Respiratory Flashcards
What are the adverse effects of bosentan?
Hepatotoxicity 10%
Which drugs may be associated with a prognostic / survival benefit in group 1 PAH?
Macitentan - may be associated with improved morbidity / mortality
Bosentan - favourable survival outcomes
Mortality benefit of PDE5 inhibitors and soluble guanylate cyclase stimulators unknown in PAH
What are the echocardiographic features of pulmonary hypertension?
- Use tricuspid regurgitant velocity (TRV) to estimate RVSP. RVSP is a surrogate for PASP, provided there is pulmonary stenosis or RVOT obstruction
Uses modified Bernoulli equation
Estimated PASP = RVSP = 4 x [TRV]^is 2 + RAP - RV hypertrophy / dilatation / systolic function
- RA enlargement
- Mid-systolic notch on pulmonary artery doppler
- Septal blowing (intraventricular septum shifts towards the LV cavity resulting in flattening, during systole)
- Can estimate the PCWP using the E/e’ ratio. PCWP is an indirect measurement of LA pressure.
Work up of suspected pulmonary hypertension
Overview of pulmonary hypertension management
Management of suspected VTE in pregnancy
Risk factors for developing CTEPH after PE
Management of haemodynamically stable PE
What are the mutation classes in cystic fibrosis?
- > 2000 mutations in CFTR (cystic fibrosis transmembrane conductance regulator) gene on chromosome 7
- autosomal recessive inheritance
- 5 classes of mutations - class I - III have more severe phenotype, class IV-V have milder phenotypes
Class I - no functional CFTR produced (22%), 2nd most common type, due to nonsense mutations, splice mutations and deletions
Class II - MOST common (88%), TRAFFICKING detect, CFTR is produced but misfolds and therefore does not move appropriately to cell surface membrane. MOST COMMON IS F508 deletion (“processing” mutation)
Class III - CFTR protein is produced and moves to cell surface but channel gate does not open correctly (6%). G551D (“gating” mutation)
Class IV - CFTR protein produced, moves to cell surface, but function of channel is faulty
Class V - normal CFTR protein is produced and moves to the cell surface, but in insufficient quantities
What is the Well’s score?
- Low (<2) –> do a PERC score and if low can rule out clinically
- Moderate (2-4) –> do a D-dimer
*High (>4) –> do a CTPA
What is the PERC criteria?
- If NONE of the 8 PERC criteria are present, PE can be ruled out clinically
Lung volumes
- Tidal volume - volume of air breathed in and out at rest (500mL)
- Inspiratory reserve volume - volume of air that can be inspired on deep inspiration in addition to TV (1900mL)
- Expiratory reserve volume - volume of air that can be expired in addition to TV on deep expiration (700mL)
- Residual volume - the volume of air that remains in the lungs in order to maintain airway patency, after a deep & forceful expiration (1100mL)
- Inspiratory capacity - the maximum volume of air that can be inspired after quiet expiration (2400mL)
TV + IRV - Functional residual capacity - the volume of air that remains in the lungs after quiet expiration during tidal breathing (1800mL)
RV + ERV - Vital capacity - the volume of air that can be expired after deep inspiration
TV + IRV + ERV - Total lung capacity - total volume of air that can be contained within the respiratory system, volume of air in the lungs after maximal voluntary inspiration
TV + IRV + ERV + RV
rarely also pulmonary sarcoidosis
What does an elevated residual volume to total lung capacity ratio indicate?
High RV: TLC, normal TLC - gas trapping
High RV: TLC, high TLC - gas trapping & hyperinflation
Normal RV: TLC, high TLC - large lung capacity (athletes etc.)
High RV: TLC ratio, low TLC but normal RV - chest wall deformity / neuromuscular weakness, obesity
Normal RV: TLC ratio, TLC reduced, RV reduced - restriction
What indicates gas trapping on RFTs?
Elevated residual volume to total lung capacity ratio with normal total lung capacity (ratio > 0.4 OR > 2 standard deviations from normal)
Spirometry will likely show a mixed obstructive / restrictive ventilatory deficit - where FVC is reduced due to gas trapping rather than due to a second restrictive pathology
What is a positive bronchodilator response?
What changes on respiratory function testing would be seen in obesity?
- Spirometry : restrictive ventilatory deficit
- RV: TLC ratio increased, due to reduced TLC but preserved RV (total lung capacity and forced vital capacity may be normal)
- most significant change in obesity is reduced expiratory reserve volume (ERV)
- therefore, there is a reduction in functional residual capacity proportional to the severity of obesity
- DLCO increases due to increase pulmonary blood volume
- KCO also increased due to reduction in alveolar volume
What do the RFTs / lung volumes show in COPD?
- Spirometry: post-bronchodilator FEV1/FVC ratio <0.7, FEV1 < 0.8
*there may be an element of bronchodilator reversibility - if bronchodilator response > 400mL - consider asthma or asthma-COPD overlap; if >200mL and 12% (but <400mL) - consider asthma / COPD overlap or asthma component - DLCO reduced in emphysema / pulm HTN, may be normal in chronic bronchitis
- RV increases due to gas trapping / airway closure (RV: TLC ratio increases)
- FRC increases due to increase in RV
- eventually TLC also increases reflecting hyperinflation
- expiratory reserve volume (ERV) decreases => therefore forced vital capacity decreases
- inspiratory capacity decreases
What is the benefit of pulmonary rehabilitation / regular physical activity in COPD?
- Improves symptoms, QoL, exercise capacity, anxiety & depression
- Reduces hospitalisation for exacerbations
- Improves peripheral muscle function and sense of control
- does NOT improve survival
Who should be started on triple agent inhaler therapy in COPD? What is the benefit of triple inhaler therapy?
Indications for inhaled corticosteroid therapy:
- FEV1 < 50%
- recurrent exacerbations and significant symptoms
- eosinophilia
Indications for triple inhaler therapy (ICS + LAMA + LABA)
- at least one severe exacerbation per year requiring hospitalisation, or 2 or more moderate exacerbations in last 12 months AND significant symptoms despite LAMA / LABA or ICS/LABA therapy
- OR in patients stabilised on a combination of LABA + ICS, plus LAMA
Triple therapy (ICS / LAMA / LABA) has a mortality benefit, reduces exacerbations and hospitalisations compared to dual therapy (LAMA/LABA)
- increased pneumonia rates compared to LAMA/LABA but similar to ICS/LABA
- especially in patients with frequent exacerbations, blood eosinophil count > 200, when low-medium ICS used
Who is eligible for home O2 therapy in COPD?
Long term O2 therapy has a survival benefit for hypoxaemic COPD patients
- must use for at least 16-18 hours per day to have a benefit
- PaO2 <55mHg (severe hypoxia)
- PaO2 55-59mmHg with evidence of R heart failure, pulm HTN, polycythaemia
- No cigarettes for 3 months
- No evidence of improvement for moderate hypoxia - PaO2 60-79mmHg
Exertional (portable) oxygen
**improves exercise tolerance
- SaO2 <88% after 6 minutes walking
- SaO2 improves with O2 therapy
- No cigarettes for 3 months
Refer patients with possible persisting hypoxaemia (SaO2 <92%) for consideration of home o2
What factors determine prognosis in COPD?
BODE index- predicts 4 year survival in COPD patients
1. FEV1
2. Distance walked in 6 minutes
3. mMRC dyspnoea scale
4. BMI
Who should be referred for lung transplantation in COPD?
- progressive symptoms (despite maximal treatment including medications, pulm rehab and O2 therapy)
- NOT a canddiate for endoscopic or surgical lung volume reduction
- BODE index 5-6
- PaCO2 > 50 and/or PaO2 <60mmHg
- FEV1 <25% predicted
What determines poor prognosis in COPD exacerbations?
DECAF
- dyspnoea
- eosinopenia
- consolidation
- acidaemia
- atrial fibrillation
What are the indications for NIV in COPD exacerbations?
What are the contraindications for NIV in COPD exacerbations?
Why is NIV effective in COPD exacerbations?
Indications for use of BiPAP in COPD exacerbations (CPAP not helpful as does not improve ventilation)
- PaCO2 > 45mmHg, pH <7.35 (i.e. hypercapnic respiratory acidosis)
- Increased WOB
- Severe dyspnoea with clinical signs of respiratory muscle fatigue
Large body of evidence to support use of NIV in COPD patients that are hypercapnic
- nearly 50% reduction in mortality
- reduced rate of intubation by 65%
- reduced hospital stay
NIV improves alveolar ventilation - decreases RR, increases tidal volume, increased minute ventilation
Contraindications for NIV (scenarios where invasive ventilation is first-line)
- cardiac or respiratory arrest
- inability to cooperate, protect own airway or clear secretions
- upper airway obstruction
- high aspiration risk
- non-respiratory organ failure that is acutely life-threatening or evidence of multi-organ failure
- pneumothorax
- haemodynamic instability
- reduced GCS or coma - relative C/I, can trial NIV if hypercapnic encephalopathy
- facial trauma, deformity, surgery
- recent oesophageal anastomoses or other upper GI surgery / bleed
What is the stepwise inhaler therapy for COPD?
What is the advantage of using dual long-acting bronchodilators for COPD?
Dual therapy with LAMA & LABA reduces mod-severe exacerbations when compared to LAMA therapy alone
LAMA + LABA vs ICS + LABA leads to similar exacerbations and quality of life
What are the predictors of mortality in asthma?
- history of near fatal asthma / requiring ICU or mechanical ventilation
- history of asthma hospitalisation in last 12 months or repeated ED attendance
- history of brittle asthma (sudden, severe exacerbations)
- poor adherence with treatment
- signficant comorbidities - pneumonia, genitourinary disease, septicaemia, diabetes, arrhythmia
- escalated SABA use (more than 12 cannisters per year OR more than 1 cannister per month)
- requirement of 3 or more classes of asthma maintanence treatment
- poor lung function
- oral corticosteroid use > 75mg during previous admission and dose of oral steroids > 110mg per month
- comorbid food allergy - especially anaphylaxis
- rural or remote location
- psychosocial issues (depression or other psychiatric illness, substance misuse, smoking, social isolation, financial or domestic problems etc.)
**protective factor - ICS > 4 cannisters / year
What factors determine prognosis after discharge from admission with acute exacerbation of COPD?
CODEX - predicts mortality and/or hospital readmission from 3 months to 1 year after discharge
C = comorbidity
O = obstruction
D = dyspnoea
EX = previous severe exacerbations
NIV for specific conditions
What is the mechanism of dupilumab?
Anti IL-4 and IL-13
Targets eosinophilic asthma
Especially in patients with chronic rhinosinusitis and nasal polyposis
Risk factors for fixed airflow obstruction in asthma
- No ICS treatment
- Smoking
- Occupational exposure
- Mucus hypersecretion
- Blood eosinophilia
Who is eligible for home o2 therapy?
PaO2 <55mmHg or SaO2 <88% at rest OR
PaO2 55-59mmHg or SaO2 < 89% WITH polycythaemia (HCT > 0.55), pulm HTN or RV dysfunction / cor pulmonale
No cigarettes for 3 months
What are the features of allergic bronchopulmonary aspergillosis? (ABPA)
Characterised by:
(1) Chronic asthma
(2) Central bronchiectasis with lots of sputum production & mucus plugging
(3) Recurrent pulmonary infiltrates
- Very high total IgE (>1000)
- Evidence of aspergillus sensitivity (IgE or aspergillus precipitins testing)
- Aspergillus in sputum
What is the management of insomnia?
Address contributing factors
1st line therapy is CBT
Pharmacotherapy
-> Sleep initiation
Melatonin receptor agonist (Ramelteon), melatonin, sedating anti-depressants (mirtazepine, amitriptyline)
-> Sleep maintenance
Orexin receptor antagonists ‘orexant’ -> block orexin A and B that promote wakefulness (Suvorexant and Lemborexant), low dose doxepin, sedating antidepressants (amitriptyline, mirtazepine), gabapentin
What is the benefit of home O2 therapy for COPD?
Can improve survival if used > 16 hours per day
Improves dyspnoea, QoL, exercise capacity, cognitive function, depression
Does not reduce hospitalisations, pulmonary dynamics, polycythaemia
What are the causes of metabolic alkalosis?
Management of COPD exacerbation
- Increased frequency of short acting inhaled bronchodilators for symptoms
- Oral antibiotics (amoxicillin or doxycycline if features of infection)
- Short course of oral steroids e.g. pred 30-50mg for 5 days - reduces treatment failure, reduces length of stay & readmission, reduces severity of exacerbation
- Controlled O2 therapy - aim SaO2 88-92% or PaO2 60-70mmHg
- NIV if hypercapnic respiratory acidosis
- Prevent future exacerbations
- refer to pulm rehab as soon as pt stabilises from acute exacerbation
- GP review in 7 days
- Smoking cessation
- Vaccinations
- Education
- Inhaler technique
- COPD action plan
What is the role of oral corticosteroid therapy for management of bronchiectasis?
No role
Why can hypoxia worsen in an asthma patient treated with salbutamol?
Worsening of V/Q mismatch
Salbutamol indiscriminately opens up airways -> including in parts of the lung that may not be well perfused -> leading to worsening of hypoxia
What are the benefits of monoclonal antibodies for asthma?
All biologics will reduce asthma exacerbations by 50%, improve asthma control, reduce corticosteroid use / dose, modest improvement in lung function
Limited evidence re improvement in QOL
Omalizumab does NOT lead to significant improvement in lung function OR change in oral steroid dose -> but other biologics do
What is the mechanism of action of benralizumab & mepolizumab?
Benralizumab - anti IL-5 receptor
Mepolizumab - anti IL-5
Helpful in eosinophilic asthma, adult onset
Criteria: eosinophils > 0.25
Eosinophils > 0.3 may indicate responsivesness
Step-wise approach to asthma treatment
NEVER use LABA monotherapy - associated with increased risk of asthma exacerbations and asthma-related death
ICS-formoterol as reliever therapy is associated with reduced exacerbations compared to SABA as reliever therapy
What are the risk factors for fatal or near fatal exacerbations of asthma?
- Prior history of poorly controlled asthma
Increasing symptoms, especially nocturnal awakenings
Hospital admissions or ED visits in last year
Recent use of PO steroids
Lack of ICS - Prior history of near fatal asthma requiring intubation or ICU admission
- Low FEV1
- Post bronchodilator FVC < 70% suggestive of gas trapping
What factors suggest uncontrolled asthma?
- Poor symptom control
Asthma Control Questionnaire > 1.5
Asthma control test <20 - Frequent severe exacerbations - 2 or more courses of systemic steroids in last year
- Serious exacerbations - 1 or more hospitalisation or ICU stay
- Airflow limitation - FEV1 < 80% and FEV1/FVC < LLN
What factors predict the need for hospitalisation in CAP?
What is the utility of bronchial provocation testing in asthma?
What is the role of long-term low dose antibiotic therapy in bronchiectasis?
Should only be considered if 3 or more exacerbations per year
- Macrolides (e.g. azithromycin or erithromycin - 500mg azith three times per week or 250mg daily)
Mechanism:
-> inhibit pseudomonas biofilm formation by inhibiting ‘quorum sensing signals’
-> multiple anti-inflammatory effects
-> MUST rule of NTM (impair intracellular killing of NTM by macrophages)
BENEFITS
- reduce exacerbation frequency (likely due to anti-inflammatory effects)
- variable improvement in symptoms and QOL
RISKS
- QTc prolongation
- significant increase in antibiotic resistance
- GI side effects - Inhaled aminoglycosides (e.g. tobramycin)
- role only if > 3 exacerbations per year
- limited evidence
- reduces bacterial infection (especially Pseudomonas)
- can increase bronchospasm and cough
What is the difference between narcolepsy type 1 and type 2?
Narcolepsy type 1
3 months of daytime sleepiness PLUS one of:
- low hypocretin in CSF
- positive MSLT and definite cataplexy
- equally common in men & women
Narcolepsy type 2
- no cataplexy
- normal CSF hypocretin
- positive MSLT
- daytime sleepiness for 3 months
What are the clinical features of narcolepsy?
- daytime sleepiness (do not get more sleep than healthy individuals) but rapidly doze off during day
- cataplexy
- hypnagogic hallucinations
- sleep paralysis
What is the diagnostic work up of narcolepsy?
- Sleep study / PSG
- exclude other sleep disorders
- should be done day before MSLT (helps to ensure minimum of 6 hours sleep achieved night prior to MSLT)
- in narcolepsy, sleep study will show - spontaneous awakenings, mildly reduced sleep efficiency, increased light NREM sleep
- in type 1 narcolepsy and occasionally type 2 narcolepsy - REM sleep occurs within 15 minutes of onset of sleep (health individuals - 80-100 minutes) - Diagnostic test is mean sleep latency test (MSLT)
Daytime test after PSG
Average sleep latency <8 minutes and/or at least two sleep onset REM periods
What is the management of narcolepsy?
- non-pharmacological - daytime naps to help with alertness
-1st line stimulant therapy (dexamphetamine) - no max dose, typically 10-30 mg - 2nd line wake promoting agents e.g. modafinil
- SSRIs and SNRIs for cataplexy
AVOID caffeine (worsens insomnia), sedatives, prazocin (worsens cataplexy)
What is Samter’s triad? How is it managed?
= Aspirin exacerbated respiratory distress
- Triad:
(1) Asthma
(2) Aspirin & NSAID intolerance - acute asthma, urticaria, rhinorrhoea, GI symptoms
(3) Nasal polyps
- Mechanism - COX1 inhibition leads to loss of PGE2 which is involved in mast cell homeostasis (inhibits degranulation & inflammation)
COX2 inhibitors do not cause the same reactions
Management
- Aspirin desensitisation is 1st line
- Polyps are managed with intransal steroids as they are refractory to surgery (however, they can be debulked prior to desensitisation if needed)
What is Young’s syndrome?
Tried of bronchiectasis, infertility (vas deferens obstruction) and chronic rhinosinusitis
CF and primary ciliary dyskinesia must be excluded
Caused by ? mercury poisoning in childhood
What is the role of eradication therapy for Pseudomonas aeruginosa in colonised patients with bronchiectasis?
Patients with bronchiectasis who are colonised with Pseudomonas (i.e. identified in 2 or more cultures, at least 3 months apart)
In newly identified Pseudomonas -> currently evidence is lacking to support eradication therapy - NOT appropriate to treat if patient is clinically stable
In patients with long term colonisation with Pseudomonas, no evidence that eradication therapy reduces exacerbations or eliminates Pseudomonas
What are the HRCT features of bronchiectasis?
HRCT is gold standard for diagnosis of bronchiectasis
1. Dilatation of airway greater than that of accompanying arteries (signet sign)
2. Lack of tapering of airways
3. Presence of radiographically visible airways in the perimeter
What is the role of inhaled hypertonic saline in bronchiectasis?
Assists with airway clearance
Some evidence that it is superior to isotonic saline
- improved QOL, reduced exacerbations, mildly improved RFTs
Avoid if FEV1 < 1L due to risk of bronchospasm
Poorly tolerated due to bronchospasm (can consider pre-medication with bronchodilators)
What is the role of bronchodilator therapy for management of bronchiectasis?
Essentially no role
- unless comorbid asthma
Only 34% patients with bronchiectasis have airflow obstruction on spirometry, 48% have normal spirometry
LABAs may have some symptomatic benefit in patients with bronchiectasis and significant SOB
Low level evidence for salbutamol PRN
Can consider as pre-medication before inhaled hypertonic saline or inhaled aminoglycosides
What is the antibiotic therapy of choice for acute exacerbations of bronchiectasis?
- depends on whether severe or non-severe & if known pseudomonas colonisation
- Non-severe, no known pseudomonas colonisation
- amoxicillin 1g TDS or doxycyline 100mg BD; if recent beta-lactam producing haemophilus influenza or moraxella catarrhalis -> Aug DF BD - Severe, no known pseudomonas colonisation
- trial of oral therapy reasonable (as per non-severe exacerbations)
- if parenteral therapy required:
Ceftriaxone 2g daily or cefotaxime 2g TDS or Augmentin 1+0.2 IV TDS - Non-severe, known colonised by pseudomonas
- trial of empiric therapy as above (amoxicillin or doxy or Aug DF)
- if not improving AND pseudomonas identified on MCS -> change to cipro 750mg BD for 14 days - If severe and known colonisation by pseudomonas
- empiric combination therapy of anti-pseudomonal beta lactam PLUS aminoglycoside
Ceftazidime 2g TDS OR tazocin 4.5g QID PLUS
Gentamicin or tobramycin or cipro (gent or tobra preferred)
If anaphylaxis to penicillin -> mero PLUS gent or tobra or cipro
What are some prognostic tools used in bronchiectasis?
FACED score (predicts morbidity & mortality)
F = FEV1 <50% (2 points)
A = age > 70 yrs. (2 points)
C = chronic colonisation with Pseudomonas (1 point)
E = extension - > 2 lobes affected ( 1 point)
D = dyspnoea using MMRC scale
Bronchiectasis Severity Index - predicts morbidity & mortality at 1 and 4 years
BMI
FEV1
Previous hospital admission, hospitalisation for previous severe exacerbation in last 2 years
Number of exacerbations in last year
MMRC score
Pseudomonas colonisation
Colonisation with other organisms
Radiological severity
When should a patient with CF be referred to a lung transplantation centre?
- PO2 <60mmHg
- PCO2 >50mmHg
- increasing clinical resistance
- reduced QOL
- FEV1<35%
- rapid rate of decline in FEV1
- increasing frequency of IV antibiotics needed
CONTRAINDICATION - active mycobacterium abscessus infection
What is the mechanism of action of CFTR modulators?
CFTR modulators improve FEV1, improve symptom-related QOL, reduce exacerbations
- IVACAFTOR
- CFTR potentiator - opens the channel and allows Cl reflux
- for type 3 mutations - G551D (where CFTR produced and moved to membrane but channel does not open properly)
- increases FEV1 by > 10 % very rapidly - TEZACAFTOR or ELEXACAFTOR
- CFTR corrector -> moves the CFTR protein to the cell surface
- works for type 2 mutations (F508 deletions where CFTR protein does not make it to the cell membrane due to misfolding)
Combinations
-> Dual therapy - Ivacaftor / tezacaftor (Symdeco). Improves FEV1 by 3.5%
-> Triple therapy - Elexacaftor / tezacaftor / ivacaftor (Trikafta). Improves FEV1 by 14% and reduces exacerbations
Currently class IB recommendation for triple therapy in homozygous F508 deletion and class 2B recommendation for dual therapy in heterozygous F508 deletion
What are the common causes of high severity community acquired pneumonia?
- Streptococcus pneumoniae is the most common cause of high severity CAP
- Legionella species
- Gram negative rods / Enterobactericae (e.g. Klebsiella pneumoniae)
- Staph aureus
- Legionella species
Empiric therapy for HAP
What factors predict the need for admission to ICU in patients with CAP?
SMART-COP has good sensitivity & NPV, poor specificity & PPV
Who requires drainage of parapneumonic effusions / empyema?
Small parapneumonic effusions do not need to be sampled or drained
Any clinically significant effusion should be sampled
- causing dyspnoea, >10mm on lateral XR, >30mm on CT
Criteria for drainage:
- Purulent pleural fluid
- pH < 7.20 (lidocaine contamination can drop pH)
- Positive gram stain
- Positive culture or PCR
What are the most common causes of HAP?
What are the most common causes of VAP?
Most common cause of HAP is Streptococcus pneumonia
Other causes of HAP
- GNRs
- Enterobacter
- Pseudomonas (especially if ICU)
- Staph aureus
- Atypical organisms much less likely
Causes of VAP
- if <4 days of ventilation (antibiotic-susceptible)
Streptococcus pneumoniae
Haemophilus influenzae
MSSA
- if > 5 days of ventilation (more resistant organisms)
Pseudomonas aeruginosa
Acinetobacter spp.
MRSA
ESBL enterobactericae (Klebsiella pneumoniae, E. Coli, Enterobacter spp.)
What happens in methaemoglobinaemia?
What happens in carboxyhaemoglobinaemia?
What determines delivery of O2 to tissues by arterial blood? (O2 delivery equation)
What are the features of severe bronchiectasis exacerbations?
When should antibiotics be used for the treatment of acute exacerbations of bronchiectasis?
Features of severe bronchiectasis exacerbations:
- worsening respiratory distress
- worsening hypoxaemia
- acute onsent confusion
- signs of sepsis or septic shock
Only use antibiotics for the treatment of bronchiectasis exacerbations if all 3 of the following are present
(1) increased sputum volume or viscosity
(2) increased sputum purulence
(3) increased cough (which may be associated with wheeze, SOB or haemoptysis)
O2 & CO2 partial pressures
O2 : CO2 partial pressures - dependent on ventilation (concentration of gases in alveoli remain relatively constant during respiration because only 10% lung volume is exchanged with each breath)
O2 : CO2
Inspired air - 150 : 0
Alveoli - 100 : 40
Arterial blood - 98 : 40
Venous blood - 40 : 46
Pulmonary arteries - PAO2 = 40
Pulmonary veins - PAO2 = 98
Risk factors for asthma exacerbations
- Ever intubated for asthma
- Uncontrolled asthma symptoms
- Having one or more exacerbation in last 12 months
- Low FEV1
- Incorrect inhaler technique
- Poor adherence
- Smoking
- Elevated FENO with allergic asthma
- Obesity
- Pregnancy
- Blood eosinophilia
What determines airflow?
What determines airflow resistance?
Flow is directly proportional to pressure gradient, and inversely proportional to airflow resistance
Airflow resistance is inversely proportional to radius (greatest determinant of resistance) and directly proportional to viscosity & length
What is the diagnostic work up for suspected chronic thromboembolic pulmonary hypertension (CTEPH)?
- suspect in patient with new dyspnoea / reduced ET after PE ; or if persisting mismatched perfusion deficits on VQ scan after 3 months of anticoagulation
V/Q scan is the MOST SENSITIVE investigation for CTEPH (i.e. negative VQ scan excludes CTEPH)
- it is NON-SPECIFIC (i.e. will detect pulmonary vascular obstruction from other causes as well e.g. pulmonary artery sarcoma, extrinsic compression of pulmonary arteries / veins, pulm. veno-occlusive disease, fibrosing mediastinitis, large vessel pulmonary vasculitis). ALSO may underestimate central pulmonary clots
If VQ is suggestive of CTEPH -> proceed with CTPA -> this will confirm PEs and exclude DDx for pulm. vascular obstruction. ALSO helps define surgical accessibility of obstructing thrombotic lesions
Negative CTPA does NOT exclude CTEPH
If VQ and CTPA suggestive of CTEPH -> digital subtraction angiography - gold standard for diagnosis and determining surgical eligibility
screen for anti-phospholipid syndrome
What determines the partial pressure of a gas in an alveolus?
Partial pressure is directly proportional to wall tension and indirectly proportional to the radius
What determines diffusion of a gas during gas exchange? (Fick’s law)
Factors affected in disease states include
* Surface area (e.g. emphysema)
* Barrier thickness (e.g. IPF, CCF)
* Pressure gradients (e.g. ventilatory failure)
Solubility of O2 = 0.03 mL/L/mmHg
Solubility of CO2 = 0.7 mL/L/mmHg (ie. 20x more)
- It takes 0.25 seconds for oxygen to diffuse across the AC membrane (i.e. for PaO2 to equal PAO2), though blood spends 0.75 seconds in the capillary
- Diffusion of CO2 is 20 times faster, and limitation only occurs with very severe abnormalities of the A-C membrane
–> an elevated PaCO2 is due to inadequate alveolar ventilation (VA), not due to gas exchange abnormalities
–> PaCO2 is proportional to 1/VA
What factors affect haemoglobin’s affinity for O2?
Factors that increase Hb affinity for O2 (favours uploading of O2), shifts Hb-O2 dissociation curve to the left
- Decreased pCO2
- Decrease H+ ions / increased pH
- Colder temperature
- Decreased DPG (DPG produced by RBCs in response to hypoxia -> decreases affinity of Hb for O2 in order to increase O2 delivery to tissues)
- Decreased PO4
- Increased fetal Hb, CO-Hb, met-Hb
Factors that decrease Hb affinity for O2 - favour tissue O2 delivery, shift Hb-O2 dissociation curve to the right
1. Increasing pCO2
2. Increased H+ ions (decreased pH)
3. Warmer temperatures
4. Increased DPG
5. Sulfhemoglobinemia (Sulf-Hb)
5. HbSS (sickle cell)
When is pulmonary vascular resistance lowest?
Pulmonary vascular resistance = resistance to blood as it flows from pulmonary artery to LA
Pulm. vascular resistance = 80 x (mean pulmonary artery pressure - pulmonary capillary wedge pressure / CO)
Pulm. vasc resistance increases during inspiration (due to increased resistance in the alveolar vessels) and also increases during expiration (due to increased resistance in the arteriolar vessels)
Pulm. vascular resistance is LOWEST at functional residual capacity and HIGHEST at total lung capacity
What is the management of CTEPH?
Pulmonary endarterectomy as treatment of choice for proximal PA fibrotic obstructions
Balloon pulmonary angioplasty for inoperable PH or residual PH after PEA or distal obstructions amenable to BPA
Medical therapy (Riociguat) for inoperable candidates OR for persistent/recurrent PH after PEA
What are the medical therapy options for CTEPH?
Riociguat
Soluble cyclic guanylate cyclase stimulators
In PH -> impairment of NO synthesis and NO-mediated stimulation of soluble guanylate-cyclase - cyclic guanosine monophosphate pathway
Riociguat directly stimulates soluble guanylate cyclase, independently of NO; AND increases sensitivity of soluble guanylate cyclase to NO
This increases levels of cyclic guanosine monophosphate -> resulting in vasorelaxation, antiproliferative and antifibrotic effects
In CHEST 1 trial - this led to improve exercise capacity and pulm. vascular resistance in patients that were inoperable or had persistent PH after PEA
What are the causes of Group 1 pulmonary ARTERIAL hypertension?
- Worldwide most common cause is schistosomiasis (parasitic infection)
- Without endemic schistosomiasis -> 50% is idiopathic PAH, 10% heritable PAH
- Idiopathic PAH
- Heritable PAH - bone morphogenetic protein 2 mutations (most common - constitute up to 80% of heritable PAH). BMPR2 mutations lead to proliferation of pulm. vascular cells => vascular remodelling. Autosomal dominant with incomplete penetrance and variable expressivity. 25% with BMPR2 mutation develop PAH - i.e. lifetime risk of developing PAH is 20% in patients with BMPR2 mutations (more likely to manifest in female carriers than male). Tend to present at younger age, more severe disease, increased risk of death
- PAH associated with other conditions
- HIV - 0.5% of pts with HIV will have PAH
- CTD - systemic sclerosis (5-20%), Raynaud’s, RA, mixed CTD
- Portal hypertension
- Congenital heart disease - septal defects, Eisenmenger syndrome
- Schistosomiasis - Drug & toxin induced PAH
- definite associations - methamphetamines, dasatinib, weight loss drugs - aminorex, benfluorex, fenfluramine, dexfenfluramine
Who should be screened for Group 1 pulmonary arterial hypertension?
- Connective tissue diseases (esp. scleroderma, SLE, mixed CTD) should be screened annually (can include TTE, BNP, RFTs)
- Unexplained DLCO <80% (normal TTE does not exclude PAH, may need RHC)
- Patients with HIV with Sx of PAH or risk factors (co-infection with Hep C, IVDU - cocaine, female, high incidence country)
- Portal hypertension - screen with TTE, if RV dilation or dysfunction, TRV > 3.4 m/s -> RHC
What is the mechanism of action of omalizumab?
Omalizumab is a monoclonal antibody against IgE
- targets allergic pathway
- helpful in childhood onset allergic asthma
- criteria - IgE > 26 AND demonstrated sensitisation to a perennial allergen (e.g. dust mite)
Elevated FENO may indicate responsiveness to omalizumab
How is the group 1 pulmonary arterial hypertension diagnosed?
Requires a RHC
- mPAP ≥20 mmHg at rest AND pulmonary vascular resistance > 2 AND PCWP ≤15 mmHg
What are the clinical signs of pulmonary hypertension?
- Loud P2 (S2 is narrowly split or single if RV function is preserved)
- Can develop palpable P2 as pulm HTN becomes more severe
What are the clinical signs of RV failure?
- Elevated JVP
- prominent a wave initially
- prominent v waves suggest significant TR and RV failure - Pulsatile hepatomegaly, hepatojugular reflux
- Ascites
- Left parasternal heave or downward subxiphoid thrust
- Right sided S3 and S4
- Holosystolic murmur from functional TR
- In severe disease, can develop a diastolic pulmonary regurgitation murmur
- Pulmonic flow murmur (occasionally)
- Rarely splenomegaly (can be seen in PAH due to schistosomiasis or portopulmonary HTN)
What are the adverse effects associated with macicentan?
Nasopharyngitis and anaemia
What is the mechanism of action of brensocatib?
Brensocatib is a new small molecule inhibitor for the treatment of bronchiectasis
It is an inhibitor of DPP1 (dipeptidyl peptidase 1) -> decreases damage from neutrophil elastase / neutrophil serine proteases are activated by DPP1
Delays time to exacerbation
Adverse effects are periodontal disease and dermatological SEs
What haplotype is associated with narcolepsy?
DQB1*0602
80% pts have this HLA allele BUT not very specific
Management of group 1 pulmonary arterial hypertension
For idiopathic, heritable or drug-induced group 1 PAH - start with acute vasoreactivity test (assesses the haemodynamic response to a vasodilating agent (NO, epoprostenol or adenosine) using RHC.
Vasoreactive group 1 PAH may benefit from 3 month trial of CCB therapy (long-acting nifedipine or diltiazem)
1st line combination therapy ambrisentan (PBS; endothelin receptor antagonist) / macicentan (ERA) and tadalfil (PDE5 inhibitor)
What is the pathophysiology of narcolepsy?
Autoimmune destruction of hypothalamic neurons which produce hypocretin or orexin
- orexins stabilise wakefullness, prevent inappropriate transitions into REM or NREM sleep and inhibit REM sleep
What are the drives of endothelial dysfunction in group 1 pulmonary arterial hypertension?
- High endothelin 1
- Vasoconstrictor & mitogen
- Low nitric oxide
- Vasodilator and anti-proliferative, reduced in PAH
- Vaso-active intestinal peptide
- Neuropeptide that functions as a neuro-modulator & neuro-transmitter + vasodilator of smooth muscle
- Low serotonin
- Induces growth of pulmonary artery smooth muscle cells
- Less of this increases risk of developing PAH
- Low prostacyclin
Vasodilator, anti-proliferative, inhibits platelet function (reduced in PAH)
What are the predictors of prognosis / 1 - year mortality in pulmonary arterial hypertension?
Hypocapnoea (not hypoxia) predicts mortality in PAH
Changes in RVEF (NOT in pulmonary vascular resistance) are associated with survival
Mean pulmonary artery pressure
Pulmonary vascular resistance
9 factors used as part of risk assessment in PAH
- 6MWT
- Cardiopulmonary exercise testing
- Signs of right heart failure
- Progression in symptoms
- WHO functional class
- Syncope
- Imaging (TTE, CMR)
- NT-pro BNP
- Renal impairment
- Male, aged > 60 yrs.
- Familial PAH and portopulmonary hypertension have worse prognosis, as well those with PH associated with CTD (to a lesser extent)
- SBP, HR
- Presence of pericardial effusion on TTE
- DLCO
- mean right atrial pressure > 20mmHg within 1 year on RHC
- Pulmonary vascular resistance > 32 Wood units on RHC
- Haemodynamics (R atrial pressure, cardiac index SvO2)
Principles of anticoagulation for malignancy associated VTE
Most patients with active cancer associated VTE should be anticoagulated indefinitely
(i.e. beyond 3-6 months)
LMWH and factor Xa inhibitors have equal efficacy in malignancy; NOACSs are preferred; of the factor Xa inhibitors - apixaban is preferred
Reduced dose NOAC is not recommended in malignancy
Rivaroxaban is associated with higher risk of GI bleeding in upper GI malignancy compared to apixaban or LMWH
What is the mechanism of action of tadalafil for management of group 1 PAH?
Phosphodiesterase (PDE) 5 inhibitor
- PDE5 normally degrades cyclic guanosine monophosphate (cGMP) to GMP
- PDE5 inhibitors (sildenafil & tadalafil) increase intracellular concentration of cGMP and cAMP => pulm. vasodilation.
- improves WHO functional class, exercise capacity, QoL, haemodynamics in PAH
- Mortality impact not known
Do NOT combine with soluble guanylate cyclase stimulator (riociguat) - risk of hypotension and death
What are the ECG features of pulmonary hypertension?
- RAD
- Incomplete or complete RBBB
- RV strain pattern - ST depression +/- TWI in right praecordial leads (V1-V4) and inferior leads
- RV hypertrophy -R wave / S wave ratio > 1 in V1
- P pulmonale (peaked P wave) - due to RA enlargement
What is the mechanism of action of ambrisentan?
Ambrisentan / bosentan / macitentan are endothelin receptor antagonists
Endothelin 1 levels are increased in PAH - stimulation of endothelin receptor A leads to increased vasoconstriction & proliferation
- stimulation of endothelin receptor B leads to decreased proliferation and vasodilation
Ambrisentan is a selective endothelin receptor A antagonist and bosentan and macitentan are non-selective endothelin receptor A and B antagonists
Ambrisentan - Improves Sx, WHO functional class, 6MWT, haemodynamics, QoL
Macitentan -Improved composite endpoints of morbidity/mortality, WHO functional class, 6MWT
Bosentan - improves Sx, WHO functional class, 6MWT, TTE, timing to clinical worsening, favourable survival outcomes
What are the adverse effects associated with ambrisentan?
Hepatotoxicity 1-3%
Worsening of ILD in patients with IPF
What are the diagnostic criteria for narcolepsy?
Mean sleep latency time < 8 minutes and/or at least two sleep onset REM periods
Normal PSG
