respiratory
Asthma is most correctly defined as a chronic inflammatory airway disease associated with excessive tracheobronchial reactivity.
Thethi A "Asthma: Diagnosing, Treating and Managing this Condition-Mayo Clinic."
"Arveen Thethi, M.D., an asthma and allergy specialist at Mayo Clinic in Jacksonville, Fla., shares information about the chronic condition asthma, which affects more than 235 million people, according to the World Health Organization."
The reactive airway may be provoked by a number of stimuli.
Airway constriction may resolve following pharmacological intervention or spontaneously; however, manifestations including wheezing, cough, and dyspnea are prevalent.
Before considering implications of asthma and other pulmonary disease in the context of preoperative, and properties, and postoperative anesthesia management, we'll consider basic physiological, pathophysiological, and biochemical aspects of pulmonary disease generally.
1 Formal definition:
"Asthma is a chronic inflammatory disorder of the airway is, in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells.
In susceptible individuals, this inflammation causes recurrent episodes of wheezing, restlessness, chest tightness, and coughing, particularly at night or early morning.
These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.
The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli."--Expert Panel of the National Institutes of Health, National Asthma Education and Prevention Program (NAEPP)
Background:
By way of background, asthma is characterized by relatively asymptomatic periods with occasional acute attacks.
These episodes may resolve fairly rapidly pursuant to pharmacological intervention; moreover, sometimes patients may chronically experienced some degree of airway resistance.
A serious condition, status asthmaticus, occurs when significant obstruction persists for extended periods.
Status asthmaticus is defined as a therapeutic emergency.
1,2 Frequency of occurrence
Asthma affects about 5% of the United States population, which corresponds to about 14-15 million individuals in the United States.
This frequency is comparable to that observed in other countries
Typically asthma is first noted early in life, although it occurs at all ages.
In terms of age distribution about 50% of cases are noted in patients less than 10 years of age with another 33% occurring before the age of 40.
Initially (childhood), males appear about twice as likely to present with asthma as females; however, this the gender difference is not noted following the age of 30.
Asthma, affecting about 5 million children, is the most common chronic illness among children with minorities particularly affected.
African-American individuals exhibit about 19% higher asthma incidence compared to whites and are two times more likely to be hospitalized for asthma.
Based on 1990 data, about 10 million schooldays were missed due to asthma resulting in a cost of about $1 billion due to lost family income.
Another concern is the trend indicated in the timeframe from 1980-1993 that the "age-specific" death rate due to asthma increased file over twofold.
Asthma mortality appears highest among African-American individuals indicated by a 400% higher likelihood of death compared to other groups.
From the point acute classification, one approach has been to categorize based on the factor(s) that precipitate the occurrence, although this approach may be overly simplistic given the heterogeneous nature of asthma
Generally, following this approach, "allergic" and "idiosyncratic" are the two principal types of asthma classifications
1Atopy constitutes the largest risk factor for asthma ("hereditary allergy characterized by symptoms (e.g. as asthma, hayfever, or hives) produces upon exposure to the exciting antigen without inoculation" Merriam-Webster Collegiate dictionary) development.
1Allergic asthma is associated with a family history (or personal history) of allergic diseases including urticaria (hives), rhinitis, and/or eczema with positive wheal-and-flare reactions to intradermal injection of airborne antigen extracts and would be associated with increased levels of serum IGE and/or positive response to specific inhaled antigen
1Many individuals do not exhibit personal/family allergy history and shell normal IGE serum levels and negative skin tests.
Consequently, this type of asthma is not classified within immunological context and is instead described as idiosyncratic asthma.
In this setting the initial provocative event for asthma development may be an upper respiratory illness.
In particular, the initial event could be a common cold but wheezing and dyspnea which may last four days-months may be exhibited within a few days.
This phenomenon is different from an individual with chronic bronchitis or bronchiectasis and could then manifest bronchospasm as a consequence.
Mechanisms involved in pathology associated with asthma
A generalized tracheobronchial hyperirritability is a central aspect of asthma.
Airway reactivity may vary and with heightened reactivity more obvious and severe symptoms present and more aggressive pharmacotherapy are required.
Lung function exhibits fluctuations throughout the day with dyspnea more apparent at night and in the early morning.
Airway reactivity varies in all individuals as a function of exposure to oxidant air pollutants as well as following respiratory tract viral infections.
Of these two insults, viral infections are more predominant in their long-term effects on airway reactivity.
Furthermore, allergens produce rapid increases in airway responsiveness (reactivity) which remains heightened for weeks.
With significant allergen exposure, obstruction may occur rapidly and last for some time.
The current working framework for the understanding of asthma is based on the presence of continual airway inflammation which can be exacerbated under certain circumstances.
Asymptomatic asthmatic patients therefore exhibit the presence of inflammation confirmed by endobronchial biopsy.
The airway is characterized as edematous with eosinophil, neutrophils, and lymphocyte infiltration. Increased capillary density with increased cellularity represents probably the most common finding.
Overall asthma manifestation is probably a complex result of interactions between airway inflammatory cells, inflammatory mediators, cytokines, and surface epithelium.
Cell types most likely involved include mast cells, eosinophils, epithelial cells, and lymphocytes.
Also, there is the possibility of macrophage and neutrophil involvement. Cells primarily involved release mediators which include: histamine, leukotrienes (C, D & E), bradykinin, platelet-activating factor, and prostaglandins (E2, F2, & D2).
The above mediators produce an immediate, intense inflammation that is characterized by vascular congestion, edema, and bronchoconstriction.
Leukotrienes which act to promote airway smooth muscle contraction as well as mucosal edema also may inhibit mucociliary transport and increase mucus production.
Chronic events follow these initial actions with chemotactic factors recruiting eosinophils, polymorphonuclear leukocytes, and platelets to the reaction site.
"Chemokines: (chemoattractant cytokines) are short soluble peptides (70-90 amino acids) which can be divided into two groups.
Alpha (or C-X-C) chemokines contain a single amino acid between the first and second cysteine residues, and are primarily involved in neutrophil activation.
Beta (or C-C) chemokines have adjacent cysteine residues and are generally involved in activation of monocytes, lymphocytes, basophils and eosinophils"6.
These chemotactic factors include eosinophil and neutrophil anaphylactic factors and leukotriene B4.
These recruited cells in addition to macrophages already present as well as the bronchial epithelium provides sources for additional mediators enhancing immediate and cellular phases.
Airway epithelial cells serve both as a target and a contributor to the inflammation process since they amplifying the bronchoconstrictive aspect by liberating endothelin-1 and enhance vasodilatation by liberation of nitric oxide ( ), PGE2 as well as the 15-hydroxyeicosatetranoid acid (15-HETE) arachidonic acid metabolic products. These cells also produce cytokines including:
Granulocyte-macrophage colony stimulating factor (GM-CSF)
Interleukin (IL)8
Rantes
Eotaxin
Eotaxin is an eosinophilic chemoattractant cytokine which is upregulated in allergic airways inflammation. Figure below: attribution--Tim Williams PhD, Imperial College of Medicine, South Kensington, London.
8The accumulation of eosinophilic leukocytes in the lungs of asthmatic patients is probably due to the effect of chemoattractant small molecules.
Eotaxin has been identified as a potent eosinophil chemoattractants that is produced by several different cells in the stimulated by interleukin-4 and interleukin-13, both of which are synthesized by T-helper (Th)2 lymphocytes.
8Eotaxin interacts with the eotaxin receptor which is a C-C chemokine receptor (CCR)3.
Small molecules have been synthesized without interfere with eotaxin binding to its chemokine receptor, suggesting a possible therapeutic intervention that will limit eosinophilic recruitment in the lung with subsequent possible prevention of damage and pulmonary dysfunction.
8The eosinophil represents a white cell that has a two-lobed (bilobed) nucleus and has cytoplasmic granules which stain pink following exposure to eosin.
It has been suggested that eosinophils are important in the immunological defense system against helminths (worms).
Parasitic worms causing immunological response particularly towards TH2 lymphocytes which regulate IgE production. Immunoglobulin E binds to mast cells providing the means for specific antigen recognition (especially important in acute responses to worms).
TH2 lymphocytes regulate eosinophil accumulation important chronic responses to worms.
In eosinophils accumulating around these parasites then become stimulated to release O (free radicals) molecules as well as toxic proteins including basic protein, eosinophil peroxidase, eosinophil cationic protein and eosinophil-derived neurotoxin.
According to this view, allergy may be a host response originally developed against helminths but now triggered in an inappropriate manner by other stimuli.
The particular importance of eotaxin is that it provides the mechanisms by which selective eosinophil accumulation may be mediated, given that other chemoattractants have more generalized effects (i.e. they promote neutrophil attraction; these other chemoattractants include C5a, leukotriene B4 and platelet-activating factor)
8Concerning the eotaxin receptor: there been > 50 chemokines identified which mediate effects through at least 15 different 7-transmembrane-spanning, G-proteins-coupled receptors.
Most chemokines produce effects by mediation through several different receptors; however, eotaxins are fairly unusual in that there signaling process involves a single receptor, the CCR3 receptor which has been cloned and noted to be highly expressed on eosinophils.
The CCR3 receptor has been found also on TH2 lymphocytes which regulate eosinophilic recruitment.
Following eotaxin binding with theCCR3 eosinophil surface receptor a number of molecular events occur in including:
Calcium mobilization
CD11b up-regulation
Mitogen-activated protein kinase activation
Oxygen radical production
Actin polymerization and
Receptor confomrational change which is connected to granule release and chemotaxis.
Mechanisms for CCR3 internalization have also been described.
6"The beta-chemokines include RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted) as well as macrophage inflammatory protein-1 (MIP-1) alpha and beta, and interleukin-8...."
6"Here, the structure of RANTES is shown (Chung et al. Biochemistry 34:9307, 1995). It is a small (8 kDa) dimeric protein that is highly basic (pI 9.5) and which is made up of two identical subunits of 68 amino acids each. The two monomers are shown here"
"Granulocyte-macrophage colony stimulating factor (GM-CSF) stimulates the growth and differentiation of hematopoietic precursor cells from various lineages, including granulocytes, macrophages, erythrocytes, and eosinophils
The overall structure is highly compact and globular with a predominantly hydrophobic core. The main structural feature of rhGM- CSF is a four a-helix bundle, which represents approximately 42% of the structure. The helices are arranged in a left-handed antiparallel bundle with two overhand connections. Within the connections is a two-stranded antiparallel b-sheet. In this ribbon drawing, the N terminus is the upper right-hand corner."--7Ealick SE
Ribbon Form: Three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor.
Experimental method: X-ray Diffraction; Protein Data Bank:
1 Whereas the mast cell is important in the early stages of the reaction, eosinophils play a central role in the infiltrative aspect.
Granular eosinophilic proteins (eosinophilic cationic protein & basic protein) as well as oxygen-derived free radicals probably destroyed the airway epithelial lining medicine and sloughed into the bronchial lumen as 5Creola bodies.
5Attribution for the Creola body image: SUNY Upstate Medical University, Content maintained by: Susan Stowell, copyright © 2002, SUNY Upstate Medical University;
5"Creola bodies ...are characterized... by cilia, the evenly distributed chromatin, and the smooth nuclear membranes"
1 Damage described above not only affects barrier and secretory processes but also causes additional chemotactic cytokine production which promotes additional inflammatory responses. Such localized processes may translate to generalized reactions secondary to activation of neurogenic inflammatory pathways possibly by direct excitation of sensory nerve endings.
T lymphocytes are central to the inflammatory response with an increased presence in the asthmatic airway; furthermore,T lymphocytes are activators of cell-mediated immunity through cytokines as well as humoral (IGE) immune reactions.
T- activated lymphocytes which have been harvested from asthmatic patient lungs express mRNA for those cytokines involved in eosinophil & mast cell recruitment + activation. With respect to subpopulations,TH1 &TH2 lymphocytes both probably influence asthma responses. For example, cytokines IL2 and interferon (IFN) , Substances Produced by TH1 Lymphocytes promote differentiation & growth of Type B lymphocytes and cause macrophage activation, Respectively. Similarly IL-4 & IL-5, TH2 cytokine products promote B-cell growth and immunoglobulin secretion [IL-4] and eosinophil proliferation, differentiation, & activation [IL-5].
1 Cytokine production:
This process is an important, vital component in asthma inflammatory processes. Cytokines synthesized and released from these inflammatory cells discussed earlier as well as from epithelial cells, fibroblasts, endothelial cells, and airway smooth muscle activate many specific cell-surface receptors.
Cytokines that are thought to most important in asthma pathogenesis and are secreted by T lymphocytes are:
IL-3 -- lengthens mast cell surviva
IL-4 & IL-13 -- activates B lymphocytes IgE synthesis and adhesion molecule expression.
IL-5 -- differentiation and lengthens eosinophil survival.
Pro- inflammatory cytokines which also could amplify the inflammatory response include IL-1B, IL-6, IL-11, tumor necrosis factor (TNF-) and GM-CSF .
Pharmacological Agents Used in Asthma Management
Albuterol (Ventolin,Proventil)
Bitolterol (Tomalate)
Ephedrine
Epinephrine
Pirbuterol (Maxair)
Terbutaline (Brethine)
Ethylnorepinephrine
Isoetherine (Bronkosol)
Isoproterenol (Isuprel)
Metaproterenol (Alupent)
Salmeterol (Serevent)
Anticholinergic Agent
Ipratropium bromide (Atrovent)
Mast Cell Stabilizers
Cromolyn sodium (Intal)
Nedocromil (Tilade)
Aerosol corticosteroids
Beclomethasone (Banceril)
Dexamethasone (Decadron)
Flunisolide (AeroBid)
Fluticasone (Flovent)
Triamcinolone acetonide (Azmacort)
Oral corticosteroids
Methylprednisolone (Solu-Medrol)
Prednisone (Deltasone)
Methylxanthines
Aminophylline
Oxtriphylline
Theophylline
Theo-dur
Slo-phyllin
Cromolyn (Intal)& Nedocromil (Tilade)
Overview
These agents must be used prophylactically by aerosol (metered-dose inhalers). Cromolyn and Nedocromil inhibit:
Antigen & exercise-induced asthma
Bronchial reactivity
Cromolyn and Nedocromil have no direct effect on airway smooth muscle tone and will not reverse asthmatic bronchospasm
Cromolyn: (Intal),
Poorly absorbed
Administered by microfine powder inhalation or aerosol
Absorption: approximately 10%
No bronchodilating activity
Nedocromil: (Tilade)
Also poorly absorbed; low bioavailability;
Aerosol form only
Mechanism of Action: cromolyn & nedocromil
Alters function of delayed chloride channels (best demonstrated for nedocromil) and inhibits cell activation
Chloride-mediated channel effects:
Inhibition of cough
Inhibition of early response to antigens (mast cells)
Mast cells specific (cromolyn --minimal mediator released inhibition on human basophils)
Inhibition of late response to antigens (eosinophils)
Clinical Use:
Cromolyn (Intal) pre-treatment:
Blocks bronchoconstriction due to antigen inhalation
Blocks aspirin-induced bronchoconstriction
Blocks bronchoconstriction induced by environmental agents (causes of occupational asthma):
Yoluene diisocyanate
Wood dusts
Soldering fluxes
Piperazine hydrochloride
Certain enzymes
Reduces bronchodilators medication requirements and symptomatic severity in patients with perennial asthma
Cromolyn (chronic treatment) appears to decrease the bronchial hyperreactivity:
Airway protection against inflammatory, chemical anaphylaxis mediators
More effective in reducing seasonal increases in bronchial reactivity (allergic asthma) but less effective when compared with inhaled corticosteroids.
Cromolyn (Intal): -- effective in reducing symptoms of allergic rhinitis & hay fever
Adverse/Side effects: cromolyn (localized effects (sites of deposition))
Throat irritation
Cough
Mouth dryness
Wheezing
Chest tightness
Additional comments:
Nedocromil: (Tilade) is equal potent to standard doses of inhaled corticosteroids (in moderate asthmatics) and improved asthma control may be obtained by addition of nedocromil to standard dosage of inhaled corticosteroids
Methylxanthines -- (theophylline: some utility in asthma treatment; theobromine;caffeine: major sources (tea, cocoa, coffee)
Chemistry
Theophylline: 1,3-dimethylxanthine
Theobromine: 3,7 dimethylxanthine
Caffeine: 1,3,7-trimethylxanthine
Most commonly used theophylline preparation is aminophylline (theophylline-ethylenediamine complex)
dyphylline (synthetic theophylline analog): less potent; shorter acting
Metabolic products include demethylated xanthines (not uric acid) which are excreted in the urine.
Proposed mechanisms of action: no mechanism has been established to account for bronchodilation methylxanthine effects.
High concentrations (may not be reached in vivo): phosphodiesterase inhibition
Results in increased intracellular cAMP which may account for:
Cardiac stimulation
Smooth muscle relaxation
Inhibition of adenosine cell surface receptors (modulators of adenylyl cyclase activity)
Adenosine: isolated airway smooth muscle contraction
Histamine release from lung cells
Both effects antagonist by theophylline
Other xanthine agents without adenosine-antagonistic characteristics are more potent than theophylline in bronchoconstriction inhibition
Anti-inflammatory action:
Low-dose theophylline inhibits late response to antigenic challenge
Overview Pharmacodynamics:
Multiple methylxanthine effects:
CNS
Kidney
Cardiac/skeletal muscle
Smooth muscle
Theophylline: smooth muscle effects dominate
Caffeine: CNS effects most prominent
Central Nervous System Effects:
Increased alertness; reduced fatigue
In more sensitive individuals: caffeine -- nervousness/insomnia
Very high methylxanthine doses: medullary stimulation, convulsions
Primary side effect in patients requiring aminophylline (large doses) for control of asthma: nervousness & tremor
Cardiovascular Effects:
Direct positive chronotropic
Direct enhanced myocardial contractility
Mechanism of Effects:
Low doses: increased catecholamine release secondary to inhibition of presynaptic adenosine receptors
High doses: cAMP-mediatedspace for (secondary to phosphodiesterase inhibition) enhanced calcium influx
Reduced blood viscosity: unknown mechanism
Pentoxifylline (Trental): management of intermittent claudication.
Gastrointestinal Tract Effects:
Methylxanthines: enhanced secretion of gastric acid and digestive enzymes
Coffee (decaffeinated) stimulates secretion; secretagogue not caffeine
Renal Effects:
weak diuretic, not therapeuticly important
Increased glomerular filtration
Reduced tubular sodium reabsorption
Smooth Muscle Effects:
Major Therapeutic Effect: Bronchodilation
Adverse Effects: dose limiting
Skeletal Muscle Effects:
Enhanced skeletal muscle contraction
May improve contractility; responsible for reversing diaphragmatic fatigue in COPD patients.
In patients with airflow obstruction improved diaphragm skeletal muscle contraction may enhance ventilatory response to hypoxia and reduce dyspnea
Methylxanthines: Clinical Use
Theophylline: most effective xanthine bronchodilator
Relieves airway obstruction:
In acute asthma
Reduces symptoms severity;
In chronic asthma:reduces off-time from work or school in chronic asthma
Theophylline:Less effective bronchodilator compared to inhaled beta2-agonists
Slower onset of action
Some modest anti-inflammatory effect
Relatively limited usefulness in acute asthma, compared other drugs, theophylline:
Decreased frequency and severity of symptoms in chronic asthma
Theophylline base: slightly water-soluble; often administered as salts containing various amounts of theophylline base:
Aminophylline: 86% theophylline (by weight)
Oxtriphylline: 64% theophylline (by weight)
Concerns: Theophylline Blood Levels
Therapeutic/toxic effects: related to plasma concentration
Pulmonary function improvement: effective plasma concentration range: 5-20 mg/L.
At concentrations > 20 mg/L:
Nusea, headache, insomnia, nervousness
Higher concentrations (> 40 mg/L) leads to:
Seizures, neuromuscular irritability, tremor,
Arrhythmias,hypokalemia, hyperglycemia, vomiting
Reasonable theophylline administration: pharmacokinetics crucial
Factors affecting theophylline administration/ blood levels:
Loading dose: given slowly; "IV push" may induce transient toxicity (seizures/cardiac arrhythmias)
Plasma clearance: wide variation
Decreased liver function may cause toxic theophylline levels (theophylline is hepatically metabolized)
Changes in hepatic function:
Reduced blood flow secondary to heart failure
Attenuated function due to hepatic cirrhosis
Increased metabolism due to hepatic enzyme induction (dietary/cigarette smoking)
Oral theophylline, although effective, is not a primary agent in maintenance treatment:
Improves long-term asthma control as monotherapy or when added to inhaled corticosteroids.
Minor side effects: insomnia.
Risk of accidental/intentional overdosage with the consequence of death or severe toxicity.