fear....


Asthma, a condition usually caused by allergic reactions to substances in the environment, affects many people. The allergic reactions cause the bronchioles to spasm. Hence, the flow of air into and out of the lungs becomes impaired. For some unknown reason, the flow of air out of the lungs is more impeded than the flow of air into the lungs. Hence, the person with asthma often finds it more difficult to expire (expel the air) than to inspire. Furthermore, such labored breathing, after many years, often results in the asthma-sufferer having a barrel-shaped chest.

Antiasthma Drugs

Asthma is a disease characterized by reversible airways obstruction and increased responsiveness of the airways to specific and nonspecific bronchocon-strictor stimuli. Indeed, the latter feature may be used in diagnosis of asthma (vide infra). Obstruction to the flow of air in asthma is the product of three factors smooth muscle contraction, mucosal edema, and augmented mucus secretion. Pathological features, such as infiltration of the airway walls with inflammatory cells (e.g., eosinophils, neutrophils), and the efficacy of anti-inflammatory steroids in treating the disease have pointed to an important role of inflammation in the disease process. Episodes of airway obstruction or bronchoconstriction may be induced in asthmatics by exposure to stimuli to which they are sensitized, such as inhalation of a specific pollen or house dust mite, or exposure to an occupational stimulus, e.g., red cedar dust 47 . Binding of antigen (e.g., pollen) to specific receptors (antibodies) on the...


Theophylline has utility in patients with significant side effects from high dose beta agonists as well as in patients with nocturnal symptoms. It has been shown to improve airflow, decrease dyspnea, and improve ventilation, arterial blood gases, exercise tolerance, and respiratory muscle function. 3. Dosage of long-acting theophylline. 200-300 mg bid. Theophylline preparations with 24 hour action may be administered once a day in the early evening. Theo-24, 100-400 mg qd 100, 200, 300, 400 mg . E. Corticosteroids 1. Corticosteroids produce a favorable response during acute COPD exacerbations, improving symptoms and reducing the length of hospitalization. Short courses of corticosteroids should be considered in patients with acute exacerbations who are unresponsive to aggressive inhaled bronchodilator therapy.

Management of asthma

Asthmatics must be managed in a well-monitored area. If clinical features are severe, they should be admitted to an intensive care unit where rapid institution of mechanical ventilation is available. Monitoring should comprise, as a minimum, pulse oximetry, continuous ECG, regular blood pressure measurement and blood gas analysis. If severe, an intra-arterial cannula central venous access should be inserted. 4. IV bronchodilators, e.g. salbutamol, magnesium sulphate.

Patterns of asthma

Asthma attack may progressively worsen over days, with more frequent, severe, and long-lasting episodes of bronchial obstruction, often associated with thick and viscid expectorations. A striking feature among clinical signs of severity is exhaustion. In contrast, the attack may supervene suddenly in an apparently previously symptomless patient and develop in a fulminant way leading to severe respiratory failure in minutes or a few hours. This has been called sudden asphyxic asthma. Most of these patients are in coma, with a high incidence of respiratory arrest and cardiovascular instability. They develop marked mixed acidosis or extreme hypercapnia (with PaCO2 reaching values above 200 mmHg (26.7 kPa)). Response to therapy is usually very rapid, with fast normalization of PaCO2 and pulmonary function tests. In view of the scanty expectorations and rapid time course, which contrasts with other asthmatics experiencing slow-onset attack, bronchospasm may be the preponderant pathogenic...


Bronchodilators relax smooth muscles around the bronchioles restoring airflow to the lungs. Sympathomimetics are bronchodilators that increase the production of cyclic AMP, causing dilation of the bronchioles by acting as adrenergic agonistic. Ipratropium bromide (Atrovent) is an anticholinergic drug that inhibits vagalmediated response by reversing the action of acetylcholine, producing smooth muscle relaxation. It is a newer medication that dilates bronchioles with few systemic effects. Ipratropium bromide (Atrovent) is used five minutes before glu-cocorticoid (steroid) or cromolyn are inhaled so the bronchioles dilate enabling the steroids to be deposited in the bronchioles. Sometimes ipratropium bromide is combined with albuterol sulfate (Combivent) to treat chronic bronchitis for more effective and longer duration than if each is used alone. Methylxanthine (xanthine) derivatives are a second group of bronchodilators used to treat asthma. They include aminophylline, theophylline,...

Status Asthmaticus

Status asthmaticus is a life-threatening exacerbation of asthma symptoms that is unresponsive to standard therapy. It must be treated very aggressively, and hospital-ization may be necessary. A provocative factor such as prolonged allergen exposure or a respiratory infection often precedes status asthmaticus. A rapid increase in the daily use of bronchodilators to control acute symptoms is a danger sign of an impending crisis. Treatment includes oxygen, inhaled short-acting p2-agonists, and oral or parenteral corticosteroids. Subcutaneous p-agonists can be given to those who respond poorly to inhaled adrenomimetics. Inhaled ipratropium may be effective in some patients.


A variety of agents act on airway smooth muscle to affect its state of contraction (tone), the majority of which act by specific receptors on the smooth muscle cell (Table 2). Bronchodilator drugs may be agonists of receptors subserving airway smooth muscle relaxation (e.g., b2-adrenoceptor agonists) or antagonists of receptors mediating airway smooth muscle concentration (e.g., muscarinic cholinoceptor antagonists). Other drugs may exert actions on cellular mechanisms that influence the intracellular processes of airway smooth muscle contraction or relaxation (e.g., xanthine derivatives). The sites of action of these drugs are shown in Fig. 2.

COPD and asthma

It is generally believed that COPD increases the risk of postoperative pulmonary complications. There are few or no data estimating the surgical risk in the asthmatic patient. Ideally, medical management is maximized prior to surgery. The patient should be free of wheezes and active infection. In one study, a forced vital capacity in 1 s (FEV. ) of less than 65 per cent of the predicted value and a forced vital capacity of less than 70 per cent of the predicted value resulted in a 100 per cent complication rate. However, there are also studies where patients with severe air-flow obstruction did not suffer any pulmonary complications. Other than in pulmonary resection, there is no level of pulmonary function that is an absolute contraindication to surgery. The preoperative test with the most utility in predicting postoperative complications is a reduced arterial PO2. In the case of a pulmonary resection, an FEVi below 800 ml contraindicates surgery. COPD and asthma pose special...

Foreword to the First Edition

The metered-dose aerosol inhaler is not only a most convenient system for the delivery of therapeutically active drugs but it has proven to be a life-saving device for many asthmatics. This system has made it possible for millions of asthma sufferers to lead normal lives. The convenience of self-administering a dose of drug accurately and quickly has made the metered-dose aerosol the dosage form of choice for the delivery of drugs to the respiratory system. From epinephrine to albuterol, from triamcinolone to flunisolide, from proteins and peptides to hormones, this dosage form has proven its value.

Setting up the mechanical ventilator Tidal volume

Conventionally set at 7-10ml kg, though recent data suggest lower values (6-7ml kg) may be better in severe acute respiratory failure, reducing barotrauma and improving outcome. In severe airflow limitation (e.g. asthma, acute bronchitis) smaller VT and minute volume may be needed to allow prolonged expiration.

Anatomy Of The Airways

Exchange constitute the conducting zone of the airways and extend from the trachea to the terminal bronchioles. This region is the principal site of airway obstruction in obstructive lung diseases, such as asthma. The respiratory zone includes airways involved with gas exchange and comprises respiratory bronchioles, alveolar ducts, and alveolar sacs. As such, conducting and respiratory zones of the airways may be distinguished simply by the absence or presence of alveolar pockets (which confer the gas exchange function). Regions within each zone may be classified further on a histological basis. For example, the contribution of cartilage to the airway wall is one means of differentiating the trachea from bronchi and bronchioles because cartilage exists as incomplete rings in the trachea, regresses to irregularly shaped plates in bronchi, and is absent from bronchioles. Also, respiratory bronchioles may be discriminated from terminal bronchioles by the presence of associated alveoli.

Inspiratory flow resistance

The expiratory resistance may also influence the distribution of ventilation. Chronic obstructive lung disease (asthma, chronic bronchitis, emphysema) causes airway narrowing that may become apparent mainly or solely during expiration because of an expiratory muscle activity that compresses the lung and the airways. Lung regions that have not emptied completely because of an expiratory resistance exert an increased elastic recoil which will impede the inspiration of gas to those regions. It is not clear to what extent this has any bearing on acute lung disease requiring intensive care.

Contrastinduced Nephrotoxicity

Over the years, many drug therapies have been proposed to reduce the incidence of CIN. Attempts to improve upon saline administration alone by adding other drugs such as mannitol, furosemide, theophylline, calcium antagonists, dopa-mine, endothelin receptor blockers, prostaglandin E1, and atrial natriuretic peptide have not proven uniformly successful (36-38). Many of these drugs have side effects the significance of which are not yet fully understood. The search for pharmaco-therapeutic agents that might mitigate the nephrotoxic effects of contrast media continues, however.

Intrinsic PEEP autoPEEP air trapping PEEPi

Increased level of PEEP due to insufficient time for expiration, leading to 'air trapping', CO2 retention, increased airway pressures and increased FRC. Seen in pathological conditions of increased airflow resistance (e.g. asthma, emphysema) and when insufficient expiratory time is set on the ventilator. Used clinically in inverse ratio ventilation to increase oxygenation and decrease peak airway pressures. High levels of PEEPi can, however, slow weaning by an increased work of breathing use of extrinsic PEEP may overcome this. PEEPi can be measured by temporarily occluding the expiratory outlet of ventilator at end-expiration for a few seconds to allow equilibration of pressure between upper and lower airway and then reading the ventilator pressure gauge (or print-out).

Radiographic and Other Studies

If patient is oversedated with narcotics or benzodiazepines, consider administration of specific antidote. Electrolyte abnormalities (eg, hypokalemia, hypophosphatemia, hypocalcemia) may lead to muscular weakness and should be rapidly corrected. If patient has a neuromuscular disorder, noninvasive ventilation, such as continuous or bilevel positive airway pressure (CPAP or BiPAP), may be helpful. Extrinsic pulmonary disease (eg, pneumothorax, pleural effusion) should be treated specifically. Foreign bodies will require removal. Severe bron-choconstriction, as in asthma, should be aggressively treated with 0-agonists, steroids, ipratropium, and possibly magnesium. Endotracheal intubation and mechanical ventilation should be considered if mental status is abnormal, if patient appears to be tired from the high work of breathing, if there is poor response to initial therapies, or if oxygenation is compromised.

Obesity as a Chronic Disease

Many of the 21st-century healthcare challenges will be directed toward management of chronic diseases. Congestive heart failure, asthma, and diabetes are examples of chronic diseases that command a tremendous amount of medical resources and provider time. The prevalence of these diseases in the American population is staggering. For instance, a person aged 40 or older has a 1 in 5 lifetime chance of developing congestive heart failure 1 . An infant born in the year 2000, depending on ethnicity, has a1in3toa1in2 lifetime chance of developing diabetes 2 . The National Health Interview Survey reported that for 2001 an estimated 31 million Americans would be diagnosed by a healthcare provider with asthma within their lifetime 3 . These three chronic diseases impact the lives of millions of patients every day. Healthcare systems, procedures, and protocols are in place to assist the patient in living with the disease. However, the key factor in controlling any chronic disease is patient...

Respiratory muscle fatigue

Temporal adaptation allows a significant disability to be tolerated with a reduction or absence of symptoms. This can be clinically dangerous, since it may result in underestimation of actual risk. About 25 per cent of the change in lung volume is necessary in acute asthma before any change in symptoms is noticed. Thus larger changes in background load are required in patients with abnormal pulmonary mechanics, i.e. patients with chronic background load (e.g. chronic inadequately treated asthma), before changes in sensation occur. However, if the change in background load is recent, smaller changes in sensation are noticed. There are considerable variations between individuals. Identification of the subgroup of patients who have impaired perception of breathlessness (e.g. external loading) is clinically important.

Chapter References

Burdon, J.G.W., Juniper, E.F., Killian, K.J., Hargreave, F.E., and Campbell, E.J.M. (1982). The perception of breathlessness in asthma. American Review of Respiratory Disease, 126, 825-8. Killian, K. and Campbell, E.J.M. (1995). Dyspnea. In The thorax (ed. C. Roussos), pp. 1709-47. Marcel Dekker, New York. Lougheed, M.D., Lam, M., Forket, L., Webb, K.A., and O'Donnell, D.E. (1993). Breathlessness during acute bronchoconstriction in asthma pathophysiologic mechanisms. American Review of Respiratory Disease, 148, 1452-9.

Pharmacological intervention

Although obstruction is not reversible with bronchodilator treatment, it is possible that commonly used drugs may have an extrapulmonary action in reducing dyspnea. Theophylline improves diaphragmatic contraction, increases cardiac output, and reduces dyspnea, but its clinical significance has not been determined. Breathlessness is common in bronchial carcinoma related to airflow obstruction, and bronchodilator therapy may provide alleviation.

Mechanisms involved in indirect pulmonary insults

The primary mechanism responsible for causing ARDS after extrathoracic injuries is the delivery to the lung of activated cells, inflammatory mediators, and microaggregates originating from a remote site. This form of ARDS constitutes a specific expression of a generalized inflammatory reaction, in which blood-borne cells (monocytes, polymorphonuclear neutrophils, platelets, erythrocytes) and vascular endothelial cells are the principal actors. After severe trauma, infection, or shock states with ischemia followed by reperfusion, cellular functions are activated in situ, initiating a localized inflammatory reaction. Phagocytic cells are stimulated by the trauma itself or by bacterial toxins, while endothelial cells are activated by both the initial lesion and the stimulated leukocytes. Under these circumstances, the usually antiaggregant and anticoagulant activity of the endothelium (via production of prostacyclin, thrombomodulin, etc.) becomes predominantly procoagulant (decreased...

Strategies to reduce the inspiratory load caused by intrinsic PEEP

As indicated in Fig 2, the aim of treatment of COPD patients with respiratory failure should be to reduce respiratory frequency (and hence increase expiratory time) and decrease flow resistance. To the extent that tachypnea is due to fever and or airway infection, an improvement of these variables by conventional treatment should be beneficial. Similarly, administration of bronchodilators may be useful in reducing both flow resistance and intrinsic PEEP. A less conventional but promising approach to dealing with intrinsic PEEP is the use of continuous positive airways pressure (CPAP). Indeed, CPAP has been found to reduce the magnitude of inspiratory muscle effort and work of breathing in stable patients with severe COPD and in patients with severe COPD during weaning from mechanical ventilation. This is related to a reduction in the inspiratory load imposed by intrinsic PEEP, and considerably improves patient-ventilator synchrony by decreasing the number of breaths where the patient...

Preface to the First Edition

Includes chapters on BALT and pulmonary diseases, mucosal immunity in asthma, respiratory infections, and inhalant allergy (Chapters 43-46). Section G presents information on the oral cavity, upper airway, and mucosal regions in the head and neck (Chapters 47-50), as well as ocular immunity, tonsils and adenoids, and middle ear. Sections H and I are devoted to mammary glands and genitourinary tract, respectively. These sections consist of chapters on milk, immunological effects of breast feeding (Chapters 51 and 52), IgA nephropathy, immunology of female and male reproductive tracts, endocrine regulation of genital immunity, mucosal immunopathophysiol-ogy of HIV infection, and genital infections relative to maternal and infant disease (Chapters 53-58).

The Central Role of the Tryptophan Metabolic Pathway in Tolerance and Immunity to Fungi

Early Treg cells, by affecting IFN-y-production, indirectly exert a fine control over the induction of late tolerogenic Treg cells. Thus, a unifying mechanism linking natural Treg cells to tolerogenic respiratory Treg cells in response to the fungus is consistent with the revisited 'hygiene hypothesis' of allergy in infections, and may provide at the same time mechanistic explanations for the significance of the variable level of IFN-y seen in allergic diseases and asthma and for the paradoxical worsening effect on allergy of Th1 cells. IDO has a unique and central role in this process as it may participate in the effector and inductive phases of anti-inflammatory and tolerogenic Treg cells.

Respiratory consequences

With the development of hyperinflation, auto-PEEP, and higher airways resistance, initiation of inspiratory flow requires greater force. Normal inspiration is achieved by inspiratory muscle work generating intrapleural pressures from -3 to -6 cmH2O. During asthma, profound negative intrapleural pressures are necessary to obtain normal tidal volume. Expiration requires active muscle contraction. This results in increased work of breathing, with increased CO 2 production and O2 consumption. Furthermore, increased minute ventilation, which is wasted in many areas with impaired ventilation-perfusion ratio, is stimulated. Dyspnea is a usual finding, and patients may be able to evaluate the degree of bronchial obstruction better than physicians. However, perception of breathlessness is reduced in some patient categories, particularly after severe attacks or in older asthmatics.

Cardiovascular consequences

Hyperinflation may compress and stretch the capillary network, contributing to an increase in pulmonary arterial resistances. Intra-alveolar pressure is the extramural pressure for capillaries. It is positive in distended alveoli ventilated by partially occluded bronchi (auto-PEEP), profoundly negative in completely occluded areas, and approaches zero to -3 cmH2O in normally ventilated alveoli. Globally, this results in a mean pressure value approaching zero, which is greater than intrapleural pressure. These phenomena result in an increase in afterload for the right ventricle which is surrounded by deep negative pressures, i.e. intrathoracic pressures. Hence the right ventricular ejection fraction falls, leading to increased end-diastolic volume. The right ventricle dilates and squeezes the left ventricle, since both are contained in a common inextensible pericardium. This effect, which is known as diastolic ventricular interference, occurs in parallel. Preload of the left ventricle...

Measures of Airway Caliber

Perhaps the simplest measurement of expiratory airflow involves the use of a peak flowmeter. Subjects inspire maximally (i.e., to total lung capacity) and expire rapidly and maximally to residual volume into the mouthpiece of the instrument that provides a measurement of the peak expiratory flow. These instruments are simple to operate and often are provided to asthmatic patients for self-measurement and documentation of their ventilatory function.

Monitoring and investigations

Patients with acute asthma should have arterial blood gases measured early in their hospital course both the absolute values and changes in response to therapy are invaluable in assessing the potential need for mechanical ventilation. The most common pattern of blood gas abnormality is a combination of hypoxemia, hypocapnia, and respiratory alkalosis. Ventilation-perfusion abnormalities are common in severe asthma and maximal inspired oxygen concentrations should be used during resuscitation of the patient to achieve normal saturation and PaO2 values. A normal or increased PaCO2 has long been regarded as a danger sign, but the trend of repeated measurements is more important than one absolute value. Even patients presenting with gross hypercarbia can be managed without mechanical ventilation if they can be carefully observed in an ICU or high-dependency unit (HDU), and medical therapy produces rapid improvement. In contrast, a patient with a low PaCO2 which is increasing despite...

Long Term Control of Obesity

The second behavior is regular monitoring of weight and food intake. About three-fourths of the subjects weigh themselves at least weekly, and most monitor the amount of fat they consume. Self-monitoring of weight is the obesity patient's equivalent of the diabetic's glucose monitor and the asthmatic's PFM. Individuals who do not know where they are in terms of their weight cannot make a timely intervention to control the tendency for regaining weight.

Betasympathomimetic agents

Inhaled b2-adrenergic agonists are by far the most effective bronchodilators in common use. These agents have a rapid onset of action and are indicated as first-line treatment for the short-term relief of bronchoconstriction and acute exacerbations of asthma symptoms. Commonly, initial treatment consists of 2.5 mg albuterol (salbutamol) (0.5 ml of a 0.5 per cent solution in 2.5 ml normal saline) by nebulization every 20 min for 1 h (three doses) followed by hourly treatments during the first few hours of therapy. Inhaled treatments can be given continuously to severely obstructed patients until an adequate clinical response is achieved or adverse side-effects (excessive tachycardia, arrhythmias, or tremor) limit further administration. The available data do not support the routine use of intravenous infusion of b-agonists in the treatment of patients with severe asthma. Several studies have demonstrated that inhaled therapy is equal to or better than intravenous therapy in treating...

Ventilators modes of ventilation and settings

The aim of mechanical ventilation is to maintain adequate arterial oxygenation and control acidosis while using specific therapeutic measures to reverse bronchospasm, reduce bronchial epithelium inflammation, mobilize secretions, and suppress airway hyper-reactivity. The simplest type of control-mode ventilator (either volume- or pressure-cycled) will serve to support an asthmatic patient. However, the current generation of volume-and time-cycled pressure-limited ventilators, capable of several modes of ventilation, provide the flexibility and safety features which make them preferable to the less sophisticated machines. During the initial stages of stabilization of the patient following intubation, control-mode ventilation is ideal. As the patient recovers from sedation, synchronized intermittent mandatory ventilation may be possible. If pressure-limited ventilation is adopted, minimal tidal volume alarms must be set so as to avoid inadvertent (uncontrolled) hypoventilation. Present...

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Peak pressure probably determines the risk of barotrauma and is primarily determined by VT and, in acute asthma, by the peak inspiratory flow. To minimize peak pressure (ideally below 40 cmH2O), a VT of 8 to 10 ml kg and an inspiratory flow of 30 to 40 l min might be chosen. Achieving an adequate alveolar ventilation then depends on setting the ventilator rate between such settings and invariably results in some compromise being accepted in terms of the I E ratio which may approach 1 1. An overlying principal that should be adopted is the use of controlled hypoventilation, whereby hypercapnia ( PCO2 5-15 kPa (37.5-112.5 mmHg)) is tolerated in the belief that it is less harmful than barotrauma. Indeed, hypocapnia should be avoided since it may produce an increase in airway resistance in the asthmatic patient. Recent studies of permissive hypercapnia in patients with acute respiratory distress system suggest that moderate levels of hypercapnia are associated with acceptable levels of...

Therapeutic considerations

If fatigue results from the imbalance between energy supply and demand, the objectives of therapy must be to restore this balance. Energy supplies can be increased by treating hypoxemia and improving cardiac output, and the demands for energy can be decreased by treating bronchospasm or pulmonary edema. If the usual methods of restoring the balance between energy supply and demand fail, and clinical manifestations of inspiratory muscle fatigue persist, serious consideration must be given to resting the muscles by the use of artificial ventilation. Just how much rest is required is not known. Obviously, total rest is not required in normal subjects. If it were, recovery from experimental fatigue would not be possible. However, a body respirator that allows the diaphragm to rest may be useful for some patients. If these patients are in a chronic state of fatigue during quiet breathing, complete rest may restore their respiratory muscle function.

Ventilation as exercise

Normally, spontaneous ventilation at rest requires less than 5 per cent of total O 2 delivery to meet its demand. However, in subjects with lung disease where the work of breathing is increased, such as pulmonary edema or bronchospasm, or with markedly increased minute ventilation requirements, such as breathing at high altitudes, the requirements for O2 may increase to 25 or 30 per cent of total O2 delivery, and maximum minute ventilation limits will define maximum exercise level. Furthermore, if cardiac output is limited, blood flow to other organs and to the respiratory muscles may be compromised, inducing both tissue hypoperfusion and lactic acidosis. Supporting the respiratory efforts of a subject with marginal cardiovascular reserve will relieve the metabolic demand on the cardiovascular system, reduce lactic acidosis, and increase mixed venous O2 saturation SvO2. Similarly, weaning from mechanical ventilation or spontaneous ventilatory efforts against an increased load or at an...

Pharmacogenetic Targets In Respiratory Disorders

There are four major classes of asthma pharmacotherapy currently in widespread use (72) (i) 2-agonists (b-agonist) used by inhalation for the relief of airway obstruction (e.g., albuterol, salmeterol, fenoterol) (ii) glucocorticoids for both inhaled and systemic use (e.g., fluticazone, beclomethasone, triamcinolone, prednisone) (iii) theophylline and its derivatives and (iv) inhibitors and receptor antagonists of the cysteinyl-leukotriene pathway (e.g., montelukast, pranlukast, zafirlukast, zileuton). The following section summarizes pharmacogenetic work reported on -agonists and inhibitors of the cysteinyl-leukotriene pathway in asthma comprehensive accounts of these effects are contained in the chapter on respiratory disease.

Therapeutic approach

The weaning process is started when the patient's general condition is stable and the likelihood of success is judged to be good. Weaning is unlikely to be successful and must not be started if the conditions in Table.3 are not satisfied. Potential causes of weaning failure should be excluded. Patients with heart failure or chronic obstructive pulmonary disease may experience cardiopulmonary stress induced by weaning. This weaning-initiated left ventricular dysfunction should be recognized, and appropriate diuretic, vasodilator, or bronchodilator therapy given. The optimum level of arterial PCO2 to maintain prior to weaning is unknown. Zealous correction of hypercarbia in patients with ventilatory dysfunction shortly before weaning may subsequently increase the patient's work of breathing. With patient-assisted ventilation, the patient will usually maintain a satisfactory PCO2 level. Weaning is best started in the morning, when a full complement of staff is available. Close...

Genetic Variation and Pharmacology

Diseases with complex patterns of inheritance, and where genetic variation comes into play after an exposure, account for the vast majority of the disease burden in the population. Examples of both the strategies and the problems involved in identifying genes with roles in these complex diseases can be appreciated from reading recent papers describing efforts to identify genes associated with risk for prostate cancer (Nwosu et al., 2001), type 2 diabetes, (Cox et al., 2001), and asthma (Xu et al., 2001). Cox (2001) outlines the challenges in moving from the identification of a chromosomal region associated with an elevated risk of disease via linkage mapping to the definitive estimate of risk associated with specific variants in specific genes. It should be noted that common refers to the relatively high incidence of the disease in the population and complex describes the pattern of inheritance of the genetic factors neither term relates to the clinical characteristics of a disease....

Pharmacokinetic Factors

Once a drug has been deposited on the lumenal surface of the airway segment, pharmacokinetic processes (viz., absorption, distribution, metabolism or biotransformation, excretion) will govern the amount of drug that reaches its therapeutic site of action. The pharmacokinetic pressures exerted on a drug deposited in the central airways differ from those in the peripheral airways, primarily as a result of the varying constituent cellular populations in each region. For demonstrative purposes, the fates of a bronchodilator drug in the central airways and of a drug destined for systemic absorption in the alveolus are considered in the following sections and are shown in Fig. 1.

Spontaneous pneumothorax

Secondary spontaneous pneumothorax is a complication of many lung diseases, mainly chronic obstructive pulmonary disease, cystic fibrosis and, more recently, AIDS. In chronic obstructive pulmonary disease, airway inflammation increases airway resistance which results in hyperinflation with intrinsic positive end-expiratory pressure (PEEP). Subsequently, pulmonary emphysema and thinning of the lung parenchyma occur. If the transpleural pressure gradient exceeds a certain level because of a high intrinsic PEEP, the overdistended emphysematous bulla and visceral pleura rupture, causing pneumothorax. As severity of chronic obstructive pulmonary disease and level of intrinsic PEEP are closely related, the risk of secondary spontaneous pneumothorax is higher in patients with chronic obstructive pulmonary disease who are more critically ill. Pneumocystis carinii pneumonia, treatment with inhaled pentamidine, and cigarette smoking are risk factors for spontaneous pneumothorax in AIDS...

The Candidate Gene Approach for Identifying Risk Genes

The candidate gene strategy emphasizes identification of amino acid substitution variants and other variations of potential functional relevance in genes believed to be have roles in the biology of a disease and or expected to have a potential role in susceptibility to environmental exposure- or lifestyle factor-related disease. Examples of the disease outcomes that directed the selection of biological pathways and processes, and thus the genes included in these variation screening efforts, include cardiovascular disease, cancer, and asthma (Cambien et al., 1999 Cargill et al., 1999 Halushka et al., 1999 Shen et al., 1998). These studies to identify genetic variants have reported results from the screening of over 200 different genes. The results can be generalized as follows (1) approximately three different amino acid substitution variants per gene were detected in the screening of 100-200 chromosomes from generally healthy individuals (2) it is not uncommon to observe specific...

Leukotriene Pathway Pharmacogenetics

The leukotrienes are eicosatetraenoic acid compounds that are derived from arachidonic acid and exhibit a wide range of pharmacological and physiological actions (81). Three enzymes are exclusively involved in the formation of the leukotrienes, including the 5-lipoxygenase (ALOX5), the leukotriene C4 synthase (LTC4), and LTA4 epoxide hydro-lase. ALOX5 is the central enzyme required for the production of both the cysteinyl-leukotrienes (LTC4, LTD4, and LTE4) and the potent neutrophil chemo-attractant, LTB4. Drugs that inhibit ALOX5 activity or antagonize the action of the cysteinyl-leukotrienes at their receptor site have been shown to attenuate broncho-constriction in asthma patients (82). The leukotriene LTC4 synthase is another enzyme with a known SNP in its promoter region (A 444C) with a C allele frequency that is reportedly higher in patients with severe asthma (71,72), wherein the 444C variant is associated with enhanced cysteinyl-leukotriene production, suggesting that patients...

Pharmacological Actions

Propranolol increases airway resistance by antagonizing p2-receptor-mediated bronchodilation. Although the resulting bronchoconstriction is not a great concern in patients with normal lung function, it can be quite serious in the asthmatic. The cardioselective p-blockers produce less bronchoconstriction than do the nonselec-tive antagonists.

Adverse Effects and Contraindications

Whenever p-blocker therapy is employed, the period of greatest danger for asthmatics or insulin-dependent diabetics is during the initial period of drug administration, since the greatest disruption of the au-tonomic balance will occur at this time. If marked toxi-city does not occur during this period, further doses are less likely to cause problems.

BAdrenoceptor Agonists

Agonists of b-adrenoceptors have been used for many years as bronchodilators in the treatment of asthma, and they remain the most widely used group of bronchodilators in therapy. Epinephrine, an agonist exhibiting relative selectivity for b-adrenoceptors, was the first b agonist used in the treatment of asthma. Through the years, agonists have been developed that are selective for the b-adrenoceptor mediating human airway smooth muscle relaxation, viz. the b2-adrenoceptor. Examples of drugs of this type include albuterol (salbutamol), fenoterol, terbutaline, and metaproterenol. Further development has led to drugs, such as formoterol and salmeterol, which exhibit longer residence times in the airways and consequent increases in duration of action 29 . Stereoisomers of Bronchodilators

Physician as Catalyst

Unlike those in the Not Interested group, patients triaged into the second or third category are concerned about their weight and can be moved into the Personal Responsibility category. I do this by spending time in trying to help the patient first understand that obesity is a chronic, recurrent disease. Just like asthma or diabetes, once present it will never go away. Then I ask the patient, Do you want control of this disease If the answer is yes, then I would consider the patient in the fourth category. If the answer is no, then as a catalyst I would continue to provide information and encouragement but realize that the spark to ignite behavioral change is without effect at this time.

Discovery of Novel Drug Targetable Genes

Several studies have made an attempt to associate glucocorticoid (GC) resistance to known polymorphic variations in genes that constitute the GC response pathway (119123). Although both structural and functional alterations in the glucocorticoid receptor units or their response elements are important determinants of glucocorticoid responsiveness, no relevant clinical prediction has emerged from these studies. In a recent study using microarray to examine gene expression profiles in peripheral blood cells (PBM) cells obtained from asthmatic patients who were either glucocorticoid therapy responders or nonresponders, glucocorticoid responders could be separated from nonresponders with more than 85 accuracy using only a few genes (124). The glucocorticoid-resistant patients were also clustered into families and examined for linkage (125). Microarray has also been applied in combination with genetic linkage studies to dissect out disease susceptibility genes in experimental models. A...

ECG evidence of acute ischemia in the ventilatedanesthetized patient

Where b-blockade has not been carried out or is inadequate, as manifest by persisting tachycardia, further b-blockers can be given, initially intravenously. Contraindications are known asthma and heart failure. If ECG changes do not resolve within 1 h with this regimen, consideration should be given to cardiac catheterization and coronary angiography with a view to an immediate endovascular procedure such as angioplasty or stenting. The decision depends on the amount of territory deemed to be at risk and the hemodynamic upset associated with the ischemia.

Physical Exam Key Points

Auscultate lungs and assess effectiveness of ventilation. Listen for decreased breath sounds (consolidation, pneumonia, pleural effusion, or pneumothorax), rales (pneumonia, bronchiolitis, or pulmonary edema), and wheezing (asthma, bronchiolitis, foreign body aspiration, pulmonary edema), which are suggestive of lower airway disease, or stridor (foreign body, croup, tracheitis, epiglottitis, retropharyngeal abscess), suggestive of upper airway disease.

Inhibition of Mediator Release or Synthesis

Prevention of the release or synthesis of biologically active mediators from inflammatory cells has represented an important target for drugs in the treatment of asthma. Inhaled drugs, such as cromolyn, b2-adrenoceptor agonists, and glucocorticoids, have proven to be effective in the prophylactic treatment of asthma, i.e., administered before exposure to a provocative stimulus such as antigen 50 . The mechanisms by which these groups of drugs inhibit mediator release are not well understood. Studies of their mechanisms not only provide valuable leads to new directions for drug development but also serve to elucidate the processes involved in the mediator secretory process. Cromones. Cromolyn sodium was first available for use as a therapeutic agent in the United States in 1973. Administered as an aerosol, it is widely used for the prophylactic treatment of asthma, with the onset of activity manifesting after several weeks, and it causes few side effects. Nedocromil sodium possesses...

Genetic Counseling The Discipline and the Provider

As our knowledge of genetic disorders and complex inheritance patterns has expanded, so have the options for molecular-based genetic testing. With this growth, complex ethical and social issues have come to the forefront, such as genetic discrimination. As medical research has advanced, we have come to appreciate the strong influence of genetics in common disorders, such as cancer, diabetes, Alzheimer disease, asthma, and hypercholesterolemia. The burden of passing on an abnormal gene or trait is not limited to individuals and families faced with rare disorders of Mendelian inheritance. It is a reality for everyone. Increasing anxiety about genetic risk for disease and concern about passing on abnormal genes to future generations for common conditions has expanded the need for genetic counseling. There are now subspecialties of genetic counseling, such as prenatal, pediatric, cancer, and neuro-genetics. Genetic counselors also are working in clinical molecular diagnostic laboratories...

Mucus Secretion and Clearance

The rate of removal of mucus from the airways is determined by such factors as mucus viscosity, the amount of mucus produced, and the degree of ciliary activity. These processes may be influenced by a variety of diseases, including asthma, cystic fibrosis, and chronic bronchitis 82,83 . In patients suffering from cystic fibrosis or chronic bronchitis, mucus hypersecretion is evident and mucociliary function is impaired. The failure to clear mucus from the airways leads to airway obstruction and to chronic colonization of the airways with bacterial organisms (which leads to lung infections and airway inflammation and damage). In asthmatic subjects, airway mucus is more viscous and ciliary transport mechanisms are inhibited 82,83 . In these diseases, the therapeutic objective is to improve mucus clearance from the airways. For example, aerosols of water or saline (especially hypertonic saline) promote clearance of mucus by liquefying secretions 84,85 . Acetylcysteine is a compound that...

S Health economic statements

The economic implications of encouraging patient autonomy are uncertain. An intensive patient education programme for self-management in people with asthma resulted in improved outcomes in the intervention group with no significant difference in costs.28 However, the patient group and the geographical location (Finland) undermine the relevance of these to the population of people with MS in the UK. The balance of resource burden between the NHS and the patient and their family is an important factor in any move towards self-management.

Atrial premature contractions

Atrial premature contractions are not treated unless they are believed to precipitate atrial tachycardia, flutter, or fibrillation. Removing precipitating factors, including drugs such as caffeine and theophylline as well as metabolic abnormalities, may decrease atrial premature contractions. Congestive heart failure and infection may also precipitate atrial premature contractions that will resolve as the patient's condition improves. Occasionally, digitalis may be helpful, particularly if congestive heart failure is a factor. However, the most effective medication is an antiarrhythmic class IA drug such as quinidine or procainamide.

Epithelial Permeability

Studies on changes on epithelial permeability have centered on investigations of mechanisms associated with induction of airway hyperreactivity. In support of an important role for epithelium in regulating the biological activity of inhaled substances, airway reactivity to aerosolized bronchoconstrictors has been correlated inversely with the epithelial thickness 127 . A variety of irritant stimuli, such as antigen and cigarette smoke, increase airway epithelial permeability to small solutes in animal models 128,129 . On the basis of such studies, this process has been suggested to enhance the penetration of irritants or bronchoactive substances to their bronchoconstrictor sites of action (such as sensory nerves, inflammatory cells, or smooth muscle cells) and thereby to contribute to airway hyperreponsiveness 130,131 . The mechanism by which the permeability of the epithelium changes is not well understood, although disruption of intercellular epithelial tight junctions 130 and...

Future Directions For Aerosol

In general, drugs currently administered as aerosols are used principally for the treatment of pulmonary disorders. This line of thinking centers on providing a high local concentration while diminishing systemic absorption and associated side effects. Current research emphasizes this doctrine, examples of which are the development of longer-acting bronchodilator drugs by hindering absorption through molecular modifications (e.g., salmeterol, formoterol) 29 or incorporation into liposomes 147 . What then lies in the future for aerosols in pharmacology, other than the treatment of obstructive airways disease The potential of aerosols as a means of delivering drugs to the pulmonary and systemic circulations is now starting to be explored and it represents a valuable direction for future research. The rapid onset of action and circumvention of firstpass hepatic metabolism favor the airways as a site of drug disposition for systemic activity. With continuing advancements being made in...

Maintenance Treatment

-Salmeterol (Serevent) 2 puffs bid not effective for acute asthma because of -Bitolterol (Tornalate) MDI 2-3 puffs q1-3min, then 2-3 puffs q4-8h prn. -Fenoterol (Berotec) MDI 3 puffs, then 2 bid-qid. -Ipratropium (Atrovent) MDI 2-3 puffs tid-qid. Prevention and Prophylaxis -Cromolyn (Intal) 2-4 puffs tid-qid. -Nedocromil (Tilade) 2-4 puffs bid-qid. -Montelukast (Singulair) 10 mg PO qd. -Zafirlukast (Accolate) 20 mg PO bid. -Zileuton (Zyflo) 600 mg PO qid.

Clinical Trials And Observational Data

Longitudinal data are critical to the planning and interpretation of clinical trials as it would be foolhardy to design a trial whose length is too short to detect the events of interest or is underpowered for lack of information about the frequency of an outcome. It would be difficult to design a clinical trial in asthma with the intent of reducing Emergency Department (ER) admissions if the trialists had little insight into how frequently ER visits occur or how to at least identify the characteristics of the patients who do use the ER most frequently for their asthma. Disease natural history is critical to determine the appropriateness and effectiveness of clinical interventions, especially for those illnesses whose measures of treatment effect are unclear. Research from the Rochester Epidemiology Project illustrates this point well in work on benign prostatic hypertrophy (Guess et al., 1995), again pointing to the relative value of the data and the data source.


In the presence of digitalis toxicity because of the possibility of producing complete A-V block and ventricular asystole. Patients receiving anesthetic agents that tend to depress myocardial contractility (ether, halothane) should not receive propranolol. Propranolol should be used with extreme caution in patients with asthma.

Table 71 Examples of Environmentally Caused Diseases

Asthma in children and adults exposed to indoor or outdoor air pollution The first six examples in Table 7.1 represent large doses of an environmental agent that can be quite easily documented by a good medical history e.g., pack-years of smoking (number of cigarette packs smoked per year multiplied by number of years that the person has smoked), quantity of alcohol consumed, length of time and the dose of drug taken, length of time living in a radonexposed house . The next three examples represent exposures to sun and the outdoors and to chemicals in the workplace quantitation in these cases is generally more difficult than the first six examples (e.g., What is the actual number of days worked Was the exposure identical for all these days Are we dealing with a single chemical or a mixture of multiple chemicals ). The last four examples in Table 7.1 depict even fuzzier cases in which a cause-effect correlation can be inferred only by an epidemiological study of large human...

Inhibition of Mediator Induced Macromolecular Leakage

Theless they all inhibit macromolecular leakage in postcapil-lary venules, thus emphasizing that in spite of increased blood flow and perfusion pressure in the arterioles that should favor plasma leakage from the venules, the effect of the drug localized to receptors on the endothelial cells of the postcapillary venules is the dominant factor in the regulation of plasma leakage in inflammation. Neutrophil-induced changes in vascular permeability are the result of a complex interaction between adhesive proteins expressed on the surface of leukocytes and endothelial cells, selectins, and integrins, which finally results in the firm adhesion of leukocytes in postcapillary venules. It is possible to interfere with the leukocyte-endothelial cell interaction at different steps. Monoclonal antibodies against adhesion glycopro-teins have been used to elaborate mechanisms of leukocyte rolling and adhesion. Dextran sulfate, and possibly also heparin, acts by neutralizing charged peptides...

What are key characteristics of the cough

Is cough paroxysmal, as in cystic fibrosis, asthma, pertussis, or foreign body aspiration 7. Is mucus clear (indicating asthma) or yellow or green (indicating suppurative lung disease) Is blood present in mucus, as in cystic fibrosis, foreign body aspiration, tuberculosis, or bronchiectasis

A chronic relapsing disorder

This approach argues that dependence on alcohol should be managed like other relapsing disorders, such as diabetes and asthma, (2) by using long-term monitoring coupled with intermittent or continuous treatment. However, social and cultural influences are stronger than in relapsing medical conditions and have more effects on outcome.

Opportunities For Control Of Deposition And Targeting

Except in situations when an aerosol is deliberately targeted for deposition in the mouth or in the nose, the material landing in these regions has no useful purpose for the therapy of respiratory diseases. Therefore, minimizing the extrathoracic deposition of inhalation aerosols is usually a desirable design feature of these delivery systems. Although there are many studies providing the evidence that inhalation therapy is improved by shifting the deposition from the oropharyngeal to the pulmonary region, data that would show that a more selective targeting within the latter region is desirable are rather scarce. The advantages of delivering pentamidine aerosols selectively to the lung periphery is the clearest case, because the receptors, the infecting microorganisms, reside in the alveolated parts 21 . Bronchodilator drugs contained in particles or droplets with smaller mass median aerodynamic diameters achieve a more potent therapeutic effect than the coarser aerosols 76,77 , but...

GSTT1 and Health Conditions

The deletion is associated with an increased risk of lung, larynx, prostate, cervical, and bladder cancers (34,80,86-89), and asthma (90). When broccoli consumption was factored into a study of the incidence of colorectal adenomas, a protective effect was observed in GSTT1 ( ) with individuals consuming highest amounts of broccoli (91).

Distributing The Messages

In certain situations, particularly if the hazard is potentially life-threatening, it may be appropriate to include boxed warnings'' on patient information leaflets and or the packaging. An example of such a case is the contraindication to use of beta-blockers in patients with a history of asthma or bronchospasm, where it is vital that the patient does not use the product. Here, good patient information adds an extra safeguard in the event of a prescription being dispensed which would have potentially lethal consequences for the patient.

Histamine The Role of Mast Cells

Numerous natural compounds inhibit the release of histamine from mast cells. This release is referred to as mast cell granulation, since histamine is stored in in-tracellular pouches called granules. Natural compounds that inhibit mast cell granulation are listed in Table 8.3. Note that many of these compounds occur in traditional herbal formulas used to treat asthma and allergies, which are diseases mediated by histamine release. Some compounds listed in the table are PTK inhibitors, which have been reported to inhibit histamine release from mast cells in some circumstances.124,125 PKC inhibitors may also inhibit histamine release.126 Apigenin, luteolin, and EGCG are PTK and PKC inhibitors, and genistein inhibits PTK.

VIP Clinical Implications

Contribute to each characteristic disorder of gastrointestinal motility. Similarly, patients with cystic fibrosis or asthma have diminished respiratory airway content of VIP that may account in part for the respective abnormalities of exocrine secretion and bronchial reactivity. The absence of inactivating genetic anomalies of any of VPAC1, VPAC2, or PAC1 receptors precludes specific assignment of each neuropeptide effect to one type of receptor (Said et al. 1980 Goetzl, Adelman, and Sreedharan 1990).

General Considerations

Contain enzyme activities much higher than corresponding activities found in the liver 29 . Metabolism of drugs in respiratory tract tissue will most likely lead to the formation of more than one metabolite because of the variety of enzymes and their differential location throughout the respiratory tract. The metabolic profile of a particular drug will depend on a number of factors, which include ease of access of the drug to the enzyme active site, availability of cofactors, Vmax and Km of the enzyme(s), and possible competition at the active site with other exogenous or possible endogenous substrates and inhibitors, inducers, activators, and so on. Other factors are cell type, age, and health. A recent review addressed the localization of drug-metabolizing enzymes in the respiratory tract 1 . Although pulmonary metabolism may be seen as a disadvantage, particularly in the case of peptides and proteins, because of the wide variety of peptidases and proteinases found in respiratory...

P2Adrenoceptor Agonists

Drugs acting at -adrenoceptors are the most common group of agents used in the treatment of asthma and other related respiratory diseases. Although several drugs in this group, such as isoproterenol and salbutamol, have been used for many years in the symptomatic treatment of bronchospasms, recent research has focused on the use of b2-adrenergic stimulants as prophylactic drugs because of their ability to inhibit the release of spasmogens and inflammagens from human mast cells in fact, short-acting b2-agonists represent an important treatment for the relief of asthma symptoms 33 . Furthermore, asthmatics patients are known to have greater response to bronchodilators than do patients of chronic obstructive pulmonary disease 34 . Early structure-activity studies designed to provide selective b2-receptor drug-binding clearly established the value of N-substitution for enhancing the b2 selectivity of norepinephrine analogues 35 , and subsequent work also highlighted the importance of...

Clinical dilemmas associated with pneumothoraces

Pneumothoraces in ventilated asthmatics The diagnosis of a pneumothorax in acute asthma may be extremely difficult. All ventilated asthmatics are at risk of pneumothorax, with a reported incidence of up to One discriminating point is that ventilated asthmatics usually exhibit normal arterial oxygen saturation at moderate FiO 2 (e.g. 0.5), whereas those with a significant pneumothorax may be hypoxic owing to shunt through associated collapsed lung. In addition, an extended period of apnea ( 20 s) should see significant hemodynamic improvement in asthma, although not in tension pneumothorax. We believe that there is no indication for needle aspiration in asthma. If no pneumothorax is present before aspiration, it certainly will be following blind needling and will mandate subsequent pleural cavity drainage. If a pneumothorax is suspected, intercostal tube placement, often bilateral, is appropriate. The potential for direct damage to the hyperinflated lung, which will not collapse away...

Red blood cell mass regulation

Erythropoietin, a hormone produced mainly by the kidney, stimulates bone marrow differentiation and production of red blood cells. Decreased renal oxygen delivery secondary to hypoxia, anemia, or ischemia augments erythropoietin synthesis. Additional stimulants of erythropoietin production include vasoconstrictors such as norepinephrine, ADH, and angiotensin. Suppressants of erythropoietin synthesis include hyperoxia, increased red cell blood volume, and reduced renal mass. Furthermore, the adenosine antagonist theophylline inhibits erythropoietin production.

Hongming Zhuang MD PhD Jian Q Yu MD Abass Alavi MD

Numerous reports have demonstrated increased FDG uptake at the sites of infection and inflammation. FDG is applicable to almost any type of infection or inflammation or any anatomic location, including the following abscesses 11-17 , pneumonia 18-20 , tuberculosis 21-25 , Mycobacterium avium-intracellulare infection 26-28 , cryptococcosis 29 , mastitis 30 , enterocolitis 31-33 , infectious mononucleosis 34 , parasitic disease 35 , Clostridium perfringens infection 36 , osteomyelitis 37-42 , infection or loosening following arthrop-lasty 43-45 , fever of unknown origin (FUO) 46-48 , thrombosis 49-51 , amyloidosis 52 , sarcoidosis 53,54 , asthma 55 , bronchitis 56 , encephalitis 57 , costochondritis 58 , radiation pneumonitis 59 , esophagitis 60,61 , pancreatitis 62 , thyroiditis 63-65 , sinusitis 66 , myositis 67 , mediastinitis 68 , gastritis 69 , lobular panniculitis 70 , dental cavity 71 , and inflammation caused by foreign body 72-74 . Despite all of these findings, however,...

Some Structural Factors Governing The Uptake Of Drugs

Replacing the N-t-butyl group in salbutamol with a highly lipophilic group results in a drug with high affinity for lung tissue and long duration of drug action. It is puzzling, however, that the bronchodilator effects of these drugs are still present even when the drug is no longer detectable or, indeed, even predictable, from elimination half-lives, in plasma 114,115 . This observation may relate to the possible retention in lung of a microfraction of the absorbed dose, presumably in the vicinity of the drug-receptor site.

General Laboratory Screening Tests

The Clinical and Laboratory Immunology Committee of the American Academy of Allergy, Asthma and Immunology has assembled a set of practice parameters for the diagnosis and management of immunodeficiency (37). These may help provide guidelines for the allergist-immunologist and the referring physician to those screening tests that might first be ordered and interpreted by the primary physician, as compared with situations in which referral to the specialist becomes appropriate. Often, the specialist is called by the primary care physician to determine whether a patient should be referred. In addition to assessing the airways and lung parenchyma, the chest radiograph should be reviewed for the absence or presence of a thymus in infants and for the possibility of a thymoma, which may be associated with hypogammaglobulinemia in adults (39). Hyperinflation with patches of atelectasis, suggestive of asthma, might suggest that additional details of the past history should be carefully...

The Social Consequences of Disease Stratification

Inherent in a number of applications of pharmacogenetics is the stratification of patient populations based on the subclassification of disease. For example, common conditions, such as asthma, diabetes, schizophrenia, and heart disease, are starting to be subdivided into different diagnostic categories according to their response to particular medicines. The profiling and stratification of patients based on the creation of new disease categories has many potential benefits. Diagnosis could be more precise and treatment more specific. However, one consequence may be that some individuals become categorized and are labeled as good responders and others as non-responders or difficult to treat (15). This might have a number of implications for patients

Patients presenting with neuromuscular transmission defects after admission to the ICU

A distinctive syndrome occurs in children or adults in the setting of sudden severe asthma or at the post-transplant state ( Lacomis ef al 1996). Endotracheal Although the subject is still controversial, the author believes that neuromuscular blocking agents should be used to ease ventilation in asthmatics only when there are clear-cut indications, and at as low a dosage and for as short a period as possible. The use of steroids should also be limited as much as possible.

Tissue Specific Expression of AMs in the Lung Microvasculature

Leukocyte trafficking and endothelial migration in the systemic circulation of the lungs is not well studied. Only 1 percent of the cardiac output is directed to the airway circulation to supply the central airways and bronchi. These vessels form a plexus network around the airways, supplied by the bronchial artery, sending branches into the muscle and submucosa. It remains unknown whether leukocyte infiltration close to the bronchi is occurring from the bronchial circulation or the pulmonary circulation. It seems unlikely that tissue-infiltrating leukocytes such as eosinophils found in and around the bronchi in airway conditions such as asthma exit through the pulmonary circulation. Thus, it is important to know the recruitment properties of this circulation. As mentioned previously, we have developed a model of intravital microscopy in the upper airways to address this issue 8 . Although this model uses the tracheal circulation, the function and regulation of tracheal muscle and...

Conclusions and Future Directions

Be under positive growth control by p-adrenoreceptors. In the case of ER-breast cancer cells, GABA has been shown to counteract the p-adrenergic stimulation of cell migration. In light of the prominent inhibitory effects of this neurotransmitter in the central nervous system, it is to be expected that GABA may also inhibit p-adrenergic receptor-mediated stimulation of cell proliferation in adenocarcinomas of the lungs, pancreas, and breast. Studies to test this hypothesis are currently underway in our laboratory. In addition, p-adrenergic signaling counteracted by GABA has been implicated in the migration and metastatic potential of adenocarcinomas of the colon 79 . On the other hand, the a7nAChR has documented stimulatory effects on the growth of SCLC and this response appears to be counteracted by p-adrenergic receptor signaling. The susceptibility of these neurotransmitter receptors to agonists and antagonists can be greatly modulated by preexisting disposition, environmental...

Effects of medication on sleep

A variety of drugs commonly used in the ICU may disrupt sleep. Benzodiazepines reduce (or abolish) REM sleep and stage III and IV sleep and increase stage II sleep. After treatment is discontinued 'REM rebound' occurs, and patients may have an increased number of vivid and frightening dreams. Opioid drugs tend to suppress REM activity in addition, morphine increases the frequency of arousals and stage I sleep. Tricyclic antidepressant drugs depress REM sleep. Theophylline, in higher doses, decreases total sleep time and increases sleep fragmentation. Intravenous catecholamines may increase wakefulness.

In Memoriam W James Metzger Jr MD October 30 1945November 17 2000

Jim was a fellow at Northwestern University from 1974 to 1976 and spent his career in academic medicine at the University of Iowa and East Carolina Medical School where he was Division Chief of Allergy Asthma and Immunology and Vice-Chair of the Department of Medicine. He moved to Denver to the National Jewish Hospital in

Control During Inhalation Of A Radiolabeled Aerosol And Subject Variables

When designing protocols to measure deposition, a number of clinical factors need to be considered and incorporated into the study design subjects' age, sex, smoking history, and current drug regimens, presence of a viral infection, severity of disease, stability of pulmonary function, and other outcome measures that could affect the inhalation of the radioaerosol, the measurement of deposition, and the results. Some of these also apply when using healthy volunteers as subjects for deposition studies. For example, we allow a 4- to 6-week recovery period between repeat studies for subjects who have suffered an exacerbation of their asthma or developed a chest cold or infection after enrollment.

Was the substance truly blood Was it the patients blood

Epistaxis Swallowed nasopharyngeal bleeding from trauma or mucosal ulceration can cause hematemesis. Was there a possible ingestion Does patient regularly take medication(s) Possible ingestions resulting in mucosal irritation include NSAIDs, aspirin, theophylline, steroids, batteries, and alcohol. In toddlers or mentally handicapped patients, consider the possibility of a foreign body.

Aerosols Used In Clinical Investigations Of Disease

Several diagnostic tests utilizing specific-size nonradioactive aerosols and also radioactive aerosols with standard nuclear medicine technology are practiced in respiratory medicine (Table 2). For example, inhalation of aerosols of methacholine and histamine is widely used to assess nonspecific bronchial responsiveness in asthma the concentration of the challenge aerosol that provokes a specific fall in FEV1 gives an indication of the severity of the disease. Changes in the disease with treatment or with exposure to sensitizing agents can be monitored over time with repeated measurements. These measurements are coupled with clinical outcomes such as spirometry and pharmacokinetic and pharmacodynamic measurements in the same group of subjects. In the research laboratory, measurements using radioactive aerosols of these challenge agents have determined the change in distribution effected with changes in airway caliber 124,125 as well as compared techniques and outcomes in inhalation...

Observedtoexpected Analysis

This method works best when the background rate for the clinical event of interest is very low. In the above examples, the background rates were in the range of a few per 100 000 to a few per million per year. With more common events, such as myocardial infarction or asthma, the expected number of cases becomes large, thereby greatly reducing the signal-to-noise ratio. Because of the presence of large-scale underreporting of ADR cases, the lack of an excess number of reports over the number expected cannot be interpreted by itself as invalidating the signal. However, the strength of the method is demonstrated in those situations where the reported number ( observed ) is close to or exceeds the expected number. Because of underreporting, the actual level of risk is much greater than that obtained. In such instances, one has moved beyond signal towards establishing an association.

Measurement of Total IgE

Asthma tend to have higher total serum IgE concentrations. About half of such patients have total IgE concentrations that are two standard deviations above the mean of a normal control group. Significant overlap of total serum IgE concentrations in normal subjects and in patients with allergic asthma and hay fever has been demonstrated (Fig 3.3). Therefore, the total serum IgE concentration is neither a specific nor sensitive diagnostic test for the presence of these disorders. Total serum IgE has been found to be markedly elevated in atopic dermatitis, with the serum IgE concentration correlating with the severity of the eczema and with the presence of allergic rhinitis, asthma, or both. Patients with atopic dermatitis without severe skin disease or accompanying asthma or hay fever may have normal IgE concentrations (45). Total IgE concentrations have been found to be markedly elevated in allergic bronchopulmonary aspergillosis.

Richard Lemen PhD Eula Bingham PhD

Who gives an extremely graphic description of the effects of exposure to silica on stonecutters (4). Diemerbroeck gives an interesting account of several stonecutters who died of asthma when he dissected their cadavers he found, he says, piles of sand in the lungs, so much of it that in cutting with his knife through the pulmonary vesicles he felt as though he were cutting a body of sand.

Classical Pharmacokinetic Methods

Influence of Disease-State on Pharmacokinetic Studies. It is important to realize that pharmacokinetics might differ in asthmatics and healthy volunteers. Falcoz et al. and Daley-Yates reported a 2-3 times reduced systemic availability for inhaled fluticasone propionate in asthmatics 69,70 , while there was no significant difference in the kinetic parameters after intravenous administration between healthy volunteers and asthmatic patients. This indicates that differences after inhalation between healthy volunteers and asthmatics are due to differences in the pulmonary fate of the drug. These differences are likely to be related to decreased inhalation efficiency in asthmatics or to an increased removal of inhaled drug by increased mucociliary clearance 70 . This decreased systemic availability in asthmatics seems to depend on the severity of the disease. Moderate-to-severe asthmatics exhibited marked PK differences when compared to healthy volunteers, while PK properties were similar...

Measures to control the effects of hyperthyroidism

Propranolol (80 mg orally or 1-2 mg intravenously as required) blocks the b-adrenoreceptor effects of thyroxine and is particularly useful for reducing sinus tachycardia. It also impairs conversion of thyroxine to tri-iodothyronine and inhibits release of thyroid hormone. Propranolol is contraindicated in patients with cardiac insufficiency or air-flow limitation, although newer more specific b-blockers such as atenolol can be used in patients with congestive cardiac failure, bronchospasm, or peripheral vascular disease. Rapid atrial fibrillation should be managed by standard protocols involving digoxin administration (up to 1.5 mg as a loading dose) following correction of hypokalemia and anticoagulation. Thyrotoxicosis accelerates the metabolism of digoxin. Conversely, patients with thyrotoxicosis are more sensitive to warfarin because vitamin-K-dependent clotting factors are metabolized more rapidly. Verapamil may also be useful in this setting to reduce the ventricular rate....

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