Pocket Medicine (Pocket Notebook Series)

DYSPNEA

Pathophysiology	Etiologies
Airway obstruction (↑ resistance to airflow)	Asthma, COPD, bronchiectasis, cystic fibrosis, tumor, foreign body, vocal cord dysfunction, anaphylaxis
Alveolar / Parenchymal disease	Pulmonary edema: cardiogenic or noncardiogenic ILD; pneumonia; atelectasis
Vascular (V/Q mismatch)	Large vessel: PE, tumor emboli Small vessel: PHT, vasculitis, ILD, emphysema, PNA
Chest wall (↑ resistance to expansion; weakness of respir. muscles)	Pleural disease: large effusion, fibrosis, pneumothorax Chest wall/diaphragm: kyphoscoliosis, ↑ abd girth Neuromuscular disorders (ALS, GBS, MG) Hyperinflation (COPD, asthma)
Stimulation of receptors	Chemoreceptors: hypoxemia, metabolic acidosis Mechanoreceptors: ILD, pulmonary edema, PHT, PE
↓ O2 carrying cap. (but nl PaO2)	Anemia, methemoglobinemia, CO poisoning
Psychological	Anxiety, panic attack, depression, somatization

Evaluation

• History: quality of sensation, tempo, positional dependence, exac./allev. factors, exertion

• Cardiopulmonary exam, S_aO₂, CXR (see Appendix & Radiology inserts), ECG, ABG, U/S Predictors of CHF: h/o CHF, PND, S₃, CXR w/ venous congestion, AF (JAMA 2005;294:1944) Dyspnea w/ nl CXR: CAD, asthma, PE, PHT, early ILD, anemia, acidosis, NM disease

• Based on results of initial evaluation: PFT, chest CT, TTE, cardiopulmonary testing

• BNP & NT-proBNP ↑ in CHF (also ↑ in AF, RV strain from PE, COPD flare, PHT, ARDS) BNP <100 pg/mL to r/o CHF (90% Se), >400 to r/i (NEJM 2002;347:161) NT-proBNP <300 pg/mL to r/o CHF (99% Se); age-related cut points to r/i: >450 pg/mL (<50 y), >900 (50–75 y), >1800 (>75 y) (EHJ 2006;27:330)

↑ in chronic HF, ∴ need to compare to known “dry BNP.” May be falsely low in obesity.

PULMONARY FUNCTION TESTS (PFTs)

• Spirometry: evaluate for obstructive disease

Flow-volume loops: diagnose and/or localize obstruction

Bronchodilator: indicated if obstruction at baseline or asthma clinically suspected

Methacholine challenge: helps dx asthma if spirometry nl, >20% ↓ FEV₁ → asthma

• Lung volumes: evaluate for hyperinflation or restrictive disease including NM causes

• D_LCO: evaluates functional surface area for gas exchange; helps differentiate causes of obstructive and restrictive diseases and screens for vascular disease & early ILD

ASTHMA

Definition and epidemiology (Lancet 2018;391:783)

• Chronic inflam disorder w/ airway hyperresponsiveness + variable airflow obstruction

• Affects 5–10% population; ~85% of cases by age 40 y

Clinical manifestations (NEJM 2013;369:549)

• Classic triad = wheezing, cough, dyspnea; others include chest tightness, sputum; symptoms typically chronic with episodic exacerbation

• Precipitants (triggers)

respiratory irritants (smoke, perfume, etc.) & allergens (pets, dust mites, pollen, etc.)

infections (URI, bronchitis, sinusitis)

drugs (eg, ASA & NSAIDs via leukotrienes, βB via bronchospasm, MSO₄ via histamine)

emotional stress, cold air, exercise (increase in ventilation dries out airways)

Physical examination

• Wheezing and prolonged expiratory phase

• Presence of nasal polyps, rhinitis, rash → allergic component

• Exacerbation → ↑ RR, ↑ HR, accessory muscle use, diaphoresis, pulsus paradoxus

Diagnostic studies (JAMA 2017;318:279)

• Spirometry: ↓ FEV₁, ↓ FEV₁/FVC, coved flow-volume loop; lung volumes: ± ↑ RV & TLC

⊕ bronchodilator response (↑ FEV₁ ≥12% & ≥200 mL) strongly suggestive of asthma

methacholine challenge (↓ FEV₁ ≥20%) if PFTs nl: Se >90%

• Allergy suspected → consider checking serum IgE, eos, skin testing/RAST

Ddx (“all that wheezes is not asthma…”)

• Hyperventilation & panic attacks

• Upper airway obstruction or inh foreign body; laryngeal/vocal cord dysfxn (eg, 2° to GERD)

• CHF (“cardiac asthma”); COPD; bronchiectasis; ILD (including sarcoidosis); vasculitis; PE

“Asthma plus” syndromes

• Atopy = asthma + allergic rhinitis + atopic dermatitis

• Aspirin-exacerbated respiratory disease (Samter’s syndrome) = asthma + ASA sensitivity + nasal polyps (J Allergy Clin Immunol 2015;135:676)

• ABPA = asthma + pulmonary infiltrates + hypersensitivity to Aspergillus (Chest 2009;135:805)

Dx: ↑ IgE to Asperg. & total (>1000), ↑ Asperg. IgG levels, ↑ eos, central bronchiectasis

Rx: steroids ± itra-/voriconazole for refractory cases (NEJM 2000;342:756)

• Eosinophilic granulomatosis w/ polyangiitis (EGPA, previously Churg-Strauss) = asthma + eosinophilia + granulomatous vasculitis

CHRONIC MANAGEMENT

“Reliever” medications (used prn to quickly relieve sx)

• Low-dose inhaled corticosteroids (ICS) + long-acting inh β₂-agonists (LABA): budesonide-formoterol (NEJM 2019;380:2020)

• Short-acting inh β₂-agonists (SABA): albuterol Rx of choice

• Short-acting inh anticholinergics (ipratropium) ↑ β₂-agonist delivery → ↑ bronchodilation

“Controller” meds (taken daily to keep control) (JAMA 2020;324:2301)

• ICS Rx of choice. Superior to LAMA if sputum w/ ≥2% eos (NEJM 2019;380:2009). PO steroids may be needed for severely uncontrolled asthma; avoid if possible b/c of systemic side effects.

• LABA (eg, salmeterol, formoterol) safe & ↓ exacerb. when added to ICS (NEJM 2018;378:2497)

• Long-acting inh antimuscarinics (LAMA; eg, tiotropium, umeclidinium): may consider if sx despite ICS+LABA (JAMA 2018;319:1473)

• Leukotriene receptor antagonists (LTRA): some Pts very responsive, esp. ASA-sens and exercise-induced. Warning for serious neuropsychiatric effects, including suicide.

• Nedocromil/cromolyn: limited use in adults. Useful in young Pts, exercise-induced bronchospasm; ineffective unless used before trigger or exercise exposure.

Immunotherapies (NEJM 2017;377:965)

• Allergen ImmunoRx (“allergy shots”) may help if sig. allerg. component (JAMA 2016;315:1715)

• Anti-IgE (omalizumab) for uncontrolled mod-to-severe allergic asthma (w/ IgE >30) on ICS ± LABA (JAMA 2017; 318:279); ↓ exacerbations in severe asthma (Cochrane 2014;CD003559)

• Anti-IL5 (mepolizumab, reslizumab) ↓ exacerb in severe asthma (NEJM 2014;371:1189 & 1198)

• Anti-IL5Rα (benralizumab) ↓ steroid use, ↓ exac. in sev asthma w/ eos (NEJM 2017;376:2448)

• Anti-IL4Rα (dupilumab) blocks IL-4 & IL-13; ↓ exacerb in severe asthma, ↓ steroid use, ↑ FEV₁ (NEJM 2018;378:2475 & 2486)

• Anti-TSLP (tezepelumab-ekko) ↓ exacerbations in severe asthma; can use in non-allergic/non-eosinophilic asthma (NEJM 2021;384:1800)

Principles of treatment

• Education and avoidance of environmental triggers (Lancet 2015;386:1075); yearly flu shot

• Use quick-relief rescue medication as needed for all Pts

• Goal to achieve complete control = daily sx ≤2/wk, Ø nocturnal sx or limitation of activity, reliever med ≤2/wk, nl peak expiratory flow rate or FEV₁; partly controlled = 1–2 of the above present in a wk; uncontrolled = ≥3 of the above present in a wk

• Step up treatment as needed to gain control, step down as tolerated

• Can abort exacerb by quadrupling ICS if deteriorating control (NEJM 2018;378:902)

Category for sx determined by most severe day or nocturnal element

EXACERBATION

Evaluation

• History: baseline PEF, steroid requirement, ED visits, hospital admissions, prior intubation

Current exacerbation: duration, severity, potential precipitants, meds used

Risk factors for life-threatening: prior intubation, h/o near-fatal asthma, ED visit/hosp for asthma w/in 1 y, current/recent PO steroids, not using ICS, overdependent on SABA, Ψ, h/o noncompliance

• Physical exam: VS, pulm, accessory muscle use, pulsus paradoxus, abdominal paradox

Assess for barotrauma: asymmetric breath sounds, tracheal deviation, subcutaneous air → pneumothorax, precordial (Hamman’s) crunch → pneumomediastinum

• Diagnostic studies: peak expiratory flow (know personal best; <80% personal best c/w poor control, <50% c/w severe exacerbation); S_aO₂; CXR to r/o PNA or PTX; ABG if severe (low P_aCO₂ initially; nl or high P_aCO₂ may signify tiring)

Severity of Asthma Exacerbation
	Mild-Moderate	Severe	Life-Threatening
Symptoms	Talks in phrases	Talks in words, tripod positioning	Drowsy Confused
Vitals/ Exam	RR >20, HR 100–120, Room air SaO2 90–95%	RR >30, HR >120 Room air SaO2 <90%	Silent chest Bradycardia
PEF	>50% predicted or best	≤50% predicted or best	Not indicated
Initial Treatment	O2, SABA 4–10 puffs q20min, prednisone	Tx to acute facility, SABA, ipratropium, methylpred, IV Mg	Tx to acute facility, prepare for intubation SABA, ipratropium, methylpred, IV Mg

Initial treatment details (GINA 2021 Guidelines)

• Oxygen to keep S_aO₂ ≥93–95%

• Inhaled SABA (eg, albuterol) by MDI (4–8 puffs) or nebulizer (2.5–5 mg) q20min

• Corticosteroids: prednisone 40–60 mg PO if outPt; methylpred IV if ED or inPt

• Ipratropium MDI (4–6 puffs) or nebulizer (0.5 mg) q20min if severe (Chest 2002;121:1977)

• Reassess after 60–90 min of Rx

Mild–mod exacerbation: cont SABA q1h

Sev exacerbation: SABA & ipratropium q1h or cont.; if refractory, consider Mg ± heliox

• Decide disposition within 4 h of presentation and after 1–3 h of Rx

• High-dose steroids: methylpred 125 mg IV q6h (NEJM 1999;340:1941)

ICU-level care

• Invasive ventilation:

Large ET tube, P_plat <30 cm H₂O (predicts barotrauma better than PIP), max exp time

PEEP individualized to patient physiology

Paralysis, inhalational anesthetics, bronchoalveolar lavage w/ mucolytic, heliox (60–80% helium) and ECMO have been used with success

IV ketamine: bronchodilating effects and can be used for refractory status asthmaticus

• NPPV likely improves obstruction (Chest 2003;123:1018), but controversial and rarely used

ANAPHYLAXIS

Definition and pathophysiology (Ann Emerg Med 2006;47:373)

• Severe, rapid onset (mins to hrs), potentially life-threatening systemic allergic response

• IgE-mediated mast cell degranulation with release of histamine, tryptase, and TNF

• Precipitates systemic reactions (bronchospasm, tissue swelling, fluid shifts, vasodilation)

• Common triggers: penicillins, cephalosporins, shellfish, nuts, insect stings, IV contrast (not truly an IgE-mediated mechanism, but clinically similar)

Diagnosis: any of the three following criteria

1) Acute illness with skin ± mucosal involvement (rash, flushing, hives), AND at least one of:

Respiratory compromise (wheeze, stridor, dyspnea, hypoxemia)

Hypotension or hypoperfusion (syncope, incontinence)

2) Two or more of the following after exposure to a likely allergen: skin/mucosal involvement, respiratory compromise, ↓ BP or hypoperfusion, GI symptoms

3) Hypotension after exposure to known allergen for that Pt

Treatment

• Epi: 0.5 mg IM (0.5 mL of 1 mg/mL solution) q5–15min as needed. For those who do not respond, IV infusion starting at 0.1 mcg/kg/min.

• Airway: suppl O₂ ± intubation or cricothyroidotomy (if laryngeal edema); β₂-agonists

• Fluid resuscitation w/ ≥1–2 L crystalloid (may extravasate up to 35% of intravasc volume)

• Antihistamines relieve hives & itching, no effect on airway or hemodynamics; H1RA (diphenhydramine 50 mg IV/IM)

• Methylprednisolone 1–2 mg/kg/d × 1–2 d for those who do not respond to epi

• Avoid unopposed α-adrenergic vasopressors

Disposition

• Mild rxn limited to urticaria or mild bronchospasm can be observed for ≥6 h; admit all others

• Watch for biphasic reaction; occurs in 23%, typically w/in 8–10 h but up to 72 h

Angioedema (J Allergy Clin Immunol 2013;131:1491)

• Localized swelling of skin/mucosa; involves face, lips, tongue, uvula, larynx, and bowels

• Etiologies: mast cell-mediated (eg, NSAIDs); bradykinin-mediated (eg, ACEI, ARNi, hereditary angioedema, acquired C1 inhibitor deficiency); idiopathic

• Diagnosis: C4 and C1 inhibitor level, tryptase (if suspect anaphylaxis), ESR/CRP

• Rx: intubation if risk of airway compromise. Allergic angioedema: H1/H2 antihist., steroids.

If 2° ACEI: d/c ACEI, antihist., icatibant (bradykinin-receptor antag; NEJM 2015;372:418).

Hereditary angioedema: plasma-derived C1 inhibitor, ecallantide (kallikrein inhibitor)

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Definition and epidemiology (Lancet 2017;389:1931)

• Progressive airflow limitation caused by airway and parenchymal inflammation

Emphysema vs. Chronic Bronchitis
	Emphysema	Chronic Bronchitis
Definition	Dilation/destruction of parenchyma (path definition)	Productive cough >3 mo/y × ≥2 y (clinical definition)
Pathophysiology	Tissue destruction V/Q: ↑ dead space fraction → hypercarbia, but only mild hypoxemia	Small airways affected V/Q: ↑ shunt fraction → severe hypoxemia, hypercapnia PHT, cor pulmonale
Clinical manifestations	Severe, constant dyspnea Mild cough	Intermittent dyspnea Copious sputum production
Physical exam	“Pink puffer” Tachypneic, noncyanotic, thin Diminished breath sounds	“Blue bloater” Cyanotic, obese, edematous Rhonchi & wheezes

Pathogenesis (Lancet 2017;389:1931)

• Cigarette smoke (centrilobular emphysema, affects 15–20% of smokers)

• Recurrent airway infections

• α₁-antitrypsin deficiency: early-onset panacinar emphysema or signif basilar disease, 1–3% of COPD cases. Suspect if age <45, lower lungs affected, extrathoracic manifestations (liver disease [not if heterozygote MZ], FMD, pancreatitis). ✓ serum A1AT level (nb, acute phase reactant).

• Low FEV₁ in early adulthood associated w/ COPD (NEJM 2015;373:111)

Clinical manifestations

• Chronic cough, sputum production, dyspnea; later stages → freq exacerb, AM HA, wt loss

• Exacerbation triggers: infection, other cardiopulmonary disease, including PE

Infxn: overt tracheobronchitis/pneumonia from viruses, S. pneumoniae, H. influenzae, M. catarrhalis or triggered by changes in strain of colonizers (NEJM 2008;359:2355)

• Physical exam: ↑ AP diameter of chest (“barrel chest”), hyperresonance, ↓ diaphragmatic excursion, ↓ breath sounds, ↑ expiratory phase, rhonchi, wheezes during exacerbation: tachypnea, accessory muscle use, pulsus paradoxus, cyanosis

• Asthma-COPD overlap syndrome (ACOS; NEJM 2015;373:1241): features of both present. For example: reversibility of airway obstruction w/ bronchodilator in COPD; neutrophilic inflammation in asthma (more classic in COPD); eos in COPD.

Diagnostic studies (JAMA 2019;321:786)

• CXR (see Radiology inserts): hyperinflation, flat diaphragms, ± interstitial markings & bullae

• PFTs: obstruction: ↓↓ FEV₁, ↓ FVC, FEV₁/FVC <0.7 (no sig Δ post bronchodilator), expiratory coving of flow-volume loop; hyperinflation: ↑↑ RV, ↑ TLC, ↑ RV/TLC; abnormal gas exchange: ↓ D_LCO (in emphysema)

• ABG: ↓ P_aO₂, ± ↑ P_aCO₂ (in chronic bronchitis, usually only if FEV₁ <1.5 L) and ↓ pH

• Screen symptomatic Pts w/ spirometry; don’t screen if asx; screen for α1-AT deficiency

Chronic treatment (Adapted from GOLD 2021 Report)

COPD Staging and Recommended Therapies by GOLD Criteria
Exacerbations/Yr	Mild Symptoms	Mod/Severe Symptoms
<2	A Short-acting inh dilator prn	B LAMA
≥2	C LAMA	D LAMA + LABA ± ICS
	Consider adding PDE-4 inhib to bronchodilator

Smoking cessation & vaccinations in all. Pulm rehab in groups B–D. O₂ as indicated per S_aO₂.

• Bronchodilators (1^st-line): long-acting muscarinic antag (LAMA), β₂-agonists (LABA)

LAMA (eg, tiotropium): ↓ exacerb, slows ↓ FEV₁, ↓ admit, ↓ resp failure; better than ipratropium or LABA (NEJM 2008;359:1543; 2011;364:1093; 2017;377:923)

LABA: ~11% ↓ in exacerbations, no ↑ in CV events (Lancet 2016;387:1817)

LAMA + LABA: ↑ FEV₁, ↓ sx vs. either alone (Chest 2014;145:981) and superior to LABA + inh steroid (NEJM 2016;374:2222)

• Corticosteroids (inhaled, ICS): ~11% ↓ in exacerbations & slows ↓ FEV₁; no Δ in mortality (Lancet 2016;387:1817). Greatest benefit if eos >300 (Lancet Repir Med 2018;6:117).

• “Triple Therapy” (LAMA+LABA+ICS) ↓ exac, ↓ hosp, ↑ PNA (NEJM 2020;383:35)

• Roflumilast (PDE-4 inhib) + bronchodil: ↑ FEV₁, ↓ exacerb in Pts with severe COPD, chronic bronchitis, and a hx of exacerbations (Lancet 2015;385:857)

• Anti-IL5 (eg, mepolizumab, benralizumab): mixed data on ↓ exacerb in Pts w/ eos (NEJM 2017;377:1613 & 2019;381:1023)

• Antibiotics: daily azithro ↓ exacerbations, but not routine (JAMA 2014;311:2225)

• Oxygen: if P_aO₂ ≤55 mmHg or S_aO₂ ≤89% (during rest, exercise, or sleep) to prevent cor pulmonale; only Rx proven to ↓ mortality (Annals 1980;93:391; Lancet 1981;i:681); no benefit in Pts w/ moderate hypoxemia (S_aO₂ 89–93%) (NEJM 2016;375:1617) or nocturnal O₂ alone (NEJM 2020;383:1129); unknown benefit of isolated exertional O₂ (AJRCCM 2020;202:121).

• Night NPPV if recent exacerb & P_aCO₂ >53 ↓ risk of readmit or death (JAMA 2017;317:2177)

• Prevention: Flu/Pneumovax; smoking cessation → 50% ↓ in lung function decline (AJRCCM 2002;166:675) and ↓ long-term mortality (Annals 2005;142:223)

• Rehabilitation: ↓ dyspnea and fatigue, ↑ exercise tolerance, ↑ QoL (NEJM 2009;360:1329)

• Surgery & bronchoscopic interventions

Lung volume reduction surgery: ↑ exercise capacity, ↓ mortality if FEV₁ >20%, upper lobe, low exercise capacity (NEJM 2003;348:2059)

Bronchoscopic lung reduction w/ endobronchial valves or coils: ↑ lung fxn but significant complications (PTX, PNA) (NEJM 2015;373:2325; Lancet 2015;386:1066; JAMA 2016;315:175)

• Lung transplant: ↑ QoL and ↓ sx (Lancet 1998;351:24), ? survival benefit (Am J Transplant 2009;9:1640)

Staging and prognosis

• Assess breathlessness, cough, sputum, exercise capacity & energy (tools such as CAT and mMRC may be used as part of assessment)

• Ratio of diam PA/aorta >1 associated with ~3× ↑ risk of exacerbations (NEJM 2012;367:913)

• FEV₁ stages: I = ≥80%; II = 50–79% (~11% 3-y mort.); III = 30–49% (~15% 3-y mort.); IV = <30% (~24% 3-y mort.)

EXACERBATION

COPD Exacerbation Treatment
Agent	Dose	Comments
Ipratropium	MDI 4–8 puffs q1–2h or Nebulizer 0.5 mg q1–2h	First-line therapy (NEJM 2011;364:1093)
Albuterol	MDI 4–8 puffs q1–2h or Nebulizer 2.5–5 mg q1–2h	Benefit if component of reversible bronchoconstriction
Corticosteroids	Prednisone 40 mg/d × 5d (JAMA 2013;309:2223); some Pts will benefit from higher dose/longer course if severe Methylprednisolone 125 mg IV q6h × 72 h for more severe exacerbations	↓ treatment failure, ↓ hosp. stay ↑ FEV1 but no mortality benefit, ↑ complications (Cochrane 2009:CD001288) OutPt Rx after ED visit ↓ relapse (NEJM 2003;348:2618)
Antibiotics	Amox, TMP-SMX, doxy, azithro, antipneumococcal FQ all reasonable (no single abx proven superior). Consider local flora and avoid repeat courses of same abx. ≤5d course likely enough for mild–mod exacerbation (JAMA 2010;303:2035).	H. flu, M. catarrhalis, S. pneumo ↑ PEF, ↓ Rx failure, ? ↓ short-term mort, ↓ subseq exacerb (Chest 2008;133:756 & 2013;143:82) Consider if CRP >20 + ↑ sputum purulence or CRP >40 (NEJM 2019;381:111)
Oxygenation	↑ FiO2 to achieve PaO2 ≥55–60 or SaO2 88–92%	Watch for CO2 retention (due to ↑ V/Q mismatch, loss of hypoxemic resp drive, Haldane effect), but must maintain acceptable SaO2!
Noninvasive positive-pressure ventilation	Initiate early if moderate/severe dyspnea, ↓ pH / ↑ PaCO2, RR >25 Results in 58% ↓ intubation, ↓ LOS by 3.2 d, 59% ↓ mortality Contraindications: Δ MS, inability to cooperate or clear secretions, hemodynamic instability, UGIB (NEJM 1995;333:817; Annals 2003;138:861; Cochrane 2004;CD004104; ERJ 2005;25:348)
Endotracheal intubation	Consider if PaO2 <55–60, ↑’ing PaCO2, ↓’ing pH, ↑ RR, respiratory fatigue, Δ MS or hemodynamic instability
Other measures	Mucolytics overall not supported by data (Chest 2001;119:1190) Monitor for cardiac arrhythmias
Post-exacerb care	Follow up w/in 1 mo; smoking cessation if current smoker; vaccinations (influenza, pneumococcal), referral to pulm rehab (AJRCCM 2007;176:532)

SOLITARY PULMONARY NODULE

Principles

• Definition: single, well-defined, <3 cm, surrounded by nl lung, no LAN or pleural effusion

• Often “incidentalomas,” esp with ↑ CT use, but may still be early, curable malignancy

Etiologies
Benign (70%)	Malignant (30%)
Granuloma (80%): TB, histo, coccidio Hamartoma (10%) Bronchogenic cyst, AVM, pulm infarct Echinococcosis, ascariasis, aspergilloma GPA, rheumatoid nodule, sarcoidosis Lipoma, fibroma, amyloidoma	Bronchogenic carcinoma (75%) periph: adeno (most common) & large cell central: squamous & small cell Metastatic (20%): sarcoma, melanoma, breast, head & neck, colon, testicular, renal Carcinoid, primary sarcoma

Initial evaluation

• History: h/o cancer, smoking, age (<30 y = 2% malignant, +15% each decade >30)

• CT: size/shape, Ca²⁺, LAN, effusions, bony destruction, compare w/ old studies

Ø Ca → ↑ likelihood malignant; laminated → granuloma; “popcorn” → hamartoma

• High-risk features for malig: size (eg, ≥2.3 cm diameter), spiculated, upper lobe, ♀, >60 yo, >1 ppd current smoker, no prior smoking cessation (NEJM 2003;348:2535 & 2013;369:910)

Diagnostic studies

• PET: detects metab. activity of tumors, 97% Se & 78% Sp for malig (esp if >8 mm). Useful for deciding which lesions to bx vs. serial CT & for surgical staging b/c may detect mets.

• Transthoracic needle biopsy (TTNB): if tech feasible, 97% will obtain definitive tissue dx

• Video-assisted thoracoscopic surgery (VATS): for percutaneously inaccessible lesions; highly sensitive and allows resection

• Transbronchial bx (TBB): most lesions too small to sample w/o endobronchial U/S; bronch w/ brushings low-yield unless invading bronchus; navigational bronch 70% yield

• PPD, fungal serologies, ANCA

Management (JAMA 2022;327:264)

• Low risk (<5%): serial CT (freq depending on risk); shared decision w/ Pt re: bx

• High risk (and surgical candidate): TBB, TTNB, or VATS → lobectomy if malignant

• Subsolid nodules: longer f/u (b/c if malignant can be slow-growing) & PET

HEMOPTYSIS

Definition and pathophysiology

• Expectoration of blood or blood-streaked sputum

• Massive hemoptysis: >100 mL/h or >500 mL in 24 h; massive hemoptysis usually from tortuous or invaded bronchial arteries

Etiologies (Crit Care Med 2000;28:1642)
Infection/Inflammation	Bronchitis (most common cause of trivial hemoptysis) Bronchiectasis incl CF (common cause of massive hemoptysis) TB or aspergilloma (can be massive); pneumonia or lung abscess
Neoplasm	Usually primary lung cancer, sometimes metastasis (can be massive)
Cardiovasc	PE (can be massive), pulmonary artery rupture (2° to instrumentation), CHF, mitral stenosis, trauma/foreign body, bronchovascular fistula
Other	Vasculitis (GPA, anti-GBM, Behçet’s, SLE), AVM, anticoag (w/underlying lung disease), coagulopathy, cocaine, pulm hemosiderosis

Diagnostic workup

• Localize bleeding site (r/o GI or ENT source by H&P ± endo); determine whether unilateral or bilateral, localized or diffuse, parenchymal or airway by CXR/chest CT ± bronch

• PT, PTT, CBC to rule out coagulopathy

• Sputum culture/stain for bacteria, fungi and AFB; cytology to r/o malignancy

• ANCA, anti-GBM, ANA, urinalysis to ✓ for vasculitis or pulmonary-renal syndrome

Treatment

• Death is from asphyxiation not exsanguination; maintain gas exchange, reverse coagulopathy and Rx underlying condition; cough suppressant may ↑ risk of asphyxiation

• Inhaled tranexamic acid promising (Chest 2018;154:1379)

• Massive hemoptysis: put bleeding side dependent; selectively intubate nl lung if needed

Angiography: Dx & Rx (vascular occlusion balloons or selective embol of bronchial art)

Rigid bronch: allows more options (electrocautery, laser) than flexible bronch

Surgical resection

BRONCHIECTASIS

Definition and epidemiology (NEJM 2002;346:1383)

• Obstructive airways disease of bronchi and bronchioles, chronic transmural inflammation w/ airway dilatation and thickening, collapsibility, mucus plugging w/ impaired clearance

Initial workup

• H&P: cough, dyspnea, copious sputum production, ±hemoptysis, inspiratory “squeaks”

• CXR: scattered or focal; rings of bronchial cuffing; “tram track” of dilated, thick airways

• PFTs: obstructive; chest CT: airway dilation & thickening ± cystic Δs, infiltrates, adenopathy

Etiology	Other Features	Evaluation
Chronic infxns (eg, MTb, ABPA)	Chronic cough, freq/persist infiltrate, refract asthma (ABPA)	Sputum cx (incl mycobact, fungal), ± bronch/BAL, IgE & eos (ABPA)
1° ciliary dyskin	Sinusitis, infertility, otitis	Dynein mutations
Immunodefic	Recurrent infxns often as child	IgA, IgG, IgM, IgG subclasses
RA, Sjogren, ANCA	Resp sx may precede joint sx	RF, CCP, SS-A, SS-B, ANCA
IBD	Not relieved by bowel resection	Colonoscopy, biopsy
α1-AT deficiency	Lower lobe emphysema	α1-AT level and genotype
Anatomic	R middle lobe synd. from sharp takeoff, foreign body aspiration	Bronchoscopy

Treatment

• Acute exacerbations: antibiotics directed against prior pathogens; if no prior Cx data → FQ

• Chronic mgmt: treat underlying condition, chest PT, inhaled hypertonic saline, bronchodil.; prophylactic azithro shown to ↓ exacerb in non-CF bronchiectasis (JAMA 2013:1251)

• Airway clearance: guaifenesin, instrumental devices (eg, Aerobika, Acapella), chest PT

Non-tuberculous mycobacterium (NTM; eg, MAC, Mycobacterium kansaii)

• Chronic cough, ↓ wt; Lady Windermere syndrome: R middle lobe and lingula bronchiectasis in elderly ♀ who suppress expectoration

• Dx: CT scan (tree-in-bud, nodules, cavities, bronchiect.), sputum ×3 or BAL, AFB stain + Cx

• Treatment: susceptibility-based Rx pref over empiric Rx w/ [azithro or clarithro] + rifamycin & ethambutol for ≥12 mo (CID 2020;71:e1)

CYSTIC FIBROSIS

Definition and pathophysiology (NEJM 2015;372:351)

• Autosomal recessive genetic disorder due to mutations in chloride channel (CFTR gene)

• ↑ mucus thickness, ↓ mucociliary clearance, ↑ infections → bronchiectasis

Clinical features

• Recurrent PNA, sinus infections

• Distal intestinal obstruction syndrome (DIOS), pancreatic insufficiency (steatorrhea, malabsorption, failure to thrive, weight loss), CF-related diabetes, infertility

Treatment (Lancet 2021;397:2195)

• Acute exacerbations: may be assoc w/ persistent drop in FEV₁ (AJRCCM 2010;182:627); continue aggressive airway clearance, target abx based on sputum cx (incl double coverage for PsA); common pathogens include PsA, S. aureus, non-typeable H. flu, Stenotrophomonas, Burkholderia, NTM

• Chronic mgmt: airway clearance with chest PT, inhaled hypertonic saline, inhaled DNAse (dornase alfa), SABA; oral azithromycin if chronic respiratory symptoms, inhaled tobramycin or aztreonam if persistent PsA infection

• CFTR potentiator (ivacaftor) or corrector (lumacaftor, tezacaftor) depending on mutation; combo (elexacaftor+tezacaftor+ivacaftor) if homozygous for ΔF508 (Lancet 2019;394:1940)

• Lung transplantation; refer to lung transplant center when FEV₁ <30% predicted, rapidly declining FEV₁, 6MWT <400 m, evidence of PHT, significant clinical decline

INTERSTITIAL LUNG DISEASE

WORKUP OF ILD (Thorax 2008;63:v1)

May present as incidental finding, subacute dyspnea, or rapidly progressive hypox. resp fail.

Broad categories

• (1) Sarcoid; (2) Exposures (eg, drugs, XRT, organic & inorganic dusts, vaping);

• (3) Collagen vasc dis (eg, scleroderma, ANCA, myositis, RA); (4) Idiopathic PNAs (qv)

Rule out mimickers of ILD

• Congestive heart failure (✓ BNP, trial of diuresis); infection: viral, atypical bacterial; malignancy: lymphangitic carcinomatosis, bronchoalveolar, leukemia, lymphoma

History and physical exam

• Occupational, exposures (eg, birds), tobacco, meds, XRT, FHx, precipitating event

• Tempo (acute → infxn, CHF, hypersens pneumonitis, eos PNA, AIP, COP, drug-induced)

• Extrapulm signs/sx (skin Δs, arthralgias, arthritis, myalgias, sicca sx, alopecia, Raynaud’s)

Diagnostic studies (see Appendix & Radiology inserts)

• CXR and high-resolution chest CT

Upper lobe predom: hypersensitivty, coal, silica, smoking-related, sarcoidosis, Langerhan’s

Lower lobe predom: NSIP, UIP, asbestosis

Adenopathy: malignancy, sarcoidosis, berylliosis, silicosis

Pleural disease: collagen-vascular diseases, asbestosis, infections, XRT

• PFTs: ↓ D_LCO (early sign), restrictive pattern (↓ volumes), ↓ P_aO₂ (esp. w/ exercise);

If restrictive + obstructive, consider sarcoid

If combined pulmonary fibrosis and emphysema (CFPE) → near-nl lung vol on PFTs

• Serologies: ✓ ACE, ANA, RF, RNP, ANCA, CCP, SSA/SSB, Scl 70, CK, aldolase, myositis panel

• Bronchoalveolar lavage: in select cases if suspect superimposed infection, hemorrhage, eosinophilic syndromes

• Bx (transbronch w/ or w/o cryo vs. VATS depending on location) if unclear etiology

SPECIFIC ETIOLOGIES OF ILD

Sarcoidosis (AJRCCM 2020;201:e26; JAMA 2022;327:856)

• Prevalence: African Americans, northern Europeans, and females; onset in 3^rd-5^th decade

• Pathophysiology: depression of cellular immune system peripherally, activation centrally

Clinical Manifestations of Sarcoidosis
Organ System	Manifestations
Pulmonary	Hilar LAN; fibrosis; pulm hypertension. Stages: I = bilat hilar LAN; II = LAN + ILD; III = ILD only; IV = diffuse fibrosis.
Cutaneous (~15%)	Waxy skin plaques; lupus pernio (violaceous facial lesions) Erythema nodosum (red tender nodules due to panniculitis, typically on shins). Ddx: idiopathic (34%), infxn (33%, strep, TB), sarcoid (22%), drugs (OCP, PCNs), vasculitis (Behçet’s), IBD, lymphoma.
Ocular (10–30%)	Anterior >posterior uveitis; ↑ lacrimal gland
Endo & renal (10%)	Nephrolithiasis, hypercalcemia (10%), hypercalciuria (40%) Due to vitamin D hydroxylation by macrophages
Neuro (10% clin, 25% path)	CN VII palsy, periph neuropathies, CNS lesions, seizures
Cardiac (5% clin, 25% path)	Conduction block, VT, CMP
Liver, spleen, BM	Granulomatous hepatitis (25%), splenic & BM gran. (50%)
Constitutional	Fever, night sweats, anorexia & wt loss (a/w hepatic path)
Musculoskeletal	Arthralgias, periarticular swelling, bone cysts

• Löfgren’s syndrome: erythema nodosum + hilar adenopathy + arthritis (good prognosis)

• Diagnostic studies: LN bx → noncaseating granulomas + multinucleated giant cells Endobronchial ultrasonography superior to conventional bronch (JAMA 2013;309:2457) ¹⁸FDG PET can be used to identify extent and potentially targets for dx bx ↑ ACE (Se 60%, 90% w/ active dis., Sp 80%, false ⊕ in granulomatous diseases)

• To assess extent: CXR, PFTs, full ophtho exam, ECG, CBC (lymphopenia, ↑ eos), Ca, LFTs; ± Holter, echo, cardiac MRI, brain MRI, etc., based on s/s

• Rx: steroids if sx or extrathoracic organ dysfxn (eg, prednisone 20–40 mg/d), improves sx, but doesn’t Δ long-term course; hydroxychloroquine for extensive skin disease; MTX, AZA, mycophenolate, or anti-TNF for chronic/refractory disease

• Prognosis: ~²∕³ spontaneously remit w/in 10 y (60–80% of stage I, 50–60% stage II, 30% stage III), w/ relapses uncommon; ~¹∕³ have progressive disease

Exposure

• Drugs/Iatrogenic

Amiodarone: interstitial pneumonitis ↔ org. PNA ↔ ARDS; Rx: d/c amio; steroids

Other drugs: nitrofurantoin, sulfonamides, inh, hydralazine

Chemo: bleomycin, busulfan, cyclophosphamide, MTX, immunotherapy, XRT

• Pneumoconioses (inorganic dusts) (NEJM 2000;342:406; Clin Chest Med 2004;25:467)

Coal worker’s: upper lobe coal macules; may progress to massive fibrosis

Silicosis: upper lobe opacities ± eggshell calcification of lymph nodes; ↑ risk of TB

Asbestosis: lower lobe fibrosis, calcified pleural plaques, DOE, dry cough, rales on exam. Asbestos exposure → pleural plaques, benign pleural effusion, diffuse pleural thickening, rounded atelectasis, mesothelioma, lung Ca (esp. in smokers)

Berylliosis: multisystemic granulomatous disease that mimics sarcoidosis

• Hypersensitivity pneumonitides (organic dusts): loose, noncaseating granulomas

Antigens: farmer’s lung (spores of thermophilic actinomyces); bird fancier’s lung (proteins from feathers and excreta of birds or down); humidifier lung (thermophilic bacteria)

Collagen vascular diseases (Chest 2013;143:814)

• Rheumatologic disease

Scleroderma: ILD in ~50%; PHT seen in ~10% of Pts with limited disease

PM-DM: ILD & skin/muscle findings; MCTD: PHT & fibrosis; Sjogren’s: ILD & sicca sx

SLE & RA: pleuritis and pleural effusions more often than ILD; SLE can cause DAH

• Vasculitis (can p/w DAH)

Granulomatosis w/ polyangiitis (GPA): ⊕ c-ANCA w/ necrotizing granulomas

Eosinophilic GPA (EGPA): ⊕ c- or p-ANCA w/ eosinophilia & necrotizing granulomas

Microscopic polyangiitis: ⊕ p-ANCA w/o granulomas

• Goodpasture’s syndrome = DAH + RPGN; typically in smokers; ⊕ anti-GBM in 90%

• Lymphangioleiomyomatosis (LAM): cystic, ↑ in ♀, Rx w/ sirolimus (NEJM 2011;364:1595)

Idiopathic interstitial pneumonias (IIPs) (AJRCCM 2013;188:733)

• Definition: ILD of unknown cause; dx by radiographic, histologic, and clinical features

IIPs
Type	Imaging/Histology	Clinical
IPF	UIP imaging pattern: reticular opacities, honeycombing, traction bronchiectasis; peripheral, subpleural, & basal	Sx >12 mo 5-y mort ~80%
NSIP	Homogenous ground-glass opacities or consolid., reticular irreg lines; subpleural sparing; symmetric, peripheral, basal. Cellular & fibrotic subtypes.	Sx mos–y 5-y mort 10%
COP	Patchy, migratory consolidations; subpleural & peribronchial. Excessive proliferation of granulation tissue in small airways and alveolar ducts.	Post-infxn, XRT, rxn to drug. 5-y mort <5%
AIP	Diffuse ground-glass opacities, consolidations w/ lobular sparing. Path/imaging similar to DAD (diffuse, bilateral, central>periph ground glass or consolidative opacities).	Sx <3 wk 6-mo mort 60%
DIP	Diffuse ground-glass opacities, reticular lines; lower zones. Peripheral macrophage in alveoli.	30–50 yo smokers Sx wks–mos Death rare
RB-ILD	Bronchial thickening, centrilobular nodules, patchy ground-glass opacities; upper lobe predom. Mφ in alveoli.

UIP, usual interstitial PNA (IP); IPF, idiopathic pulm fibrosis; NSIP, nonspecific IP; COP, cryptogenic organizing PNA; AIP, acute IP (Hamman-Rich syndrome); DIP, desquamative IP; RB-ILD, resp bronchiolitis-assoc ILD.

• Rx for IPF: suppl O₂, pulm rehab, Rx for GERD, PHT screening, lung tx referral;

pirfenidone (antifibrotic) or nintedanib (tyrosine kinase inhib mediating fibrogenic growth factors) ↓ rate of FVC decline (Lancet 2021;398:1450)

high-dose steroids may be used for acute exacerbations, but no RCT data

• Steroids for other IIPs: NSIP (esp. cellular type) and COP (AJRCCM 2000;162:571); ? benefit for AIP and DIP/RB-ILD (for which Pts should stop smoking)

Pulmonary infiltrates w/ eosinophilia (PIE) = eos on BAL é peripheral blood

• Allergic bronchopulmonary aspergillosis (ABPA)

• EGPA

• Löffler’s syndrome: parasites/drugs → transient pulm infilt + cough, fever, dyspnea, eos

• Acute eosinophilic PNA (AEP): acute hypox febrile illness; Rx: steroids, tobacco cessation

• Chronic eosinophilic pneumonia (CEP): “photonegative” of CHF, typically in women

Miscellaneous

• Pulm alveolar proteinosis (PAP): accumulation of surfactant-like phospholipids; white & gummy sputum; BAL milky fluid (NEJM 2003;349:2527); Rx w/ lung lavage & GMCSF

• Langerhans cell granulomatosis (LCG): young ♂ smokers; apical cysts; PTX (25%)

PLEURAL EFFUSION

Pathophysiology

• Systemic factors (eg, ↑ PCWP, ↓ oncotic pressure) → transudative effusion

• Local factors (ie, Δ pleural surface permeability) → exudative effusion

Transudates

• Congestive heart failure (40%): 80% bilateral, ± cardiomegaly on CXR occasionally exudative (especially after aggressive diuresis or if chronic)

• Constrictive pericarditis (knock on exam, calcification or thickening on imaging)

• Cirrhosis (“hepatic hydrothorax”): diaphragmatic pores allow passage of ascitic fluid often right-sided (²∕³) & massive (even w/o marked ascites)

• Nephrotic syndrome: usually small, bilateral, asymptomatic (r/o PE b/c hypercoag)

• Other: PE (usually exudate), malignancy (lymphatic obstruction), myxedema, CAPD

Exudates

• Lung parenchymal infection (25%)

Bacterial (parapneumonic): can evolve along spectrum of exudative (but sterile) → fibropurulent (infected fluid) → organization (fibrosis & formation of rigid pleural peel). Common causes: Strep pneumo, Staph aureus, Strep milleri, Klebsiella, Pseudomonas, Haemophilus, Bacteroides, Peptostreptococcus, mixed flora in aspiration pneumonia.

Mycobacterial: >50% lymphs 80% of the time, ADA >40, pleural bx ~70% Se

Fungal, viral (usually small), parasitic (eg, amebiasis, echinococcosis, paragonimiasis)

• Malignancy (15%): primary lung cancer most common, metastases (esp. breast, lymphoma, etc.), mesothelioma (✓ serum osteopontin levels; NEJM 2005;353:15)

• Pulmonary embolism (10%): effusions in ~40% of PEs; exudate (75%) >transudate (25%); hemorrhagic—must have high suspicion b/c presentation highly variable

• Collagen vascular disease: RA (large), SLE (small), GPA, EGPA

• Abdominal diseases: pancreatitis, cholecystitis, esophageal rupture, abdominal abscess

• Hemothorax (Hct_eff/Hct_blood >50%): trauma, PE, malignancy, coagulopathy, leaking aortic aneurysm, aortic dissection, pulmonary vascular malformation

• Chylothorax (triglycerides >110): thoracic duct damage due to trauma, malignancy, LAM

• Other:

Post-CABG: left-sided; initially bloody, clears after several wks

Dressler’s syndrome (pericarditis & pleuritis post-MI), uremia, post-radiation therapy

Asbestos exposure: benign; ⊕ eosinophils

Drug-induced (eg, nitrofurantoin, methysergide, bromocriptine, amiodarone): ⊕ eos

Uremia; post-XRT; sarcoidosis

Meigs’ syndrome: benign ovarian tumor → ascites & pleural effusion

Yellow-nail syndrome: yellow nails, lymphedema, pleural effusion, bronchiectasis

Diagnostic studies (NEJM 2018;378:740)

• Thoracentesis (ideally U/S guided) (NEJM 2006;355:e16)

Indications: all effusions >1 cm in decubitus view

if suspect due to CHF, can diurese and see if effusions resolve (75% do so in 48 h); asymmetry, fever, chest pain or failure to resolve → thoracentesis

parapneumonic effusions should be tapped ASAP (cannot exclude infxn clinically)

Diagnostic studies: ✓ total protein, LDH, glucose, cell count w/ differential, Gram stain & culture, pH; remaining fluid for additional studies as dictated by clinical scenario

Complications: PTX (5–10%), hemothorax (~1%), re-expansion pulm edema (if >1.5 L removed), spleen/liver lac.; post-tap CXR not routinely needed (Annals 1996;124:816)

↓ PTX w/ U/S and experienced supervisor; even with INR ~1.9, on DOAC, or on clopi, risk of bleed low w/ U/S & experienced operator (Mayo 2019;94:1535)

• Transudate vs. exudate (JAMA 2014;311:2422)

Light’s criteria: exudate = TP_eff/TP_serum >0.5 or LDH_eff/LDH_serum >0.6 or LDH_eff >²∕³ ULN of LDH_serum; 97% Se, 85% Sp; best Se of all methods; however, will misidentify 25% of transudates as exudates; ∴ if clinically suspect transudate but meets criterion for exudate, confirm w/ test w/ higher Sp

Exudative criteria w/ better Sp: chol_eff >55 mg/dL (95–99% Sp); chol_eff >45 mg/dL and LDH_eff >200 (98% Sp); chol_eff/chol_serum >0.3 (94% Sp); serum-effusion alb gradient ≤1.2 (92% Sp); serum-effusion TP gradient ≤3.1 (91% Sp)

CHF effusions: TP may ↑ with diuresis or chronicity → “pseudoexudate”; alb gradient ≤1.2, chol_eff >60 mg/dL (Se 54%, Sp 92%) or clin judgment to distinguish (Chest 2002;122:1524)

• Complicated vs. uncomplicated parapneumonic (Chest 1995;108:299)

complicated = ⊕ Gram stain or culture or pH <7.2 or glucose <60

complicated parapneumonic effusions usually require tube thoracostomy for resolution

empyema = frank pus, also needs tube thoracostomy (J Thorac CV Surg 2017;153:e129)

• Additional pleural fluid studies (NEJM 2002;346:1971)

NT-proBNP ≥1500 pg/mL has 91% Se & 93% Sp for CHF (Am J Med 2004;116:417)

WBC & diff.: exudates tend to have ↑ WBC vs. transudates but nonspecific neutrophils → parapneumonic, PE, pancreatitis lymphocytes (>50%) → cancer, TB, rheumatologic eos (>10%) → blood, air, drug rxn, asbestos, paragonimiasis, Churg-Strauss, PE

RBC: Hct_eff 1–20% → cancer, PE, trauma; Hct_eff/Hct_blood >50% → hemothorax

AFB: yield in TB 0–10% w/ stain, 11–50% w/ culture, ~70% w/ pleural bx

adenosine deaminase (ADA): seen w/ granulomas, >70 suggests TB, <40 excludes TB

cytology: ideally ≥150 mL and at least 60 mL should be obtained (Chest 2010;137:68)

glucose: <60 mg/dL → malignancy, infection, RA

amylase: seen in pancreatic disease and esophageal rupture (salivary amylase)

rheumatoid factor, C_H50, ANA: limited utility in dx collagen vascular disease

triglycerides: >110 → chylothorax, 50–110 → ✓ lipoprotein analysis for chylomicrons

cholesterol: >60; seen in chronic effusions (eg, CHF, RA, old TB)

creatinine: effusion/serum ratio >1 → urinothorax

fibulin-3: ↑ plasma and/or effusion levels → mesothelioma (NEJM 2012;367:1417)

• Chest CT; pleural biopsy; VATS

• Undiagnosed persistent pleural effusions (Clin Chest Med 2006;27:309)

Transudative: most commonly CHF or hepatic hydrothorax. ✓ s/s CHF or cirrhosis, NT-proBNP_eff; consider intraperitoneal injection of technetium-99m sulfur colloid

Exudative (ensure using Sp test listed above): most commonly malig, empyema, TB, PE. ✓ s/s malig, chest CT (I⁺), ADA or IFN-γ release assay; consider thoracoscopy.

Treatment

• Symptomatic effusion: therapeutic thoracentesis, treat underlying disease process

• Parapneumonic effusion (Chest 2000;118:1158)

uncomplicated → antibiotics for pneumonia

>½ hemithorax or complicated or empyema → tube thoracostomy (otherwise risk of organization and subsequent need for surgical decortication)

loculated→ tube thoracostomy or VATS; intrapleural t-PA + DNase ↓ need for surgery

• Malignant effusion: serial thoracenteses vs. tube thoracostomy + pleurodesis (success rate ~80–90%) vs. indwelling pleural catheter, which ↓ hosp days but ↑ adverse events (JAMA 2017;318:1903); systemic steroids & pH <7.2 a/w ↑ pleurodesis failure rate

• TB effusions: effusion will often resolve spontaneously; however, treat Pt for active TB

• Hepatic hydrothorax

Rx: Δ pressure gradient (ie, ↓ ascitic fluid volume, NIPPV)

avoid chest tubes; prn thoracenteses, pleurodesis, TIPS or VATS closure of diaphragmatic defects if medical Rx fails; NIPPV for acute short-term management

spontaneous bacterial empyema (SBEM) can occur (even w/o SBP being present), ∴ thoracentesis if suspect infection

transplant is definitive treatment and workup should begin immediately

VENOUS THROMBOEMBOLISM (VTE)

Definitions

• Superficial thrombophlebitis: pain, tenderness, erythema along superficial vein

• Deep venous thrombosis (DVT): Proximal = thrombosis of iliac, femoral, or popliteal veins (nb, “superficial” femoral vein part of deep venous system). Distal = calf veins below knee; lower risk of PE/death than proximal (Thromb Haem 2009;102:493).

• Pulmonary embolism (PE): thrombosis originating in venous system and embolizing to pulmonary arterial circulation; 1 case/1000 person y; 250,000/y (Archives 2003;163:1711)

Risk factors

• Virchow’s triad for thrombogenesis. Stasis: bed rest, inactivity, CHF, CVA w/in 3 mo, air travel >6 h. Injury to endothelium: trauma, surgery, prior DVT, inflam, central catheter.

Thrombophilia: genetic disorders (qv), HIT, OCP, HRT, tamoxifen, raloxifene.

• Malignancy (12% of “idiopathic” DVT/PE; Circ 2013;128:2614)

• History of thrombosis (greater risk of recurrent VTE than genetic thrombophilia)

• Obesity, smoking, acute infection, postpartum (JAMA 1997;277:642; Circ 2012;125:2092)

Thromboprophylaxis (Blood Adv 2018;2:3198)
Patient & Situation	Prophylaxis
Low-risk med; same-day surg & <40 y	Early, aggressive ambulation ± mechanical
Moderate-risk (hosp., ≥1 risk factor) or high-risk medical (hosp., ICU, cancer, stroke)	LMWH or UFH (if renal failure) or fonda (if HIT ⊕). Pharmacologic favored vs. mechanical, but may personalize based on bleeding & thrombotic risk.
Low-risk surgery (minor surgery)	Mechanical Ppx
Moderate-risk surgery (eg, major surgery, trauma, immobilization)	If low bleeding risk: LMWH or UFH SC If high bleeding risk: mech Ppx
High-risk nonorthopedic surgery (multiple risk factors), stroke or ICH	[LMWH or UFH SC] + mech. Stroke s/p lytic or ICH: mech 24 h or until bleed stable, then + pharm.
Ortho surgery (cont pharmacoRx up to 35 d [hip] or 10–14 d [knee])	LMWH or DOAC (or fonda, UFH, or warfarin [INR 2–3]) + mech Ppx.

UFH: 5000 U SC bid or tid. Enox: 30 mg bid for highest risk or 40 mg qd for moderate risk or spinal/epidural anesthesia. For riva 10 mg/d, apixa 2.5 mg/d, edox 30 mg/d, dabi 110 mg post-op and then 220 mg/d.

Clinical manifestations—DVT

• Calf pain, swelling (>3 cm c/w unaffected side), venous distention, erythema, warmth, tenderness, palpable cord, ⊕ Homan’s sign (calf pain on dorsiflexion, seen in <5%)

• 50% of Pts with sx DVT have asx PE

• Popliteal (Baker’s) cyst: may lead to DVT due to compression of popliteal vein

“Simplified Wells” Pretest Probability Scoring of DVT (JAMA 2006;295:199)
+1 point each for: active cancer (Rx ongoing or w/in 6 mo or palliative); paralysis, paresis, or recent immobilization of lower extremities; recently bedridden for ≥3 d or major surgery w/in 12 wk; localized tenderness along distribution of deep venous system; entire leg swelling; calf ≥3 cm larger than asx calf (at 10 cm below tibial tuberosity); pitting edema confined to sx leg; collateral superficial veins (nonvaricose); previous DVT –2 points if alternative dx at least as likely as DVT
Pretest Probability Assessment (useful if outPt, less so if inPt; JAMA IM 2015;175:1112)
Score ≤0	Score 1 or 2	Score ≥3
Low probability (5%)	Moderate probability (17%)	High probability (53%)

• For UE DVT, +1 point each for venous cath, local pain, & unilateral edema, –1 if alternative dx. ≤1 = unlikely; ≥2 = likely. U/S if likely or if unlikely but abnl D-dimer (Annals 2014;160:451)

Diagnostic studies—DVT

• D-dimer: <500 helps r/o; ? use 1000 as threshold if low risk (Annals 2013;158:93)

• Compression U/S >95% Se & Sp for sx DVT (lower if asx); survey whole leg if ≥ mod prob

Clinical manifestations—PE

• Dyspnea (~50%), pleuritic chest pain (~40%), cough (~23%), hemoptysis (~8%)

• ↑ RR (>70%), crackles (51%), ↑ HR (30%), fever, cyanosis, pleural friction rub, loud P₂

• Massive: syncope, HoTN, PEA; ↑ JVP, R-sided S₃, Graham Steell (PR) murmur

Modified Wells Pretest Probability Scoring for PE (Annals 2011;154:709)
• Prior PE or DVT=1.5 points • Active cancer =1.0 • Immobilization (bed rest ≥3 d) or surgery w/in 4 wk=1.5 • Alternative dx less likely than PE=3	• Clinical signs of DVT=3 • HR >100 bpm=1.5 • Hemoptysis=1.0
Simplified Wells Probability Assessment
≤4 = ”Unlikely” (13% probability)	>4 “Likely” (39% probability)

Diagnostic studies—PE (EHJ 2014;35:3033)

• CXR (limited Se & Sp): 12% nl, atelectasis, effusion, ↑ hemidiaphragm, Hampton hump (wedge-shaped density abutting pleura); Westermark sign (avascularity distal to PE)

• ECG (limited Se & Sp): sinus tachycardia, AF; signs of RV strain → RAD, P pulmonale, RBBB, S_IQ_IIIT_III & TWI V₁–V₄ (McGinn-White pattern; Chest 1997;111:537)

• ABG: hypoxemia, hypocapnia, respiratory alkalosis, ↑ A-a gradient (Chest 1996;109:78) 18% w/ room air P_aO₂ 85–105 mmHg, 6% w/ nl A-a gradient (Chest 1991;100:598)

• D-dimer: high Se, poor Sp (~25%); ELISA has >99% NPV ∴ use to r/o PE if “unlikely” pretest prob (JAMA 2006;295:172); cut-off 500 if <50 y, 10× age if ≥ 50 y (JAMA 2014;311:1117)

• Echocardiography: useful for risk stratification (RV dysfxn), but not dx (Se <50%)

• V/Q scan: high Se (~98%), low Sp (~10%). Sp improves to 97% for high-prob VQ. Use if pretest prob of PE high and CT not available or contraindicated. Can also exclude PE if low pretest prob, low-prob VQ, but 4% false (JAMA 1990;263:2753).

• CT angiography (CTA; see Radiology inserts; JAMA 2015;314:74): Se ~90% & Sp ~95%; PPV & NPV >95% if imaging concordant w/ clinical suspicion, ≤80% if discordant (∴ need to consider both); ~1/4 of single & subseg may be false ⊕; CT may also provide other dx

• Lower extremity compression U/S shows DVT in ~9%, sparing CTA

Workup for idiopathic VTE (NEJM 2015;373:697)

• Thrombophilia workup: ✓ if ⊕ FH; may be helpful but consider timing as thrombus, heparin and warfarin Δ results. Useful for relatives, if dx APLAS (given requires warfarin), or if not planning lifelong anticoagulation for Pt.

• Malignancy workup: 12% Pts w/ “idiopathic” DVT/PE will have malignancy; age-appropriate screening adequate; avoid extensive w/u

Risk stratification for Pts with PE

• Clinical: Simplified PE Severity Index (sPESI) risk factors include age >80 y; h/o cancer; h/o cardiopulm. disease; HR ≥110; SBP <100; S_aO₂ <90%

• Imaging: TTE for RV dysfxn; CTA for RV/LV dimension ratio >0.9. Biomarker: Tn & BNP.

• Classification (EHJ 2020;41:543)

High risk (“massive”): hemodyn unstable w/ arrest, obstructive shock, or persistent HoTN

Intermediate risk (“submassive”): sPESI ≥1

“Intermediate-high” if both RV dysfunction & elevated Tn

“Intermediate-low” if either or neither RV dysfunction or elevated Tn

Low risk: clinically stable, sPESI = 0, normal RV function, normal Tn

Whom to treat (JAMA 2020;324:1765; Chest 2021;160:e545)

• Superficial venous thrombosis: elevate extremity, warm compresses, compression stockings, NSAIDs for sx. Anticoag if high risk for DVT (eg, ≥5 cm, proximity to deep vein ≤5 cm, other risk factors) for 4 wk as ~10% have VTE w/in 3 mo (Annals 2010;152:218).

• LE DVT: proximal → anticoag; distal → anticoag if severe sx, o/w consider serial imaging over 2 wk and anticoag if extends (although if bleeding risk low, many would anticoag).

• UE DVT: anticoagulate (same guidelines as LE; NEJM 2011;364:861). If catheter-associated, need not remove if catheter functional and ongoing need for catheter.

• PE: anticoagulate (unless isolated subsegmental and risk for recurrent VTE low)

Initial anticoagulation options (EHJ 2020;41:543; Chest 2021;160:e545)

• Initiate immediately if high or intermed suspicion but dx test results will take ≥4 h

• Either (a) initial parenteral → long-term oral or (b) solely DOAC if no interven. planned

• LMWH (eg, enoxaparin 1 mg/kg SC bid or dalteparin 200 IU/kg SC qd)

Preferred over UFH (especially in cancer) except: renal failure (CrCl <25), ? extreme obesity, hemodynamic instability or bleed risk (Cochrane 2004;CD001100)

• IV UFH: 80 U/kg bolus → 18 U/kg/h → titrate to PTT 1.5–2.3 × cntl (eg, 60–85 sec); preferred option when contemplating thrombolysis or catheter-based Rx (qv)

• IV direct thrombin inhibitors (eg, argatroban, bivalirudin) used in HIT ⊕ Pts

• Fondaparinux: 5–10 mg SC qd (NEJM 2003;349:1695); use if HIT ⊕; avoid if renal failure

• Direct oral anticoag (DOAC; NEJM 2010;363:2499; 2012;366:1287; 2013;369:799 & 1406)

Preferred b/c as good/better than warfarin in preventing recurrent VTE w/ less bleeding

Apixaban (10 mg bid × 7 d → 5 bid) or rivaroxaban (15 mg bid for 1st 3 wk → 20 mg/d) can be given as sole anticoagulant w/ initial loading dose

Edoxaban or dabigatran can be initiated after ≥5 d of parenteral anticoag

• DVT & low-risk PE w/o comorbidities and able to comply with Rx can be treated as outPt

• Generally safe to anticoagulate if platelets >50,000 but contraindicated if <20,000

Systemic thrombolysis (EHJ 2020;41:543; Chest 2021;160:e545)

• Typically TPA 100 mg over 2 h or wt-adjusted TNK bolus; risk of ICH ~2-5%, ↑ w/ age

• Consider if low bleed risk w/ acute PE + HoTN or cardiopulm deterioration after anticoag

• High-risk PE: ↓ death & recurrent PE each by ~50% (JAMA 2014;311:2414; EHJ 2015;36:605)

• Intermediate-risk PE: ↓ hemodyn decompensation, ↑ ICH & major bleeding, ↓ mortality in short- but not long-term; ? consider if <75 y and/or low bleed risk (JAMA 2014;311:2414)

• Half-dose lytic (50 mg or 0.5 mg/kg if <50 kg; 10-mg bolus → remainder over 2 h) in ~intermed. PE: ↓ pulm HTN & ? PE or death w/ ≈ bleeding vs. heparin alone (AJC 2013;111:273)

• DVT: consider if (a) acute (<14 d) & extensive (eg, iliofemoral), (b) severe sx swelling or ischemia, and (c) low bleed risk

Mechanical intervention (JACC 2020;76:2117)

• Catheter-directed pharmacomech: low-dose lytic infused (eg, tPA 1 mg/h for 12–24 hr per catheter) + U/S or mech fragmentation of clot. Consider if hemodyn. compromise or high risk & not candidate for systemic lysis or surgical thrombectomy. Preferred to systemic lytic by some centers. Also consider if intermediate-high risk and evidence of early hemodynamic deterioration (Circ 2014;129:479). Lack of data on hard outcomes.

• Catheter-based clot extraction (eg, AngioVac or FlowTriever): ↓ PA pressure

• Surgical embolectomy: if large, proximal PE + hemodynamic compromise + contraindic. to lysis; consider in experienced ctr if large prox. PE + RV dysfxn

• IVC filter: use if anticoag contraindic.; no benefit to adding to anticoag (JAMA 2015;313:1627)

Complications: migration, acute DVT, ↑ risk of recurrent DVT & IVC obstruction (5–18%)

Duration of full-intensity anticoagulation

• Superficial venous thrombosis: 4 wk

• 1^st prox DVT or PE 2° reversible/time-limited risk factor or distal DVT: 3–6 mo

• 1^st unprovoked prox DVT/PE: ≥3 mo, then reassess; benefit to prolonged Rx. Consider clot, bleed risk, Pt preference, and intensity of Rx when crafting strategy.

• 2^nd VTE event or cancer: indefinite (or until cancer cured) (NEJM 2003;348:1425)

Long-term anticoagulation options

• For nonpregnant Pt without severe renal dysfunction or active cancer → DOAC

• For severe renal insufficiency or APLAS → warfarin. Start w/ parenteral anticoag unless ? need for lytic, catheter-based Rx or surg; bridge to INR ≥2 × ≥24 h.

• Pregnancy or unable to take oral therapy → LMWH or fondaparinux

• Cancer → DOAC (but in Pts w/ UGI cancers, more GI bleeding w/ riva) or LMWH

Extended DOAC strategies

• After ≥6 mo of anticoag, following regimens compared w/ no extended Rx (or ASA):

• Full-dose DOAC: 80–90% ↓ recurrent VTE, 2–5× bleeding, but no signif excess in major bleeding (NEJM 2010;363:2499; 2013;368:699 & 709)

• ½ dose apixa or riva: ≥75% ↓ recur. VTE, w/o ↑ bleeding (NEJM 2013;368:699 & 2017;376:1211)

Complications & prognosis

• Postthrombotic syndrome (23–60%): pain, edema, venous ulcers

• Recurrent VTE: 1%/y (after 1^st VTE) to 5%/y (after recurrent VTE)

• Chronic thromboembolic PHT after acute PE ~2–3%, consider thromboendarterectomy

• Mortality: ~10% for DVT and ~10–15% for PE at 3–6 mo (Circ 2008;117:1711)

PULMONARY HYPERTENSION (PHT)

PHT defined as PA mean pressure ≥20 mmHg at rest (ERJ 2019;53:1801913)
PA mean = CO × PVR + PA wedge pressure. Trans pulm gradient = PA mean – PA wedge.

Etiologies (Revised WHO Classification) (JACC 2013;62:D34)
Primary pulmonary arterial HTN (PAH) (group 1) Precapillary PHT PCWP ≤15 mmHg ↑ transpulm grad ↑ PVR	• Idiopathic (IPAH): yearly incidence 1–2 per million; mean age of onset 36 y (♂ older than ♀); ♂: ♀ = ~2:1, usually mild ↑ in PAP • Familial (FPAH) • Associated conditions (APAH) • Connective tissue dis.: CREST, SLE, MCTD, RA, PM, Sjögren • Congenital L→R shunts: ASD, VSD, PDA • Portopulmonary HTN (? 2° vasoactive substances not filtered in ESLD; ≠ hepatopulmonary syndrome) • HIV; drugs & toxins: anorexic agents, SSRIs, l-tryptophan • Pulmonary veno-occlusive disease: ? 2° chemo, BMT; orthopnea, pl eff, CHF, nl PCWP; art vasodil. worsen CHF (AJRCCM 2000;162:1964) • Pulmonary capillary hemangiomatosis
Left heart disease (group 2). ↑ PCWP	• Left atrial or ventricular (diastolic or systolic) dysfunction • Left-sided valvular heart disease (eg, MS/MR)
Lung diseases and/ or chronic hypoxemia (group 3)	• COPD • Alveolar hypoventilation (eg, NM disease) • ILD • Chronic hypoxemia (eg, high altitude) • Sleep apnea • Developmental abnormalities
Chronic thrombo- embolic dis (group 4)	• Prox or distal PEs; ~½ w/o clinical h/o PE (NEJM 2011;364:351) • Nonthrombotic emboli (tumor, foreign body, parasites)
Miscellaneous/ Multifactorial (group 5)	• Sarcoidosis, histiocytosis X, LAM, schistosomiasis, ESRD • Compression of pulm vessels (adenopathy, tumor, fibrosing mediastinitis, histoplasmosis, XRT) • Other: thyroid dis., glycogen storage dis., Gaucher dis, HHT, sickle cell, etc., chronic myeloprolif d/o, splenectomy

Clinical manifestations

• Dyspnea, exertional syncope (hypoxia, ↓ CO), exertional chest pain (RV ischemia)

• Symptoms of R-sided CHF (eg, peripheral edema, RUQ fullness, abdominal distention)

• WHO class: I = asx w/ ordinary activity; II= sx w/ ord. activ; III = sx w/ min activ.; IV = sx at rest

Physical exam

• PHT: prominent P₂, R-sided S₄, RV heave, PA tap & flow murmur, PR (Graham Steell), TR

• ± RV failure: ↑ JVP, hepatomegaly, peripheral edema

Diagnostic studies & workup (JAMA 2022;327:1379)

• High-res chest CT: dilat. & pruning of pulm arteries, ↑ RA & RV; r/o parenchymal lung dis.

• ECG: RAD, RBBB, RAE (“P pulmonale”), RVH (Se 55%, Sp 70%)

• PFTs: disproportionate ↓ D_LCO, mild restrictive pattern; r/o obstructive & restrictive lung dis.

• ABG & polysomnography: ↓ P_aO₂ and S_aO₂ (espec w/ exertion), ↓ P_aCO₂, ↑ A-a gradient; r/o hypoventilation and OSA

• TTE: ↑ RVSP (but estimate over/under by ≥10 mmHg in ½ of PHT Pts; Chest 2011;139:988) ↑ RA, RV, & PA; ↑ pressure → interventricular septum systolic flattening (“D” shape) ↓ RV systolic fxn (TAPSE <1.6 cm); TR, PR; r/o LV dysfxn, MV, AoV, congenital disease

• RHC: ↑ RA, RV, & PA pressures; ✓ L-sided pressures and for shunt

if PAH: nl PCWP, ↑ transpulmonary gradient (mean PAP-PCWP >12–15), ↑ diastolic pulmonary gradient (PA diastolic – PCWP >7), ↑ PVR, ± ↓ CO

if 2° to L-heart disease: PCWP (or LVEDP) >15; if PVR nl → “passive PHT”; PVR >240 suggests mixed picture: if ↓ PCWP → ↓ PVR, then “reactive” PHT; if no Δ, then “fixed”

• CTA (large/med vessel), V/Q scan (small vessel to r/o CTEPH), ± pulm angio if ↑ concern

• Labs: ANA (~40% ⊕ in PAH), anti-Scl-70, anti-RNP; LFTs; HIV

• 6-min walk test (6MWT) or cardiopulmonary exercise testing to establish fxnl capacity

Treatment (JAMA 2022;327:1379)

• Principles: 1) prevent & reverse vasoactive substance imbalance and vascular remodeling 2) prevent RV failure: ↓ wall stress (↓ PVR, PAP, RV diam); ensure adeq systemic DBP

• Supportive

Oxygen: maintain S_aO₂ >90–92% (reduces vasoconstriction)

Diuretics: ↓ RV wall stress and relieve RHF sx; gentle b/c RV is preload dependent

Anticoag: not routinely used; ↓ VTE risk of RHF; ? prevention of in situ microthrombi; ? mortality benefit even if in NSR, no RCTs (Chest 2006;130:545)

Supervised exercise training; aggressive apnea/hypoventilatory Rx w/ CPAP/BiPAP

• Vasodilators (ideally right heart catheterization prior to initiation; NEJM 2004;351:1425) acute vasoreactivity test: use inh NO, adenosine or prostacyclin to identify Pts likely to have long-term response to CCB (⊕ response = ↓ PAP ≥10 mmHg to <40 mmHg w/ ↑ or stable CO); ~10% Pts acute responders; no response → still candidate for other vasodilators

Vasoactive Agents	Comments (data primarily in Group 1)
PDE-5 inhibitor sildenafil, tadalafil, vardenafil	↑ cGMP → vasodilatation, ↓ smooth muscle proliferation, ↓ sx, ↑ 6MWT, no data on clinical outcomes. Often 1st line b/c minimal side-effect profile: HA, vision Δ’s, sinus congestion.
Endothelin receptor antagonists (ERAs) bosentan, ambrisentan, macitentan	↓ Smooth muscle remodeling, vasodilatation, ↓ fibrosis, ↓ sx, ↑ 6MWT, ↓ worsening PAH or need for prostanoids w/ trend for ↓ PAH mortality (w/ macitentan). Side effects: ↑ LFTs, HA, anemia, edema, teratogen (NEJM 2013;369:809).
IV prostacyclin epoprostenol (Flolan)	Vasodilatation, ↓ plt agg, ↓ smooth muscle prolif; benefits ↑ w/ time (? vasc remodeling). ↑ 6MWT, ↑ QoL, ↓ mortality. Side effects: HA, flushing, jaw pain, abd cramps, N/V, diarrhea, catheter infxn.
Prostacyclin analogs [iloprost (inh), treprostinil (IV, inh, SC)]	Same mech as prostacyclin IV, but easier admin, ↓ side effects, w/o risk of catheter infxn. ↓ sx, ↑ 6MWT. Inh Rx w/ improved V/Q matching. Inh trepostinil ↑ 6MWT in ILD-PH (NEJM 2021;384:325).
Prostacyclin receptor agonist (selexipag, PO)	Indicated for WHO Group I to delay disease progression and risk of hospitalization. Add in WHO FC II & III (NEJM 2015;373:2522).
Soluble guanylate cyclase stimulator riociguat	NO-independent ↑ cGMP → vasodilatation, ↓ smooth muscle -proliferation, ↓ sx, ↑ 6MWT in PAH; ↓ sx, ↓ PVR, ↑ 6MWT in CTEPH (NEJM 2013;369:319 & 330)
Oral CCB nifedipine, diltiazem	Consider if ⊕ acute vasoreactive response. Not 1st line b/c side effects: HoTN, lower limb edema.

• Upfront combination Rx (PDE-5 inhibitor + ERA vs. monotherapy): ↓ sx, ↓ NT-proBNP, ↑ 6MWT, ↓ hospitalizations (NEJM 2015;373:834)

• Treat underlying causes of 2° PHT; can use vasodilators, although little evidence

• CTEPH: riociguat. Pulm endarterectomy potentially curative (AJRCCM 2011;183:1605) vs. balloon pulmonary angioplasty in non-operative Pts (Circ Outcomes 2017;10:e004029).

• Refractory PHT: balloon atrial septostomy: R→L shunt causes ↑ CO, ↓ S_aO₂, net ↑ tissue O₂ delivery; lung txp (single or bilateral; heart-lung needed if Eisenmenger physiology)

• PHT risk stratification based on CHF symptoms, syncope, WHO functional class, 6MWT, CPET, NTproBNP, imaging, hemodynamics (Eur Heart J 2016;37:67)

Management of ICU patient

• Avoid tachyarrhythmias & overly aggressive volume resuscitation

• Caution w/ vasodilators if any L-sided dysfunction

• Intubation can cause hemodynamic collapse

• Dobutamine and inhaled NO or prostacyclin

• Consider R-sided mechanical support (Circ 2015;132:536)

• Consider fibrinolysis if acute, refractory decompensation (eg, TPA 100 mg over 2 h)

Prognosis

• Median survival after dx ~2.8 y; PAH (all etiologies): 2-y 66%, 5-y 48% (Chest 2004;126:78–S)

• Poor prognostic factors: clinical evidence of RV failure, rapidly progressive sx, WHO (modified NYHA) class IV, 6MWT <300 m, peak VO₂ <10.4 mL/kg/min, ↑ RA or RV or RV dysfxn, RA >20 or CI <2.0, ↑ BNP (Chest 2006;129:1313)

RESPIRATORY FAILURE

• A-a gradient = P_AO₂ – P_aO₂: normal (on room air) = “4 + age/4” or “2.5 + (0.2 × age)”

• Hypoxemia + nl A-a gradient: problem is ↓ P_iO₂/F_iO₂ or ↑ P_aCO₂ (ie, hypoventilation)

• Hypoxemia + ↑ A-a gradient: problem is either

R → L shunt, anatomic (congenital heart dis) or severe pathophys (alveoli filled w/ fluid; eg, PNA, pulm edema); cannot overcome w/ 100% O₂ b/c of sigmoidal Hb-O₂ curve

V/Q mismatch where “shunt-like” areas (↓ V & nl Q) cause unoxygenated blood to mix with oxygenated blood; can be overcome w/ ↑ O₂ delivery

Diffusion limitation: generally seen with exercise/↑CO

• Cyanosis: when >5 g/dL of deoxygenated Hb in vessels of skin/mucous membranes. Central: ↓ S_aO₂ (pulm disease, shunt); abnl Hb [metHb, sulfHb, COHb (not true cyanosis)] Peripheral: ↓ blood flow → ↑ O₂ extraction (eg, ↓ CO, cold, arterial or venous obstruction)

CO binds to Hb more avidly than does O₂. Pulse oximeter (Ox) misreads COHb as HbO₂ → falsely nl sat.

Oxidizing drugs Δ Hb (ferrous) to MetHb (ferric), which cannot carry O₂. Pulse ox misreads MetHb as HbO₂.

Etiologies of High ↑ PaCO2
“Won’t Breathe”	“Can’t Breathe”
↓ RR	↓ VT		↑ VD and/or ↓ VT
Respiratory Drive	NM System	CW/Pleura	Lung/Airways
Voluntary hypervent. Nl PImax & A-a grad	↓ PImax ↓ PEmax	Abnl PEx Abnl CT	Abnl PFTs ↓ End tidal CO2
Metabolic alkalosis 1° neurologic: brain-stem stroke, tumor, 1° alveolar hypovent 2° neurologic: sedatives, CNS infxn, hypothyroidism	Neuropathies: cervical spine, phrenic nerve, GBS, ALS, polio NMJ: MG, LE Myopathies: diaphragm PM/DM, ↓ PO4, musc dystrophies	Chest wall: obesity, kyphosis, scoliosis Pleura: fibrosis effusion	Lung parenchyma: emphysema, ILD/fibrosis, CHF, PNA Airways: asthma, COPD, OSA, CF bronchiectasis

↑ VCO₂ typically transient cause of ↑ PaCO₂; Ddx: exercise, fever, hyperthyroidism, ↑ work of breathing, ↑ carbs.

MECHANICAL VENTILATION

Indications

• Improve gas exchange: ↑ oxygenation, ↑ alveolar vent and/or reverse acute resp acidosis

• Relieve respiratory distress: ↓ work of breathing (can account for up to 50% of total O₂ consumption), ↓ respiratory muscle fatigue

• Apnea, airway protection, pulmonary toilet

SUPPORTIVE STRATEGIES PRIOR TO INTUB. OR AFTER EXTUB.

Oxygen Delivery Systems (Lancet 2016;387:1867)
System or Device	O2 Flowa	FiO2 Range & Comments
Low-flow nasal cannula	1–6	24–40%, 1L adds ~3% FiO2
Standard face mask	5–10	35–50%, minimum 5 L/min
Partial rebreather mask	>10	40–70%
Nonrebreather mask	>10	60–80% (not 100% b/c air leaks)
Air-entrainment mask (Venturi or Venti mask)	10–15b	24–50%, FiO2 stays constant
High-flow nasal cannula (HFNC) (NEJM 2015;372: 2185; JAMA 2015;313:2331 & 2016;315:1354)	≤40	21–100%. In nonhypercapnic acute hypoxemic resp failure, ± ↓ intub. (espec if PaO2/FiO2 ≤200) & ↓ 90-d mort vs. stnd O2 or NPPV. Routine use after extub. ↓ need for reintub

^aL/min. ^bTotal airflow >60L/min. (Adapted from Marino P. The ICU Book, 4th ed, Philadelphia: LWW, 2014:431)

Noninvasive Positive Pressure Ventilation (NPPV) (NEJM 2015;372:e30)
Indications (Lancet 2009;374:250)	Clinical: mod–severe dyspnea, RR >24–30, signs of ↑ work of breathing, accessory muscle use, abd paradox Gas exchange: PaCO2 >45 mmHg (& significantly worse than -baseline), hypoxemia, PaO2/FiO2 <200
Contraindications (Crit Care Med 2007;35:2402)	Claustrophobia, poor mask fit, ΔMS, vomiting, cannot protect airway, extrapulm organ failure, HD instab, sev UGIB, ↑ secretions
Continuous positive airway pressure (CPAP)	≈ PEEP. Pt breathes spont. at own rate while vent maintains constant positive airway pressure throughout respiratory cycle. No limit on O2 delivered (ie, can give hi-flow → FiO2 ≈1.0) Used if primary problem hypoxemia (eg, CHF)
Bilevel positive airway pressure (BiPAP)	≈ PSV + PEEP. Able to set both inspiratory (usually 8–10 cm H2O) and expiratory pressures (usually <5 cm H2O). Used if primary problem hypoventilation; FiO2 delivery limited
Mask ventilation (? helmet better; JAMA 2016;315:2435)	Tight-fitting mask connecting patient to a standard ventilator Can receive PS ~20–30 cm H2O, PEEP ~10 cm H2O, FiO2 ~1.0 Used for short-term support (<24 h) for a reversible process
Conditions w/ strong evidence	Cardiogenic pulmonary edema: may ↓ intub. ± mortality (JAMA 2005;294:3124; Lancet 2006;367:1155; NEJM 2008;359:142) COPD exac. w/ ↑ PaCO2: ↓ intub. & mort., but if pH <7.3 → intubate Acute hypoxemic resp failure: ↓ intub. & mortality (JAMA 2020;324:57) High-risk extub. (age >65, CHF, APACHE II >12): NPPV × 24 h directly after extub. → ↓ reintub. and, if PaCO2 >45 mmHg during SBT, ↓ mortality. Does not Δ total # vent days (JAMA 2018;320:1881). Hypoxemic resp failure after abdominal surgery: ↓ reintubation Immunosupp. w/ infiltrates: ↓ complications & mortality

VENTILATOR MANAGEMENT

Ventilator Modes and Principles (NEJM 2001;344:1986; Chest 2015;148:340)
Cont mandatory ventilation (CMV), aka Assist control (AC)	Vent delivers a minimum number of supported breaths Additional Pt-initiated breaths trigger fully assisted vent breaths ∴ Vent-triggered breaths identical to Pt-triggered breaths Tachypnea → ? resp. alkalosis, breath-stacking, & auto-PEEP May be pressure targeted or volume targeted (qv)
Pressure support vent (PSV)	Support Pt-initiated breaths w/ a set inspiratory pressure & PEEP A mode of partial vent support because no set rate
Other	Synch intermittent mand. vent: deliver min # supported breaths; VT of additional Pt-initiated breaths determined by Pt’s effort Proportional assist ventilation (PAV): delivers variable pressure to achieve targeted % of work of breathing

Volume or Pressure Targeted
Volume targeted	Vent delivers a set VT; pressures depend on airway resist. & lung/CW compl. Benefit: ↑ control over ventilation (ideal initial ventilator setting); benefit in ALI/ARDS; easy to measure mechanics (PIP, Pplat, airway resist., compl.) Volume control (VC) ⊕: vent delivers variable pressure (depending on real- time lung compliance) to achieve set VT
Pressure targeted	Vent delivers a fixed inspiratory pressure regardless of VT VT depends on airway resistance and lung/chest wall compliance Benefit: may ↑ Pt comfort (PSV) requiring less sedation
General principles	Institutional/practitioner preference and Pt comfort usually dictate ventilator strategy; no strategy has proven superior Alarms can be set for ↓ or ↑ volumes and ↑ airway pressures in pressure- targeted and volume-targeted strategies, respectively Risks: volutrauma (ie, overdistention, if set volume too high; NEJM 2013;369:2126), barotrauma [can happen w/ relatively high set volumes (espec if stiff lungs) or if pressure target set too high; key is to monitor transpulmonary pressure (difference between Pplat and esophageal ≈ intrapleural), not just airway pressure]; can result in PTX, pneumomediastinum Hypo-/hyperventilation: need to ✓ minute vent & pH/PaCO2

Variables on the Ventilator
FiO2	Fraction of inspired air that is oxygen
VT (tidal vol)	Volume of breath delivered; lung-protective ventilation: goal ≤6 mL/kg IBW If no ARDS, similar # of vent days at higher VT (JAMA 2018;320:1872)
f (resp. rate)	Rate set by ventilator, f may be lower than RR if Pt triggering breaths. Adjust to achieve desired PaCO2.
Positive end- expiratory pressure (PEEP)	Positive pressure applied during exhalation via resistor in exhalation port Benefits: prevents alveolar collapse, ↓ shunt, ↑ O2 via alveolar recruitment and improved compliance, allows severely obstructed Pt to initiate breath Cardiac effects: ↓ preload by ↑ intrathoracic pressure → ↓ venous return; ↓ afterload by ↓ cardiac transmural pressure; may ↑ or ↓ CO and may ↑ or ↓ oxygen delivery based on the above Auto-PEEP or intrinsic PEEP (iPEEP): inadeq. exhalation time → lungs unable to completely empty before next breath (ie, “breath stacking”); if flow at end-expiration, there must be pressure = auto-PEEP. Will ↓ preload and may ↓ CO, espec if hypovolemic Will ↑ work of breathing as must be overcome by Pt to trigger breaths; can prevent Pt from triggering ventilator, extrinsic PEEP helps Can be detected if end-expiratory flow ≠ 0 before next breath Can measure by occluding expiratory port of vent at end-expiration Can ↓ by: ↑ exp time, ↓ RR, ↓ VT, Rx bronchospasm and secretions If iPEEP >set PEEP, minimize iPEEP, then set PEEP to ~80% of iPEEP to ↓ ineffective triggering
Inspiratory time	Normally I:E ratio is ~1:2; however, can alter I time (and consequently flow rate, see later); use in pressure-control mode
Inspiratory flow rates	↑ flow rate → ↓ I time → ↑ E time → ∴ may improve ventilation in obstructive disease, but may affect resp rate and bronchodilation/constriction
Peak inspiratory pressure (PIP)	Dynamic measurement during inspiration; set in pressure-targeted mode Determined by airway resistance and lung/chest wall compliance ↑ PIP w/o ↑ Pplat → ↑ airway resist (eg, bronchospasm, plugging) ↓ PIP → ↓ airway resistance or air leak in the system
Plateau pressure (Pplat)	Static measurement at the end of inspiration when there is no flow Determined by resp system compliance (resist. not a factor since no flow) ↑ Pplat → ↓ lung or chest wall compliance (eg, PTX, pulmonary edema, pneumonia, atelectasis), ↑ PEEP or auto-PEEP Pplat <30 cm H2O ↓ barotrauma (↓ VT, ↓ PEEP or ↑ compl [eg, by diuresis])

Tailoring the ventilator settings

• To improve oxygenation: options include ↑ F_iO₂, ↑ PEEP

S_aO₂ 88–92% acceptable (AJRCCM 2016;193:43), do not exceed 96% (BMJ 2018;363:k4169)

First, ↑ F_iO₂. If >0.6 and oxygenation remains suboptimal, then try ↑ PEEP:

If ↑ P_aO₂/F_iO₂ and P_plat stable, suggests recruitable lung (ie, atelectasis). If PEEP 20 & F_iO₂ 1.0 and oxygenation remains suboptimal, consider rescue/expt strategies (see “ARDS”).

If ↑ PEEP yields no Δ or ↓ P_aO₂/F_iO₂ or ↑ P_aCO₂, suggests additional lung not recruitable and instead overdistending lung → ↑ shunt & dead space; ∴ ↓ PEEP

If no ARDS, PEEP ≤5 (& S_aO₂ >92%) noninferior to PEEP 8 (JAMA 2020;324:2509)

• To improve ventilation: ↑ V_T or inspiratory pressure, ↑ RR (may need to ↓ I time). Nb, tolerate ↑ P_aCO₂ (permissive hypercapnia) in ALI/ARDS (qv) as long as pH >7.2.

Acute ventilatory deterioration (usually ↑ PIP)

• Response to ↑ PIP: disconnect Pt from vent, bag, auscultate, suction, ✓ CXR & ABG

(Adapted from Marino PL. The ICU Book, 4th ed., Philadelphia: LWW, 2014)

Liberating from the ventilator (NEJM 2012;367:2233; Lancet 2016;387:1856)

• Perform daily assessment of readiness for spontaneous breathing trial (SBT)

• Clinical screening criteria: VS stable, minimal secretions, adequate cough, cause of respiratory failure or previously failed SBT reversed

• Vent parameters: P_aO₂/F_iO₂ >200, PEEP ≤5, f/V_T <105, V_E <12 L/min, VC >10 mL/kg; rapid shallow breathing index (f/V_T) >105 predicts failure, NPV 0.95 (NEJM 1991;324:1445)

• Daily awakening trial (d/c all sedation; Lancet 2008;371:126): open eyes & w/o: agitation, RR >35, S_aO₂ <88%, resp distress or arrhythmias (if fail, restart sedation at ½ prior dose)

• SBT = CPAP × 30 min superior to T-piece × 120 min (JAMA 2019;321:2175) failure if: deteriorating ABGs, ↑ RR, ↑ or ↓ HR, ↑ or ↓ BP, diaphoresis, anxiety

• Tolerate SBT → extubation. Fail SBT → ? cause → work to correct → retry SBT qd

• If high-risk, extubate to either NPPV or NPPV alternating w/ HFNC (JAMA 2019;322:1465)

• ? acetazolamide in Pts w/ COPD & metabolic alkalosis (JAMA 2016;315:480)

Complications

• Oxygen toxicity (theoretical); proportional to duration + degree of ↑ oxygen (F_iO₂ >0.6)

• Ventilator-induced lung injury (see “ARDS”)

• Ventilator-associated pneumonia (~1%/d, mortality rate ~30%)

typical pathogens: MRSA, Pseudomonas, Acinetobacter and Enterobacter species

preventive strategies (AJRCCM 2005;171:388): wash hands, HOB elevated, non-nasal intub., enteral nutrition rather than TPN?, routine suction of subglottic secretions, avoid unnecessary abx & transfusions; routine oral antiseptic controversial

• Stress ulcers/GIB: prophylaxis w/ PPI ↓ GIB, but no ∆ in overall course (NEJM 2018;379:2199)

• Laryngeal

edema: for Pts vent >36 h; ? predicted by ⊕ cuff leak test. Methylprednisolone 20 mg IV q4h starting 12 h pre-extub. → ↓↓ edema and 50% ↓ in reintubation (Lancet 2007;369:1003).

ulceration: consider tracheostomy for Pts in whom expect >14 d of mech vent → ↓ duration mech vent, ↓ # ICU days (BMJ 2005;330:1243); no benefit to performing at ~1 wk vs. waiting until ~2 wk (JAMA 2010;303:1483)

• Malnutrition (for all critically ill Pts): enteral nutrition initiated early is safe but not necessary (JAMA 2012;307:795), but bolus may ↑ risk of VAP & C diff. (JPEN 2002;26:174); no clear benefit to ✓ing gastric residuals (JAMA 2013;309:249); permissive enteral underfeeding (~½ of calculated caloric req) & standard enteral feeding w/ similar outcomes (NEJM 2015;372:2398); parenteral nutrition should be delayed until after day 8 to ↓ risk of infections, cholestasis, RRT, ventilator days (NEJM 2011;365:506)

• Oversedation/delirium: BDZs and polypharmacy are risk factors

propofol: HoTN in ~25%; propofol infusion syndrome (PRIS) ? espec w/ high (>5 mg/kg/h) & prolonged (>48 h) infusions & concom vasopressors → ↑ AG, cardiac dysfxn, rhabdomyolysis, ↑ triglycerides, & renal failure (Crit Care 2009;13:R169)

dexmedetomidine: no benefit on vent-free days (JAMA 2016;315:1460 & 2017;317:1321); similar outcomes to propofol when utilized as sole agent (NEJM 2021;384:1424)

ACUTE RESPIRATORY DISTRESS SYNDROME

Berlin definition (JAMA 2012;307:2526)

• Acute onset within 1 week of clinical insult or worsening respiratory status

• Bilateral infiltrates without alternative explanation (eg, effusion, atelectasis, nodules)

• Edema not fully explained by fluid overload or congestive heart failure

• Hypoxemia: P_aO₂/F_iO₂ determined with 5 cm H₂O of PEEP

P_aO₂/F_iO₂ 200–300 = mild ARDS (may be on NPPV), 100–200 = mod, <100 = severe

Pathophysiology (Lancet 2016;388:2416)

• ↑ intrapulmonary shunt → hypoxemia (∴ Rx w/ PEEP to prevent derecruitment)

• ↑ increased dead space fraction (see Appendix), predicts ↑ mort (NEJM 2002;346:1281)

• ↓ compliance: V_T/(P_plat – PEEP) <50 mL/cm H₂O

Pathology

• Diffuse alveolar damage (DAD) seen in 40% of autopsies (AJRCCM 2013;187:761)

• If no clear inciting event and ILD considered as alt dx, consider bx (Chest 2015;148:1073)

Etiologies
Direct Injury	Indirect Injury
• Pneumonia (~40%) • Aspiration (~15%) • Near drowning • Inhalation injury • Lung contusion	•Sepsis (~25%) •Shock •DIC •Pancreatitis •Trauma/multiple fractures •Transfusion (TRALI)

Treatment (Lancet 2021;398:622)

• Goal is to maintain gas exchange, sustain life, & avoid ventilator-induced lung injury (VILI)

• In Pts on O₂ for COVID-19 PNA, dexamethasone ↓ 28-day mortality (NEJM 2021;384:693)

Mechanisms of VILI	Ventilator Strategies (see ARDSnet.org)
Barotrauma/volutrauma: alveolar dist → mech damage	VT ≤6 mL/kg, Pplat ≤30 cm H2O, tolerate ↑ PaCO2 (but keep pH >7.2), ↓ mortality (NEJM 2000;342:1301)
Biotrauma → SIRS	Low VT, open lung strategy w/ high PEEP
Atelectrauma: repetitive alveoli recruit & decruit	Titrate PEEP to prevent tidal alveolar collapse See below for options
Hyperoxia: ? injury; worsened V/Q matching	↑ PEEP rather than FiO2 (keep <0.60) O2-induced injury only theoretical in humans

The 6 Ps

• PEEP (see below)

• Proning: if P_aO₂/F_iO₂ <150, prone positioning ≥16 h ↓ mort ~50% (NEJM 2013;368:2159)

• Paralysis: no benefit routinely (NEJM 2019;380:1997); consider if Pt-vent dyssynchrony

• Peeing (fluid balance): target CVP 4–6 cm H₂O (if nonoliguric & normotensive) → ↑ vent/ICU-free days, but no Δ mortality (NEJM 2006;354:2564); PA catheter unproven (NEJM 2006;354:2213); consider BNP >200 to trigger diuresis (UOP goal 4.5–9 mL/kg/h × 3 h)

• Pulm vasodilators: inhaled NO or prostacyclins ↑ P_aO₂/F_iO_2; no ↓ mort or vent-free days (BMJ 2007;334:779)

• Perfusion (V-V ECMO): may be useful if refractory (NEJM 2018;378:1965)

PEEP titration methods (best method unclear)

• No benefit at given V_T if titrated to P_aO₂ alone (NEJM 2004;351:327; JAMA 2008;299:637)

• Best PEEP trial: incremental PEEP titration using compliance, O₂, hemodynamics

If able to ↑ PEEP w/o ↑ P_plat, suggests “recruitability”

∴↑ PEEP if → ↑ S_aO₂ (target ≥88–90%) & P_plat ≤30 cm H₂O → ↓ time on vent, better lung mechanics (JAMA 2008;299:646), ? ↓ mortality (JAMA 2010;303:865)

• ARDSnet “high” PEEP table for optimal F_iO₂/PEEP combo for goal S_aO₂ (ARDSnet.org)

• Recruitment maneuvers: stepwise preferred over sustained inflation, evidence insufficient to recommend routine use (Resp Care 2015;60:1688); recruitment maneuvers at high pressures ? ↑ mortality (JAMA 2017;318:1335)

• Esophageal balloon: used to estimate pleural pressure and thereby estimate trans-pulmonary pressure (ie, true airway distending pressure). Adjusting PEEP according to esoph pressure to maintain optimal transpulm. pressure does not ∆ ventilator-free days or mortality, although does ↓ need for advanced rescue Rx (see above) (JAMA 2019;321:846).

• Driving pressure (ΔP = P_plateau–PEEP): ↓ ΔP a/w ↑ survival; target <15 (NEJM 2015;372:747)

Prognosis (JAMA 2016;315:788)

• Mortality ~40% overall in clinical trials; 9–15% resp. causes, 85–91% extrapulm (MODS)

• Survivors: PFTs ~normal, ↓ D_LCO, muscle wasting, weakness persists (NEJM 2003;348:683), ↓ exercise tolerance, ↓ QoL, ↑ psych morbidity (NEJM 2011;364:1293); 44% of previously employed Pts jobless at 12 mos (AJRCCM 2017;196:1012)

SEPSIS AND SHOCK

Definitions (JAMA 2016;315:801; 2017;317:290 & 301)
Sepsis	Life-threatening organ dysfxn (SOFA ≥2) due to infection Quick SOFA (qSOFA): ≥2 of the following: RR ≥22, ΔMS, SBP ≤100 mmHg
Septic shock	Sepsis-induced circulatory and cellular/metabolic abnormalities severe enough to ↑ mortality; hypotension requiring pressors for MAP ≥65 and lactate >2 despite adequate fluid resuscitation
Sequential Organ Failure Assessment (SOFA): ↑ points for worsening organ dysfxn: respiration (↓ P:F ratio); coag (↓ plt); liver (↑ bili); CV (↓ MAP or ↑ pressors); CNS (↓ GCS); renal (↑ Cr or ↓ UOP)

Shock (see “PA Catheter & Tailored Therapy” for subtypes; NEJM 2013;369:1726)

• Tissue hypoxia due to ↓ tissue perfusion and hence ↓ tissue O₂ delivery and/or ↑ O₂ consumption or inadequate O₂ utilization

• Typical signs include HoTN (SBP <90 mmHg or drop in SBP >40 mmHg), tachycardia, oliguria (UOP <0.5 cc/kg/h), Δ mentation, metabolic acidosis ± ↑ lactate

• Hard to dx as ↑ SVR can maintain SBP, but tissue perfusion poor; shock index (HR/SBP) >0.9 and pulse pressure [(SBP – DBP)/SBP] <25% clues to significant shock

MANAGEMENT (Crit Care Med 2021;49:e1063)

Fluids

• Aggressive IV fluid resuscitation (30 mL/kg) admin in boluses w/in 3 h of presentation

• Crystalloid as good as colloid for resuscitation (JAMA 2013;310:1809; NEJM 2014;370:1412)

• No consistently seen benefit of balanced crystalloid (LR, Plasma-Lyte) vs. NS in terms of mortality, organ failure or need for RRT (NEJM 2018;378:829 & 2022:386:815)

• NaHCO₃ may ↓ mortality & need for RRT if AKI & pH <7.2 (Lancet 2018;392:31)

• Predictors of fluid responsiveness: pulse pressure variation >13% w/ respiration (Chest 2008;133:252); resp. variation in IVC diam, or >10% ↑ in pulse pressure w/ passive leg raise. Static CVP poor surrogate.

• After early resuscitation, if ALI/ARDS, target CVP 4–6 mmHg because additional fluids may be harmful → ↑ ventilator/ICU days (NEJM 2006;354:2564; Chest 2008;133:252)

Pressors & inotropes (also see “ICU Medications”)

• MAP target 65 mmHg as good as 80–85 and ↓ AF (NEJM 2014;370:1583; JAMA 2020;323:938)

• Norepinephrine: ↓ arrhythmia & mortality c/w dopamine (NEJM 2010;362:779; Crit Care Med 2012;40:725) and ∴ is pressor of choice in septic shock

• Vasopressin: adding to norepi (vs. using high-dose norepi) ↓ risk of AF & RRT by ~¼ (JAMA 2018;319:1889)

• If refractory vasoplegia: angiotensin II (Giaprezza), methylene blue, steroids (vide infra)

• If targets (see below) not reached after adequate fluids and pressors, consider inotropes

Targets

• Lactate clearance (≥20%/2 h) as effective as S_cvO₂ to guide resusc. (JAMA 2010;303:739)

• Targeting capillary refill time ≤3 sec (check q30min) as good if not better than lactate clearance (JAMA 2019;321:654)

Antibiotics

• Start empiric IV abx as soon as possible after recognition of severe sepsis or septic shock; every hr delay in abx admin a/w 7.6% ↑ in mortality (Crit Care Med 2006;34:1589), abx admin w/in 3 h of presentation in the ED a/w ↓ in-hospital mortality (NEJM 2017;376:2235)

• If possible, obtain 2 sets of BCx before urgently starting abx (but do not delay abx)

• Broad gram-positive (incl MRSA) & gram-neg (incl highly resistant) coverage, ± anaerobes

• Procalcitonin-guided cessation (not initiation) ↓ mortality (Crit Care Med 2018;46:684)

• Empiric micafungin in critically ill Pts w/ Candida colonization & sepsis of unknown etiology ↓ invasive fungal infxns & tended ↑ invasive fungal infxn-free survival, espec. in Pts w/ 1,3-b-D-glucan >80 (JAMA 2016;316:1555)

Steroids (Crit Care Med 2018;46:1411)

• Hydrocortisone 50 mg IV q6 + fludrocortisone 50 µg via NGT daily in septic shock ↓ duration of shock and may ↓ mortality (NEJM 2018; 378:797 & 809)

• Consider in Pts w/ refractory shock on escalating doses of pressors

Early Goal-Directed Therapy (EGDT)

• Historically: IVF & pressors for MAP ≥65 mmHg, CVP 8–12 mmHg, UOP ≥0.5 mL/kg/h; inotropes & PRBCs for S_cvO₂ ≥70% in 6 h (NEJM 2001;345:1368)

• However, now in era of early abx and adequate fluid resuscitation, no ↓ in mortality w/ EGDT vs. current usual care, and ↑ hospital costs (NEJM 2017; 376:2223)

TOXICOLOGY

Drug/Toxin	Signs/Sx and Diagnostics	Management Options
Acetaminophen	Vomiting, ↑ AG & nl OG metabolic acidosis, hepatitis & hepatic failure, renal failure	N-acetylcysteine (NAC) infusion Hemodialysis if massive O/D See “Acute liver failure”
Salicylates	Tinnitus, hyperventilation, abd. pain, vomiting, ΔMS, mixed ↑ AG & nl OG metabolic acidosis + respiratory alkalosis	IVF resuscitation Alkalinization w/ NaHCO3 Maintain respiratory alkalemia Consider hemodialysis
Opioids	↓ mentation, ↓ RR, miosis	IV naloxone
Benzodiazepines	↓ mentation, ataxia, ↓ RR	Flumazenil not rec (can precipitate withdrawal/seizures)
Calcium channel blockers	Bradycardia, AV block, hypotension, HF, hyperglycemia	IVF, vasopressors, Ca infusion, hyperinsulinemic euglycemia, ? intralipid emulsion, pacing
Beta blockers	Bradycardia, AV block, hypotension, HF, hypoglycemia	Glucagon, vasopressors, pacing
Digoxin	N/V, bradycardia, AV block, delirium, xanthopsia ✓ serum dig level (but may be inaccurate if <6 h since last dose), renal function	Correct hypokalemia Digibind if hyperkalemia, life- threatening dysrhythmia Consider hemodialysis Lidocaine for arrhythmias
Tricyclic antidepressants	Hypotension, seizures, arrhythmia, ↑ QRS, ↑ QT	IVF resuscitation, IV sodium bicarbonate, vasopressors
Lithium	N/V/D, tremor, hyperreflexia, clonus, drowsiness, seizure, ↑ QT, AV block, bradycardia	IVF (NS), maintain UOP Consider hemodialysis
Ethylene glycol	CNS depression, ↑ AG & OG metabolic acidosis	Ethanol or fomepizole, NaHCO3 Consider hemodialysis
Methanol (NEJM 2018;378:270)	CNS depression, blindness ↑ AG & OG met. acidosis	Ethanol or fomepizole, NaHCO3 Consider hemodialysis
Isopropanol	CNS depression, gastritis	Supportive care
Carbon monoxide	HA, dizziness, nausea, ΔMS carboxyHb level, CO-oximetry	100% normobaric oxygen, hyperbaric O2 in severe cases
Organopho- sphate	Salivation, lacrimation, diaphoresis, miosis, emesis, bronchospasm, ΔMS	Endotracheal intubation for respiratory failure, atropine, pralidoxime, benzodiazepines
Cyanide	Coma, seizure, metabolic acidosis, hypotension	IV Na nitrite and Na thiosulfate IV hydroxocobalamin

Call local Poison Control for assistance with management. (Chest 2011;140:1072)

LUNG TRANSPLANT

Overview

• Indications: end stage, progressive decline despite max medical Rx, <2-y life expectancy; COPD, ILD (IPF), pulmonary HTN, cystic fibrosis, alpha 1-antitrypsin

• Contraindic: age >70, uncontrolled/unRx’d infxn, malig in prior 5 yrs, severe non-pulm dis., BMI ≥35 or <16, active smoking, EtOH/drug depend., med nonadherence, psychosocial

Posttransplant care

• Immunosuppression: no single best regimen. Calcineurin inhibitor (tacro >cyclosporine, ↓ incidence of graft failure (JHLT 2021;40:S165) + steroids + MMF or AZA

• Monitoring: clinic visits, serial PFTs, chest X-ray, bronchoscopy w/ transbronchial biopsy

Complications

• Primary graft dysfunction (PGD): acute lung injury following txp; assoc w/ early mortality

• Anastomotic: vascular (stenosis, thrombosis) and airway (infection, necrosis, dehiscence, granulation tissue, tracheobronchomalacia, stenosis, fistula)

• Acute rejection: ↓ lung fxn, cough, SOB, fever; Dx w/ trans-bronch bx; Rx immunosupp

• Chronic rejection: bronchiolitis obliterans w/ obstruction; Dx w/ PFTs, trans-bronch bx; Rx limited (azithromycin, montelukast, Δ immunosuppressives)

• Infection: ↑ bacterial, fungal, viral pneumonia, systemic infections, CMV, OI

• Malignancy: 2× ↑ risk overall. 5.5× ↑ risk lung cancer. PTLD (assoc w/ EBV) common.

• Misc: GVHD, CKD, DM, CAD, CHF, stroke, encephalopathy, drug toxicity