Pulmonary Physiology part 2

Delivering oxygen through a high flow nasal cannula (HFNC)

-> Improved oxygenation -> Clearing of anatomic dead space -> Improved mucociliary/secretion clearance

Clinical Features of COPD

-Dyspnea -> Increased WOB-resistive, elastic; decreased respiratory mm fxn, Hypoxemia -Wheezing -> airflow obstruction -Coughing/sputum -> Mucus glands, airway receptors -Weight Loss -> decreased p.o. intake; systemic inflammation -Peripheral weakness -Tachypnea -> Increased WOB, Increased dead space, Decreased resp mm fxn, Hypoxemia - Accessory respiratory mm use -> Hyperinflation, Diaphragm dysfunction -Hoover's Sign -> Hyperinflation, Diaphragm dysfunction -Thoracoabdominal paradox -> Hyperinflation, Diaphragm dysfunction -Prolonged I/E ratio -> decreased air entry, wheezing -Signs of pulmonary hypertension, cor pulmonale

Mandibular Advance Devices

-For mild to moderate OSA, failed CPAP -As effective as CPAP for Sx -Less effective than CPAP for AHI and ↓ SaO2

Criteria for Diagnosis of CF

1) Clinical symptoms consistent with CF in at least one organ system***, AND 2) Evidence of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction (any of the following): -> Elevated sweat chloride level 60 mmol/L on TWO occasions -> Identification of mutations known to cause CF in both CFTR genes -> In vivo demonstration of characteristic abnormalities in ion transport across the nasal epithelium **this criterion not necessary in newborns, or siblings with CF with the shared genotype New born screening is mandatory in most states; immunoreactive trypsin (IRT) with followup genotyping

Hallmarks of Asthma

1. AIRWAY INFLAMMATION Found in all stages of asthma severity Small and large airways Correlates with severity of disease 2. AIRWAY HYPERRESPONSIVENESS (AHR) Exaggerated bronchoconstriction to stimuli Correlates w/ disease severity Anti-inflammatory Rx improves 3. AIRFLOW OBSTRUCTION Secondary to bronchoconstriction, edema, mucus plug, airway wall thickening, changes in lung mechanics

COPD and Smoking

1.3 billion habitual cigarette smokers (46 million US adults) 75-80% of COPD (15-40% of smokers) Dose and duration of exposure Cigarette smoke induces: -> Inflammation (activates alveolar macrophages) -> Oxidative stress -> Tissue injury

Alpha-1-Antitrypsin Deficiency

1/1500-1/5000 (80-100,000 in US) Most commonly PiZZ Insufficient anti-elastase activity Emphysema at early age, especially with tobacco abuse Panlobular - lower lobe Replacement therapy

Obesity Hypovention Syndrome

90% have OSA (5-20% with OSA have OHS) SYMPTOMS DURING BOTH NIGHT AND DAY Symptoms: -> Similar to OSA: snoring, fatigue, sleepiness, morning headaches, mood changes -> Related to pulm HTN/cor pulmonale: dyspnea, lower extremity edema Signs: -> Obesity, crowded UA -> JVD, ↑P2, hepatomegaly, lower ext edema -> LV failure

Immotile Cilia Syndrome-

AKA Kartageners Syndrome 50% of these patients will have reversal of internal organs

Adult Onset Asthma Risk Factors

Adult Onset Female AHR Obesity Smoking Work-related exposures

Emphysema

Anatomic alteration in lung Abnormal permanent distal (respiratory bronchioles) airspace enlargement Destructive changes of alveolar wall without obvious fibrosis

New Asthma Treatments

Anti-cytokine/chemokine therapies -> Anti-IL-5 antibodies -> Mepolizumab -> Reslizumab Anti-IL4 receptor Ab -> Dupilumab Bronchothermoplasty -> Controlled radiofrequency waves to airways to decrease the increased airway smooth muscle mass Patient-specific therapy depending on gene-profile

Asthma: Controller Medications

Asthma is a chronic inflammatory disease Inhaled glucocorticosteroids Leukotriene modifiers Long-acting inhaled β2-agonists Systemic glucocorticosteroids Theophylline, Cromones Anti-IgE

Causes of Chronic Hypoxemic Respiratory Failure

COPD Pulmonary Fibrosis (ILD) Pulmonary Hypertension Intracardiac Shunt Pulmonary arteriovenous malformation Hepatopulmonary syndrome

Laboratory: OHS Diagnosis

Cant have other things going on (ie OHS patients cant also have COPD ????) Arterial blood gas: DECREASED PaO2, ↑ PaCO2, normal A-a gradient DECREASED PaO2 → ↑ hemoglobin (polycythemia) ↑ PaCO2 → ↑ serum bicarbonate Rule out hypothyroidism Pulmonary Function Testing -> Exclude neuromuscular, restrictive, obstructive disease -> Severe obesity (fat accumulation in chest wall and abdomen) → DECREASED FRC, DECREASED ERV, DECREASED TLC Chest x-ray (exclude other lung disease) Polysomnography (detect OSA and its severity)

OHS and Leptin

Cant have other things going on (ie OHS patients cant also have COPD ????) Leptin (adipokine): secreted by adipose tissue (adipocytes) Suppresses appetite STIMULATES VENTILATION ↑ levels of leptin in obesity may be present to maintain adequate ventilation Leptin resistance in OHS, therefore ventilatory response not augmented as in obesity

OHS Pathophysiology:

Cant have other things going on (ie OHS patients cant also have COPD ????) Sleep-disordered breathing (90%OSA) & abnormal ventilatory control More severe and prolonged nocturnal ↑PaCO2 → ↑CO2 accumulation → ↑HCO3 → blunts respiratory drive → daytime ↑PaCO2 Severe sleep ↓PaO2 → blunts arousal from sleep → ↑ ↑ PaCO2 Blunted respiratory drive to ↓PaO2 and ↑ PaCO2

OHS Pathophysiology

Cant have other things going on (ie OHS patients cant also have COPD ????) Abnormal respiratory mechanics Obesity → ↑elastic & resistive load, ↑ WOB ↓ compensatory response to ↑ WOB rapid shallow breathing (↑ dead space) V/Q mismatch in dependent lower lobes ↑ chest wall and abd fat → ↓ lower RC and diaphragmatic movement → small airway & alveolar closure (end-expiration) → ↓ ventilation ? ↓ diaphragm function

OHS Treatment

Cant have other things going on (ie OHS patients cant also have COPD ????) Non-invasive ventilation Lifestyle modification -> Weight loss (most require Bariatric surgery) -> Exercise Avoid exacerbating agents Pharmacologic Rx -> Respiratory stimulants (acetazolamide, progesterone) Tracheostomy (only if OSA present)

Causes of Chronic Hypercapnic Respiratory Failure

Chronic Neuromuscular Disease ALS (anterior horn cells) Muscular dystrophy (muscles) Myasthenia (NMJ) C-spine injury (nerve) Thoracic Cage (kyphoscoliosis) Abnormal Control of Breathing (OHS) Obstructive lung disease (COPD)*

Asthma: History and Presentation

Classic Triad: intermittent wheeze, cough, dyspnea Other Sx: chest tightness, phlegm Parental history positive in 50% children Triggers: -> cold air, season, stress, pets, smoke, -> strong emotions, odors, exercise, upper respiratory tract infection (URI) -> occupational/environmental

Chronic Bronchitis

Clinical diagnosis Excess MUCOUS SECRETION Cough/Sputum most days minimum 3 months for 2 consecutive years Airflow obstruction may not be present

Delivering Oxyen via Nasal Cannula

Comfortable Allows for eating, drinking, communication, cough 0.5 to 6 Liters/min Variable FiO2 (22-40%) Humidification

CPAP

Continuous Positive Airway Pressure Used to treat OSA Reverse obstruction by using the flow of gas This therapy works in about 80% of patients. However, some patients have a lot of difficulty with the mask because they are claustrophobic or they don't like how it feels on their nose With increasing CPAP there is a progressive increase in the size of the upper airway, particularly in the lateral dimension (the anterior-posterior dimensions of the airway do not change significantly with CPAP)

Acute Exacerbations of COPD

Definition, Acute Exacerbation COPD (AECOPD) -> Increased sputum volume, purulence -> Increased dyspnea Bacterial Infection - MOST COMMON (Bronchitis) Viral Infection (May promote bacterial infection) Environmental factors: Air pollution (SO2, NO2) Acute Inflammation Rx: short-acting bronchodilators, systemic steroids, antibiotics, NIV

Diffusion Capacity and Emphysema

Diffusion Capacity is LOWERED because Alveoli have been destroyed

Bronchiectasis

Dilatation and destruction of bronchial walls - DIAGNOSTIC RETENTION OF BRONCHIAL MUCUS Bronchial infection, inflammation, edema Leads to: 1) Recurrent infection/pneumonia 2) Lung destruction 3) Fibrosis/scarring

COPD Definition

Disease state characterized by airflow limitation that is not fully reversible. Airflow limitation usually progressive Associated with abn inflammatory response to noxious particles or gases Extrapulmonary manifestations COPD -> about 70% of COPD patients will have BOTH Emphysema and Chronic Bronchitis About 15% of COPD patients have only Emphysema; about 15% of COPD patients have just Chronic Bronchitis

Causes of Acute Hypercapnic - Hypoxemic Respiratory Failure (Type II)

Drug Overdose (heroin, benzodiazepines) Acute spinal cord injury Acute Neuromuscular Disease Myasthenia Gravis Gullian-Barre Botulism COPD Exacerbation Status Asthmaticus

Respiratory Failure and Dyspnea

Dyspnea: POOR CORRELATION WITH DISEASE SEVERITY Other symptoms: lack sensitivity & specificity Acute ↓↓ PaO2 → ↑ catecholamines → ↑ HR carotid body → ↑ resp rate, ↑ VE Acute ↑↑ PaCO2 → ↓↓ pH, ↑ ICP → CO2 Narcosis

Risk Factors for COPD:

Exposures -> Tobacco smoke -> Environmental tobacco smoke -> Occupational dusts & chemicals -> Indoor/outdoor pollution -> Infection Host Factors -> BHR (bronchial hyperresponsiveness) -> BPD (bronchopulmonary dysplasia) -> Genetic -> Maternal smoking -> Childhood asthma -> HIV -> Tuberculosis -> Lowered Socioeconomic status

Genetics of Asthma

Family studies indicate heritable factors 35-80% Does not follow simple Mendelian pattern Different genes in different individuals lead to same phenotype (locus heterogeneity) Multiple genes acting in same individual (oligogenic or polygenic inheritance) Complex interaction between genetics & environmental influences Genes may influence Development of asthma Asthma severity Response to Rx (polymorphism β2 receptor)

Genetic Predisposition for COPD

First degree relative of COPD patients have: -> Increased macrophage elastase -> Increased alv MMP (collagenase) -> Decreased MMP inhibitor (TIMP) -> Increased predisposition to oxidative injury -> Decrease anti-oxidant vitamins (C,E) Responsible genes not yet ID'd (genetic polymorphisms - TNF-alpha, microsomal epoxide hydrolase) Increased risk COPD in first degree relatives of patients with early, severe COPD Alpha-1-antitrypsin deficiency

Oxygen Therapy

GOAL: maintain tissue oxygenation, avoid tissue hypoxia Acute Hypoxemia: PaO2 70-80 mmHg, SpO2 >95% High flow oxygen, face mask (FiO2 > 50%) Chronic hypoxemia: PaO2 ~ 60 mmHg, SpO2 ~ 90% COPD/Chronic hypercapnia: avoid worsening hypercapnia Low flow oxygen therapy: nasal cannula or special mask (FiO2 24-28%)

Treatment of COPD

GOALS: Relieve symptoms, decrease exacerbations, increase QOL Smoking Cessation (30% @ one yr) Inhaled Bronchodilators -> Beta agonists (SABA= albuterol, LABA= salmeterol) -> Anticholinergics (ipratropium, LAMA= tiotropium) Systemic Bronchodilators (theophylline) Anti-inflammatory -> Inhaled or Systemic Corticosteroids -> Phosphodiesterase (PDE-4) inhibitors (Roflumilast) ? Lung Volume Reduction (Surgical,Bronchoscopic) Immunization (Pneumococcal, Influenza) Nutrition -> increased resp mm strength -> Normalized control of breathing -> increased Immunocompetence Oxygen (if hypoxemic) (PaO2 <55, SpO2 <88)* Pulmonary Rehabilitation (increase exercise capacity and QOL, decrease dyspnea) -> Does not directly improve lung fxn or gas exchange -> Optimizes fxn of other systems so effect of lung dysfunction is minimized (e.g. skeletal muscle)

Treatment of Respiratory Failure

Generalized, non-specific -> Hypoxemia: supplemental oxygen -> Hypercapnia: avoid/correct Decreased Respiratory drive (sedatives, metabolic alkalosis) Decreased Resp mm function (electrolyte abn, malnutrition, meds) Increased CO2 production (fever) Increased Dead space (adeq intravascular volume)

Clinical Manifestations of OSA

Habitual snoring Daytime hypersomnolence* Nocturnal choking, resuscitative snort Non-restorative sleep, fatigue Insomnia Morning headaches Inability to concentrate, ↓cognition Altered mood, Irritability DECREASED libido, IMPOTENCE

Asthma Risk Factors

Host Factors -> Atopy (STRONGEST RISK FACTOR) -> Airway hyperresponsiveness (AHR) -> Gender -> Obesity Environmental Factors Indoor allergens Outdoor allergens Occupational sensitizers Tobacco smoke Air Pollution Respiratory Infections Diet

Inflammatory mediators associated with CF

IL-8 TNF-Alpha These are increased regardless of infection

Hypercapnic Respiratory Failure

INCREASE VD/VT Increased VCO2 + something else Decreased Resp drive = won't breathe Decreased Resp pump = can't breathe Increased Work of breathing -> Elastic, Resistive Imbalance: Load v. Capacity

Delivering oxygen through a Reservoir Mask

Inspiration: Patient breaths 100% O2 from wall (green arrow) and from reservoir bag (red arrow) allowing for higher FiO2 Expiration: A valve between patient and bag closes so CO2 rich gas exhaled thru one way valves in mask (blue arrows). While this occurs, O2 from wall (green arrow) fills bag (red arrow) with O2 which can be inspired on the next breath.

Emphysema on CT

Larger lung volume Heart appears smaller Paucity of lung markings ("black lungs")

Delivering oxygen via Standard face mask

Less comfortable Hinders eating, drinking, expectoration, talking Often become displaced Main Advantage: High Flow O2 (5-12 L/min) Avoid CO2 rebreathing Higher FiO2 but still variable

Central Sleep Apnea (CSA)

Less common than OSA NOT RELATED TO BEING FAT SYMPTOMS ONLY AT NIGHT Apneas WITHOUT (or diminished) RESPIRATORY EFFORT >5 central apneas + hypopneas/hour plus one or more symptoms of disordered sleep and no hypercapnia Symptoms similar to OSA Hyperpnea following central apnea may lead to paroxysmal nocturnal dyspnea Primary (idiopathic) -> No associated explanatory disease Secondary when CSA associated with: -> Cheynes-Stokes -> Underlying disease (AFIB, CHF, stroke) -> Recent ascent to high altitude -> Exposure to CNS depressing substance

Childhood Onset Asthma Risk Factors

Male Atopy FHx Early stressors Obesity Cig smoke Pollutants Indoor allergens 75% of Asthma patients are diagnosed by age 7

Hypoxemic Respiratory Failure

Most common mechanisms: -> shunt, V/Q PaO2 < 60 mmHg PaO2/FiO2 < 300 -> With increasing severity, P/F decreases

Obstructive Sleep Apnea

Most common sleep disorder in adults Repetitive episodes of upper airway obstruction during sleep → obstructive apneas and hypopneas. DECREASED PaO2 ( DECREASED SaO2), INCREASED PaCO2 + arousal from sleep Nocturnal & Daytime symptoms Complications (↑morbidity, ↑mortality)

Inhaled Corticosteroids

Most effective control for all pts except mild intermittent asthma! Effective for airway inflammation Underutilization results in poor outcome Side effects minimal if used properly Benefits of daily use -> Decreased symptoms -> Decreased severe exacerbations -> Decreased use of quick-relief medicine -> Increased lung function -> Decreased airway inflammation

CSA Risk Factors

NOT RELATED TO BEING FAT -> ↑ Age (especially > 65) -> Male (higher apneic threshold*) -> Heart failure -> Atrial fibrillation -> Stroke -> Long-acting opiates

CSA Pathophysiology

NOT RELATED TO BEING FAT Hypoventilation - less common Underlying condition → severe hypoventilation CNS depressant, CNS disease, neuromuscular disease Hyperventilation - more common Occurs transiently in normal sleep but adaptive mechanisms prevent central apnea CSA - apneic threshold abnormally high so apnea occurs with only mild ↓PaCO2

CSA Treatment

NOT RELATED TO BEING FAT Treat underlying condition (if present) If not, or severe CSA complications → CSA-specific Rx CSA from hypoventilation: -> Non-invasive positive pressure ventilation (NIPPV) CSA from hyperventilation (Rx goal: prevent hyperventilatory overshoot) -> CPAP → ↑ pharyngeal patency → blunts negative pressure swings when breathing resumed → ↓ compensatory hyperventilation → avoids ventilatory overshoot and ↓PaCO2 If CPAP not effective, use NIPPV If hypoxemia, Rx with supplemental O2 → ↑ PaCO2 so ventilatory overshoot blunted If CPAP, NIPPV and supplemental O2 not effective use respiratory stimulants: -> Acetazolamide -> Theophylline

Treatment for OSA

Nasal CPAP Weight loss Change in sleep position -> if OSA is positional (and mild) Avoid alcohol and sedatives Oral appliances -> Mandibular advancement splints -> Tongue retaining devices Upper airway surgery/trach

Long-Acting β-Agonists, LABA

Not substitute for anti-inflammatory Rx Not appropriate for monotherapy (CANT USE LABAs ALONE FOR TREATMENT) Synergy when added to ICS Not approved for acute symptoms or exacerbations

Obstructive Apnea vs. Obstructive Hypopnea

Obstructive Apnea: -> cessation of airflow for > 10s despite vigorous respiratory effort. "Obstructive" Hypopnea: -> reduction of airflow by >30% associated with >3% desaturation or arousal from sleep despite vigorous respiratory effort

Mucoid Pseudomonas aeruginosa infection in CF

POOR SURVIVAL (only about 60% of patients survive to 80 months post infection)

Complications of Oxygen Therapy

Pediatric -> Retinopathy of prematurity -> Bronchopulmonary dysplasia Adults/Peds -> Decreased Mucociliary clearance -> Tracheitis -> Acute lung injury Absorptive Atelectasis HYPERCAPNIA IN SOME PATIENTS WITH COPD (Due to increased dead space, Abnormal respiratory drive, Haldane effect) IN GENERAL: Use lowest FiO2 to maintain desired PaO2, SaO2

V/Q Mismatch

Peripheral Airways obstruction, Parenchymal destruction, Pulmonary Vascular Involvement lead to: 1) Areas of low V/Q => Decreased arterial PO2 2) Increased dead space => Increased arterial CO2 3) Increased minute ventilation

Disease Specific Treatment of Respiratory Failure

Pneumonia: antibiotics, secretion clearance Atelectasis: remove secretions that are occluding a bronchus ("pulmonary toilet" with suctioning of airway or bronchoscopy) COPD/asthma: bronchodilators, steroids Drug overdose: give antidote (naloxone for opiates, flumazenil for benzodiazepines)

Complications of OSA

Poor performance (ADL, job) Accidents (risk for MVAs ↑ 2-3x ) Depression Pulm hypertension* Repeated hypoxemia Esp if concomitant lung disease Cor pulmonale ↑ risk for perioperative complications Diabetes, insulin resistance*

Asthma: Reliever Medications

Rapid-acting inhaled β2-agonists Systemic glucocorticosteroids Anticholinergics Theophylline Short-acting oral β2-agonists

Dornase Alpha Treatment for CF

Recombinant human DNase I -Breaks down extracellular DNA - Transforms purulent CF to free-flowing liquid in vitro

Asthma: SABA

Short Acting Beta Agonists (SABA ) (albuterol) Most potent and rapidly acting bronchodilators First-line for relief of acute symptoms Mechanism: activates adenyl cyclase cAMP prevents myosin-actin interaction leads to smooth muscle relaxation Some anti-inflammatory properties on mast cells Not to be used on scheduled basis and never as single agent treatment

Cystic Fibrosis

Single gene mutation on chromosome 7 Encodes protein - CFTR CFTR = Cystic Fibrosis transmembrane conductance regulator ATP-binding cassette (ABC) family of proteins (transports bacteria, amino acids, nutrients across membranes) There are 6 main classes of CFTR mutations -> ∆F508 is the most common mutation

Pathophysiology of OSA: NORMALS

Tendency for UA to narrow during sleep Effects of gravity on tongue, soft palate DECREASED lung volume when supine (↓ caudal traction on airway, fluid shifts) Effect of negative pressure with inspiration DECREASED UA dilator muscle activity in sleep (↓neural drive to resp mm during sleep) major collapse point is oropharyngeal airway

Ivacaftor

Treatment for CF VX-770- CFTR potentiator This drug not only improves FEV1, but also improves symptoms and quality of life in patients with a specific genetic deficit (MOST CLEAR BENEFIT for patients with G551D mutation of CFTR -> new research suggests some use in other patients

Anti-IgE Omalizumab

Treatment for some Asthma Patients Appropriate pts: -> Inadeq control -> Atopic asthma -> ↑IgE -> + skin test

Treatment Strategies for Asthma

Trigger avoidance Acute relief medication (short acting bronchodilator, systemic steroids) Long-term control medication (inhaled corticosteroids, LT antagonists etc.) Immunotherapy (anti-IgE, anti-cytokine) Treatment of related problems (e.g. GERD, sinusitis, allergic rhinitis)

Causes of Type I Acute Hypoxemic Respiratory Failure

Type I -> -> occurs when arterial PO2 is less than 60 mmHg Pneumonia ARDS Cardiogenic pulmonary edema Lobar collapse Pulmonary embolism Pneumothorax Severe acute ILD (cryptogenic organizing pneumonia, acute interstitial pneumonia)

Types of Respiratory Failure

Type I -> Hypoxemic Respiratory Failure -> occurs when arterial PO2 is less than 60 mmHg Type II -> Hypercapnic Respiratory failure -> occurs when arterial PCO2 is greater than 45 mmHg Diagnosis REQUIRES ARTERIAL BLOOD GAS

Pulmonary Function Testing in Asthma Patients

Used for: diagnosis and management FEV1/FVC < 0.7 BUT can be normal Severity of obstruction determined by FEV1% predicted after bronchodilator challenge Peak Expiratory Flow (PEF) monitoring Bronchoprovocation (methacholine, histamine, mannitol, cold air, exercise) Exhaled nitric oxide (eNO)

Surgery: Uvulopalatopharyngoplasty (UPPP)

Used to treat Severe OSA - Effective in <50% - Depends on site of narrowing - Side effects

Obstructive Lung Disease PFTs

What disease is shown by the results in D?

Anatomical Risk Factors for Obstructive Sleep Apnea

adenoid hypertrophy tonsillar hypertrophy retrognathia macroglossia elongated/enlarged uvula

Obstructive Sleep Apnea Risk Factors

↑ Age, Race (African-Americans < 35 yrs old) Male gender (gap narrows with post-menopausal women) Obesity (waist size, neck size >17 in) Snoring (Sensitivity: 85%, Specificity: <50%) Craniofacial abnormalities Nasal obstruction/redundant soft palate Endocrine abnormalities (hypothyroid, acromegaly) Family History (genetics not worked out) Chronic disease (CHF, ESRD, lung disease, stroke) Pregnancy "Exposures" - smoking, alcohol, benzodiazepines, narcotics

Pathophysiology of OSA

↑ UA narrowing (fat deposition) ↓ compensatory UA dilator muscle activity Loss of normal reflexes during sleep to combat neg insp force UA dilator muscles inhibited by: 1) Sleep disruption, neuromuscular disease, alcohol, benzos, opiates 2) Leptin resistance (↑visceral fat, respiratory depression) 3) Inflammation/neuropathy from UA mucosal trauma Repetitive Collapse of Upper Airway during sleep Hypoventilation -> DECREASED PaO2, INCREASED PaCO2 Repeated arousal -> sleep deprivation Increased sympathetic activation -> consequences for arterial circulation

Morbidity and Mortality of OSA

↑ all-cause mortality in severe OSA (Apnea Hypopnea Index>30/hr) -> Hypopnea -> 30% or greater decrease in airflow for 10 seconds or more PLUS Decreased Oxygen Saturation of 3% or more OR AROUSAL from sleep Cardiovascular*:↑ mortality ->Systemic hypertension (50%) -> ↑ Arterial disease ->Myocardial Infarction, CHF ->Arrhythmias -> Sinus Arrest, atrial fibrillation -> Ventricular Arrhythmias -> Sudden Death Stroke*

Bronchiectasis/Cystic Fibrosis TREATMENT for INFECTION

(there are other treatments for other symptoms)