ASTHMA

Asthma• Episodes of increased breathlessness,

cough, wheezing, chest tightness. • Exacerbations may be abrupt or

progressive• Always related to decreases in

expiratory (also in inspiratory in severe cases) airflows

• Hallmarks: airway inflammation, smooth muscle constriction and mucous plugs

Epidemiology Most common chronic disease in the world: varies

between regions More prevalent in westernized countries but more

severe in developing countries Yr of cost 2005 >$11.5 billion per year 35/100.000 fatality, mostly pre-hospital & older

pop Seasonal exacerbation pattern but ICU admission

remains constant <10% life threatening exacerbation: 2-20% with

ICU admission; 4% intubation Reduction in mortality (63%) in the 1980’s due to

inhaled steroids

Asthma Prevalence

4

Pathophysiology

• Airway inflammation, smooth muscle constriction, and airway obstruction

• VQ mismatch (<0.1)- decrease vent with normal perfusion

• Intrapulmonary shunt is prevented due to collateral ventilation, hypoxic pulmonary vasoconstriction, rarely functionally complete obstruction mild hypoxemia

• Worsening of hypercapnea is indicative of impending respiratory failure in combination of lactic acidosis

• Worsening of hypoxemia after beta-agonist is common due to removal of hypoxic induced pulmonary vasoconstriction

Asthma

HistamineTryptasePGD2

LTC4

IL-4IL-5IL-6TNF-α

Eosinophilic cationic proteinsMajor basic proteinsPlatelet activating factorLTC4, LTD4, LTE4

IL-3IL-4IL-5

GM-CSF

Pathophysiology

• Lactic acidosis: – Changes in glycolysis due to high dose

beta agosist; – Increased wob, anaerobic metabolism– Coexisting profound tissue hypoxia– Over production of lactic acid by the

lungs– Decrease lactate clearance due to

hypoperfusion

Pathophysiology

• Significantly reduced: FEV1; FEV1/FVC, Peak expiratory flow; maximal expiratory flow at 75%, 50% and 25%, and maximal exiratory flow between 25% and 75% of the FVC

• Abnormally high airway resistance: 5-15x normal due to shortening of airway smooth muscle, airway edema and inflammation, excessive luminal secretions.

Pathophysiology• Dynamic hyperinflation: Auto PEEP (intrinsic

positive end expiratory pressuse PEEPi): directly proportional to minute ventilation and the degree of obstruction– Shifts tidal breathing to the less compliant part of

the respiratory system pressure volume curve– Flatten diaphragm reduces the generation of

force– Increase dead space increase minute ventilation

for adequate ventilation– “Silent chest”: lower inspiratory flow due to dynamic

hyperinflation– Asthma increases all three components of

respiratory system load: resistance, elastance and minute volume

– Diaphragmatic blood flow is reduced worsening of respiratory distress

Pathophysiology

• CV effects: “pulsus paradoxus” – decrease arterial systolic pressure in inspiration) >12mmHg– Expiration: increase in venous return, rapid

RV filling shifting of interventricular septum causing LV diastolic dysfunction

– Large negative intrathoracic pressure: increase LV afterload by impairing systolic emptying.

– Pulmonary pressure increases due to hyperinflation increase RV afterload

Clinical Presentation• Respiratory distress: sitting upright, dyspneic &

communicate using short phrases• Severe obstruction: rapid, shallow breathing and use

of accessory muscles• Life threatening: cyanosis, gasping, exhaustion,

hypotension and decreased consciousness• PE: inspiratory & expiratory wheezes silent chest• Intensity of wheezing is not a predictor of respiratory

failure• Mild hypoxemia• Blood gas: hypoxemia, hypocapnea & respiratory

alkalosis in mild asthma• Normocapnea & hypercapnea: impending respiratory

failure

Clinical Presentation• Baseline PEF and FEV1 are important

• PEF 35-50% of predicted value: acute asthmatic exacerbation

• Pre-treatment FEV1 or PEF <25% or post treatment <40% predicted: indication for hospitalization

Treatment

• Oxygen• β-agonists• Corticosteroids • Magnesium sulfate• Anticholinergics• Methylxanthines• Leukotriene modulators• Heliox• Mechanical ventilatory support

Treatment

• Oxygen: supplement to keep sat>90%– Severe hypoxemia is uncommon– Careful with 100% oxygen

supplementation: may result in respiratory depression followed by carbon dioxide retention

Treatment• β-agonists: albuterol, terbutaline; levalbuterol,

epinephrine, terbutaline– Mediate respiratory smooth ms relaxation– Decrease vascular permeability– Increase mucocilliary clearance– Inhibit release of mast cell mediator– Onset is rapid, repetitive or continuous

administration produces incremental bronchodilation

– MDIs: with spacer device have similar effects to nebulizer

– Aerolized:• Utilize adequate flow rate (10-12L/min): higher flow rate,

smaller particles (0.8-3 μm are deposited in the small airway, smaller particles tend to be exhaled)

• Continuous: more consistent delivery and allow deeper tissue penetration

Treatment• β-agonists :

• 1- Salbutamol (albuterol): racemic mixture equal R & S isomers– S-form has longer half life and pulm retention; pro-

inflammatory properties– More accumulative SE

• 2- Levosalbutamol (levalbuterol): R-salbutamol– Can be beneficial after S-form accumulate with SE– Can evoke 4x bronchodilation effects with 2x systemic

SE

• Genetic variations in β2-adrenergic receptors: may respond favourably to neb. epinephrine

Treatment• β-agonists :

– 3- Epinephrine:• Alpha 1 adrenergic receptor: microvascular constriction

decrease edema• Decreases parasympathetic tone bronchodilator• Improves PaO2

• SQ epinephrine • SQ terbutaline: loose β2 effect, can cause decrease

uterine blood flow and congenital malformations in pregnant patients

• Side effects– CV: MI especially in IV isoprenaline

(isoproterenol)– Hypokalemia– Tremor– Worsening of ventilation/perfusion mismatch

Treatment• Corticosteroids:

– Decrease inflammation– Increase the number and sensitivity of Beta-adrenergic

receptors– Inhibit the migration and function of inflammatory cells

(esp. eosinophils)– No inherent bronchodilator– Administer within 1 hr of onset: lower hospitalization

rate, improve pulm functions• Onset of action: 2-6 hrs• Dose 40mg/day, limited evidence of additional efficacy of 60-

80mg/day– SE: hyperglycemia, hypokalemia, mood alteration,

hypertension, metabolic alkalosis, peripheral edema

Treatment• Magnesium sulfate: direct smooth

ms relaxation and anti-inflammation– Controversies in inhaled mag. sulfate– 40mg/kg/dose Q6, max 2gm in adults

• Anticholinergics: ipratropium bromide– selective for muscarinic airway (proximal

airway), absence of systemic effects– Slow onset of action: 60-90 min, less

bronchodilation

Treatment• Methylxanthines: theophyline and

aminophyline–Mechanism of actions: phosphodiesterase

inhibitor; stimulate endogenous catecholamine release; beta adrenergic receptor agonist and diuretic, augment diaphragmatic contractility; increase binding of cyclic adenosine monophosphate ; prostaglandins antagonist

– No additional benefit in acute attack

Treatment• Leukotriene modulators:

– Potent lipid mediators derived from arachidonic acid with the 5-lipoxygenase pathway

– 2 main groups: LTB4 and cysteinyl leukotrienes (CysLTs): LTC4, LTD4, LTE4

– Mediators in allergic airway disease– CysLTs: produce: bronchoconstriction, mucous

hypersecretion, inflammatory cell recruitment, increased vascular permability, proliferation of airway smooth ms

– Less potent in bronchodilation and anti-inflammatory than long acting beta agonist and steroids

– Administration of single IV dose or PO doses showed improvement in acute attacks

Treatment• Heliox: 60-80% blend– Laminar flow, increase ventilation, decrease

wob, pulsus paradoxus and A-a gradient, delay onset of respiratory muscle fatigue

– Controversies in benefits– In mechanical ventilated patients, heliox

helps to lower peak inspiratory pressure, improve pH and PCO2

(Shamel et al. Helium-oxygen therapy for pediatric acute sever asthma requiring mechanical ventilation. Pediatr Crit Care Med 2003:(4))

Treatment• Non invasive positive pressure ventilation

– Decrease wob and auto-peep– Improve comfort, decrease need for sedation, decrease

VAP and LOS– No benefits of positive pressure in delivering nebulized

meds (Caroll, C. Noninvasive ventilation for the treatment o facute lower respiratory tract disease in children.

Clin Ped Emerg Med)

– Risks: aspiration, gastric distension, barotrauma– NIPPV + conventional managements associated with

improved lung function and faster alleviation of the symptoms

(Soroksy, A. et al. A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest 2003; 123:1018-25)

Treatment

• Mechanical ventilation– Avoid excessive airway pressure, min

hyperinflation– Permissive hypercapnea, low TV, low rate,

short I-time– Continuous sedation and NMB as needed– Low PEEP vs High PEEP (overcome the

critical closing pressure facilitated exhalation)

Treatment• Inhalational Anesthetics: Halothane,

Isoflurane– Beta adrenergic receptor stimulation, increase in

cAMP – ms relaxation; impede antigen-antibody mediated enzyme production and the release of histamine from leukocytes

– Continuous administration:– SE: myocardial depression and arrhythmias

(Vaschetto, R. et al. Inhalational Anesthetic in Acute Severe Asthma. Current Drug targets, 2009, 10, 826-32)

Treatment• ECMO–When all treatment modalities failed – V-V ECMO: facilitates CO2 removal; CV

stabilization; short run– Complications: brain death or CNS

hemorrhage and cardiac arrest

(Mikkelsen ME et al. Outcomes using extracorporeal life support for adult respiratory failure due to status asthmaticus. ASAIO J 2009; 55:47-52)