Courtesy of Drs. Faraaz Shah and Bryan McVerry

Acute Respiratory Distress Syndrome

Berlin Definition Timing Within 1 week of a known clinical insult, or new or worsening respiratory symptoms Chest Imaging Bilateral opacities not fully explained by effusions, lobar collapse, or lung nodules Origin of not fully explained by cardiac failure or fluid overload (an objective assessment [ex- TTE] to exclude hydrostatic edema is warranted if no trigger is identified) Oxygenation Mild: 200 < P/F ratio ≤ 300 with PEEP ≥ 5 or CPAP ≥ 5 Moderate: 100 < P/F ratio ≤ 200 with PEEP ≥ 5 Severe: P/F ratio ≤ 100 with PEEP ≥ 5 Although not included in the Berlin Definition, the underlying pathophysiology is important to remember in the management of ARDS

Inflammatory and Trigger Chemical Mediators

Alveolar Injury • Epithelial • Endothelial

Surfactant dysfunction Capillary leak Capillary thrombi Vasoconstriction

Shunt- Decreased compliance Increased dead space Decreased aerated lung

ARDS is under-recognized, how can we better identify patients at risk for ARDS?

Lung Injury Prediction Score (LIPS) Predisposing Conditions Points Risk Modifiers Points Sepsis 1.5 Alcohol use 1 Shock 1.5 Tobacco use 0.5 Trauma 0.5 Hypoalbuminemia 2 0.5 Diabetes -1.5 Aspiration 1.5 Chemotherapy 2 Pancreatitis 1.5 FiO2 > 0.35 1 Elective Surgery 1.5 1 Emergency Surgery 2 LIPS < 4 has a high negative predictive value, odds of ARDS increase with higher scores

Courtesy of Drs. Faraaz Shah and Bryan McVerry

ARDS is under-treated, start appropriate treatments early instead of as salvage therapies

Effects of ARDS last long after the inciting event, start thinking of your patients as survivors when they enter the ICU

Mortality In-hospital mortality globally ~ 40% 1 year mortality in survivors is 20-25% Lung function Spirometry and DLCO recover to normal levels at 1 year Survivors will still report dyspnea and difficulty with exertion Cognitive deficits Discharge- 70-100% of survivors report some cognitive impairment 1 year: 45-80% 5 year: 20% Psychiatric disease New or worsened psychiatric disease including depression, PTSD, and anxiety is reported in 40-60% of survivors and persists 2+ years in many studies Physical function Musculoskeletal weakness has been observed in 35-70% of survivors at hospital discharge and is associated with worse 1 and 5 year survival.

Courtesy of Dr. Ian Barbash Core Conference: Anaphylaxis

By Mikael Häggström - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=17700404

Spickett and Sproud. Clinical Medicine 2011;11(4):390-96

Kemp and Lockey. J Allergy Clin Immunology. 2002;110:341-8

Approach to Difficult Step 1: Confirm an asthma diagnosis and identify difficult to treat asthma • Obtain pre and post bronchodilator spirometry- need at least 12% and 200mL improvement in FEV1

Asthma Mimicker with normal spirometry: • Think about - symptoms out of proportion to FEV1, atypical spirometry, poor response to meds • Symptoms: cannot get air in, dry , chest tightness below the • Long history of “asthma exacerbations” on high doses of medications and poor response • Episodic cough and dyspnea around irritants- perfumes, etc.. • Flat inspiratory loop on spirometry • Diagnose with laryngoscopy

Asthma Mimickers with abnormal spirometry Obstructive Restrictive COPD Obesity ABPA Mixed Constrictive Hypersensitivity Eosinophilic granulomatosis (Churg-Strauss) Eosinophilic granulomatosis (Churg-Strauss) Asthmatic Granulomatosis

Step 2: Differentiate severe asthma from milder asthma • Requires treatment with high dose ICS plus a second controller

Compliance is complicated- don’t like taking inhalers, expensive, sign of weakness, forgetfulness, they don’t work. Watch the patient use their inhaler to ensure they are doing it right!

Comorbidities that make asthma worse: • obesity • GERD • Chronic

Step 3: Determine whether severe asthma is controlled or uncontrolled Any one of the following qualifies as uncontrolled: • Symptom control: ACQ >1.5 or ACT <20 over 3 months • Exacerbations: 2 or more steroid bursts OR 1 hospitalization in the last year • Airflow limitation: FEV1 <80% predicted with reduced ratio

Consider biomarkers to identify presence of Type-2 cytokine signature Th2-Hi Type 2-Lo Atopy, high eosinophils, high exhaled NO Absence of atopy, eos, NO Respond to inhaled corticosteroid Associated with poor corticosteroid response late onset, obesity- responds to weight loss

Maximize corticosteroids for type-2 Hi (atopic, high eos, high FeNO). For those who remain uncontrolled, consider alternatives such as T2 targeted therapies (anti IL-4 dupilumab, anti-IL-5 mepolizumab and resilizumab) and diagnostic biopsy if needed.

Chronic Obstructive Pulmonary Disease

Management Based on 2017 GOLD criteria Symptoms Risk Therapy A CAT<10, MRC 0-1 ratio <0.7 and FEV1 ≥50% (GOLD I, II) AND 0-1 LAMA or LABA exacerbations/yr B CAT ≥10, MRC ≥2 ratio <0.7 and FEV1 ≥50% (GOLD I, II) AND 0-1 1. LABA or LAMA exacerbations/yr 2. LAMA + LABA Pulmonary rehab C CAT <10, MRC 0-1 ratio <0.7 and FEV1 ≤50% (GOLD III, IV) AND 1. LABA+ICS or LAMA ≥ 2 exacerbations/yr or 1 hospitalization 2. LAMA + LABA Pulmonary rehab Consider PDE-4 inhibitor D CAT ≥10, MRC ≥2 ratio <0.7 and FEV1 ≤50% (GOLD III, IV) AND 1. LABA+ICS and/or LAMA ≥ 2 exacerbations/yr or 1 hospitalization 2. ICS+LABA+PDE4 Pulmonary rehab Consider surgery * COPD Assessment Test (CAT): http://www.catestonline.org

Ratio <70 over-diagnoses patients the older they get! So, when reading PFTs, don’t overcall obstruction for older patients.

Comorbidities in COPD are higher compared to an age adjusted population: CAD Osteoporosis depression Cancer ** 50% of COPD discharges have CHF and/or CAD and COPD is an independent predictor of CVD mortality. Risks for exacerbation: • Any exacerbation in the last year • Chronic wheezing and asthma • Every 100cc decrease in FEV1 • Plasma fibrinogen and eosinophils are possible biomarkers

The BODE index Variable Points on BODE index 0 1 2 3 FEV1 % >65 50-65 35-50 <35 6 min walk distance >350 250-350 150-250 <150 MMRC dyspnea scale 0-1 2 3 4 BMI >21 <21 For a BODE score of 7-10, survival is 50% at 3 years- think about transplant survival (~50% at 5 years)

Exacerbation reduction: • Fluticasone/salmeterol 250/50 – 30% reduction • Roflumilast – 25% reduction • Tiotropium – 14% reduction • Daily azithromycin – 27% reduction 5 days of corticosteroid is non-inferior to 14 day course in terms of re-exacerbations.

The greatness of pulmonary rehabilitation: Efficacious and cost effective Improves functional performance Less than 2% with COPD participate Improves quality of life It is exercise, education, psychosocial support Decreases healthcare utilization

Lung Volume Reduction Surgery • Most benefit: upper lobe emphysema with low exercise capacity- 30% reduction in exacerbations • High risk group: FEV <20% predicted, homogenous emphysema, DLCO <20% predicted

Diagnostic Approach to Cough Take a history, but note: character and timing of the cough and presence or absence of has been shown in one study to not help with the diagnosis. More importantly, look for symptoms suggesting an underlying diagnosis: asthma, GERD, , etc…

90% of chronic cough cases are upper airway cough syndrome (post-nasal drip), asthma, and GERD. One study showed it was 99.4% in nonsmokers, not using an ACEi, and with normal CXR.

One approach: 1. postnasal drip is really common so start with empiric antihistamine-decongestant therapy. In one study this was all that was needed in 36% and 87% got at least some benefit. 2. They smoke? Yep, that’s why they are coughing- tell them to stop. 3. Stop that ACE inhibitor 4. Infectious signs/symptoms- try some antibiotics (pertussis! Common and under-recognized) 5. Treat that GERD 6. Asthma can make you cough! Try some bronchodilators/ICS 7. If none of that is working- get a CXR

So what to do when there’s no obvious cause and CXR is normal? Some less conventional testing Diagnosis Test GERD Esophageal pH monitoring (BRAVO testing) Asthma not apparent on PFTs Methacholine test, exhaled NO Non-asthmatic eosinophilic Sputum eosinophils, exhaled NO Upper airway cough syndrome Allergy skin testing and sinus CT

And what if the cough still persists? Now you’re looking for weird stuff Diagnosis Test Lesions compressing upper airway- AVM, retrotracheal HRCT scan masses Esophagoscopy Tracheobronchomalacia, airway lesion, tracheal diverticuli Bronchoscopy PVCs EP study Laryngeal sensory neuropathy (these people clear their Laryngeal EMG, videostroboscopy throat all the time) “ear-cough”- cerumen or foreign body impaction (vagus Look in their ears! nerve) Holmes-Adie syndrome- autonomic dysfunction of the Anisocoria, hyperhidrosis, abnormal vagus nerve DTRs Psychogenic cough Sigh..

Post-infectious cough can last 3-8 weeks. So tell your patients (and yourself) to expect a cough for 2 months after something like pneumonia. Chronic Thromboembolic As a reminder: pulmonary hypertension diagnosis requires PAP >25 and PCWP <15

It is unknown why some patients with develop CTEPH and others do not. Some considerations: • CTEPH patients seem to have a higher level of Factor VIII compared with controls • Antiphospholipid antibodies are present in 10-20% of CTEPH patients • Activated protein C resistance and levels of antithrombin, protein C&S do not seem to play a role in CTEPH

One unique physical exam finding in CTEPH is a flow murmur over the lung fields. These are a high-pitched, blowing bruit heard during inspiration. Have the patient inhale and then hold their breath. Not described in other forms of PH.

Diagnosis VQ scan is the initial imaging procedure of choice Right Heart Catheterization • Differentiates proximal issues (CTEPH) from distal • The pearl here is that PA pressures may only be small vessel types (PAH) modestly elevated at rest and disproportionately elevated with exercise. • CTEPH has one or several segmental or larger • PH with exercise but not at rest may indicate CTEPH mismatches. PAH has mottled subsegmental defects • Greater sensitivity compared with CTA (96 vs 51%) CT - angiography • Can underestimate central vascular obstruction • Similar performance to angiography for central disease but less so for segmental disease Other PH disorders that show larger segmental defects on VQ: PA sarcoma, PVOD, fibrosing , large vessel vasculitis

Treatment Anticoagulation is the mainstay of therapy. ~65 – 90% will resolve in 12 months with anticoagulation. There are no data at this time regarding choice of agent or duration. Risks for incomplete resolution despite anticoagulation include: • Large thrombus • Longer time between symptoms and diagnosis • Older age • Central location • Prior history of VTE

Pulmonary Thromboendarterectomy is the only definitive treatment. Surgical outcomes are related to decreasing the pulmonary vascular resistance. If the PVR does not come down due to distal thrombus, then poor outcomes - inability to wean from bypass, postop hemodynamic instability, and death.

There should be hemodynamic abnormalities at rest on RCH, but if not: • Still consider surgery if they have PH with minimal exercise – the thought is that this will progress to at rest • Patients with one main PA involved have increased dead space and high minute ventilation requirement with poor exercise capacity without hemodynamic impairment

There are 2 main postoperative complications that will be on your boards! 1. Pulmonary artery steal – incidence is 70% - refers to redirection of blood flow from well-erfused segments to nely endarterectomized segments with subsequent VQ mismatching and hypoxemia. 2. Reperfusion – 30% incidence – non-cardiogenic edema occurring in lung where proximal thrombus was removed. Occurs 72 hours postop. Can be severe, hemorrhagic and may require VV ECMO.

Medical Therapy is for: Inoperable CTEPH As a bridge to definitive surgical intervention Suboptimal hemodynamic and functional outcome after surgery – called persistent CTEPH

Small randomized studies show that medical therapy for inoperable CTEPH has some hemodynamic and symptomatic benefits; particularly bosentan and riociguat which is preferred for functional class II to II with inoperable and persistent CTEPH. For sicker patients, class IV, consider IV prostanoid therapy. People with cystic fibrosis are living longer! Median predicted survival is 41-42 years. So you will be seeing them in your practice as a pulmonologist.

The Basic Defects in Cystic Fibrosis Cystic Fibrosis is an autosomal recessive disorder. CFTR gene is located on chromosome 7 Normal CFTR is made, reaches the cell surface, and functions properly- transfer of chloride and water Class I No functional CFTR created Class II CFTR is misfolded and cannot reach the cell surface- F508del Class III CFTR reaches the cell surface but does not function properly- G551D Class IV CFTR channel opening is faulty Class V CFTR is created in insufficient quantities

Diagnostic Testing Sweat test: >60 abnormal Nasal potential difference (salt measure) CFTR mutation analysis Semen analysis

Phenotypic Features Chronic Sinopulmonary Disease GI and nutritional abnormalities • Colonization of typical pathogens (staph) • Intestinal: DIOS, rectal prolapse • Chronic cough and sputum production • Pancreatic: insufficiency, recurrent pancreatitis • CXR changes, i.e., bronchiectasis • Hepatic: focal biliary , multinodular cirrhosis • Wheezing and air trapping • Nutritional: protein-calorie malnutrition, AEDK deficiency • Nasal polyps, digital clubbing Salt Loss Syndromes Male urogenital- obstructive azoospermia • Acute salt depletion, chronic met alkalosis

Chronic Respiratory Regimen Airway clearance- exercise, chest vest, flutter DNAse or pulmozyme Bronchodilators- albuterol Inhaled hypertonic saline 3-7% Inhaled antibiotics- tobi, colistin CTFR modulators: Macrolides (avoid with NTM colonization) Ivacaftor- G551D; ivacaftor/lumacaftor- dF508

Chronic Nutritional Regimen Pancreatic enzyme supplements Monitor for CF-related diabetes (OGTT) Proton pump inhibitor Monitor for CF-related bone disease (DEXA) AEDK, iron, zinc supplementation Monitor for liver disease (LFTs +/- RUQ US)

So you’ve got an exacerbation… • Ddx: exacerbation of chronic microbes, new bacterial growth, ABPA, non-Tb mycobacterium, , sinus disease, GERD • Mild-mod: oral fluoroquinolone • May try continuous infusion of beta lactam • Mod-severe: 2 anti-pseudomonals IV • May try short course of oral steroid • Aminoglycoside: tobra daily at 10 mg/kg/day • Airway clearance! NIV if needed

Treat those complications Pneumothorax- try to avoid VATS, NTM- check AFB sputum annually, consider treating - bronchial embolization with IR DIOS- gastrograffin enema ABPA- check IgE; treat with steroid, itraconazole Consider: pancreatitis, intusseception, colon cancer

CTFR modulators • Ivacaftor (at least one G551D mutation) - improved lung function at 2 weeks and sustained through 48 weeks. Also improvements in risk of exacerbations, patient-reported respiratory symptoms, weight. • Lumacaftor-Ivacaftor (homozygous 508del) – improved FEV1, nearly 40% lower exacerbation rate, lower use of IV antibiotics Courtesy of Drs. Phil Lamberty and Stephanie Maximous Difficult Airway Algorithm

Initial Considerations

Take the time to get resources together: personnel, meds, equipment, lines IO access

AIRWAY ANATOMY SECRETIONS ease to visualize glottis/deliver tube DL vs. video limitations on positioning suction ready, forceps consideration of secretions

BAGGING/VENTILATION/OXYGENATION BLOOD PRESSURE (SHOCK) ability to BVM will they crash? consider Bilevel/DSI (ketamine) pre-intubation cardiac US FIND LMA IO access may be needed push dose pressors

Fiberoptic Intubation ketamine .5 to 1 mg/kg IBW- repeat for effect Precedex load and infusion LOAD: mix 2mL vial in 48 mL saline give 1mcg/kg over 10 mins drip at run at .7mcg/kg/hr (.01 mcg/kg/min)

Topical Anesthesia— max LIDOCAINE ~ 400mg-600mg bottle of 2%- 10mL— load onto ATOMIZER tongue, post , then down the hatch lidocaine gel on back of tongue depressor- suck bottle of 1% - lidocaine via scope (1-2mL)

RSI: Ketamine 1.5-2 mg/kg IBW Etomidate 0.3-0.4 mg/kg TBW Propofol (10mg/mL) 1-2.5 mg/kg IBW + (0.4 x TBW) OR 1.5 mg/ kg x TBW = 100mg=10mL!!! Succ 1-2 mg/kg TBW, 4mg/kg for SHOCK Rocuronium 0.6-1.2 mg/kg IBW

PUSH DOSE PRESSORS EPINEPHRINE iono-pressor take 9mL of saline (from saline stick) 1mL of cardiac EPI (100mcg/mL) now have 10mcg/mL Onset-1 minute Duration-5-10 minutes Dose: 0.5-2 ml every 2-5 minutes (5-20 mcg)

PHENYLEPHRINE vasoconstrictor nurse makes 100mcg/mL bag (100ml) from a 1:100 dilation of the vial Onset-1 minute Duration- 10-20 minutes Dose-0.5-2 ml every 2-5 minutes (50-200 mcg

Courtesy of Dr. Rachel Givelber

5. Effect of duty hours rules on medical errors or mortality has been difficult to demonstrate. [Volpp, JAMA 2007, FIRST trial; iCOMPARE not yet reported]

6. What can you do to improve sleep and fatigue during shift work? a. Sleep hygiene: set a routine, lower thermostat i. Avoid natural and artificial light 1-2 hours before bedtime (TV, laptops, cell phones), blackout curtains, white noise (for light sleepers). ii. No hot baths/strenuous exercise before bed, no food/alcohol b. Role of melatonin: Bright light suppresses endogenous production, and exogenous dosing can help entrain circadian rhythm: 1 mg immediate release 1 hour before bedtime.

Endocrine Emergencies Adrenal Crisis • Making the Diagnosis o Take a detailed steroid hx, include topical/intra-articular steroids, ICS + HAART o Risk factors to consider: anticoagulation (Waterhouse Friedrich’s) o Primary (adrenal failure) much more common than secondary (anterior pituitary) • Lab Testing o Cortisol testing may be misleading à measuring total not free cortisol § Less than 3 ug/dL diagnostic, random > 12 rules out in HEALTHY adults § Unclear what the appropriate cortisol level is in critical illness § Cosyntropin stim tests can be helpful in acute settings o Free cortisol influenced by albumin and cortisol binding globulin (CBG) § CBG high (false neg)– high estrogen (OCPs), hypergammaglobulinemia § CBG low (false positive)—nephrotic syndrome, cirrhosis • Treatment o IV corticosteroids preferred early in the acute setting Thyroid Storm • Making the Diagnosis o Possible causes: Graves, medications (amiodarone, PD-1 therapies), iodine o Often precipitated by a stressor (surgery, pregnancy, infection, anesthesia) o Clinical suspicion important as lab findings may be misleading • Systemic Effects o Fevers, tachycardias, AMS, abd pain common (may mimic acute abdomen) § Sinus tach and afib are most common arrhythmias, but VT also possible o Hypercoagulability (increased fibrinogen and clotting factors) o Encephalitis, status epilepticus, cerebral sinus thrombosis • Treatment – Goal is decreasing T3/T4 production and conversion of T4 to T3 o Beta blockers (propranolol), corticosteroids, cholestyramine, PTU/methimazole § PTU may help reduce peripheral conversion but has liver toxicities o Potassium iodide or Lugol’s solution (must be used with methimazole or PTU) o ICU options: plasmapheresis, surgery o AVOID salicylates (may increase free T4) o Pheresis and iodides may not be as effective in setting of amiodarone toxicity Myxedema Coma • Keys to Diagnosis à don’t need to be comatose for myxedema coma o Most common cause is withdrawal of therapy, need detailed thyroid hx o Helpful PE findings: hyporeflexia, bradycardia, obtundation, goiter, myxedema • Critical care considerations o Commonly incited by infection/sepsis, also by CVA, GI bleed, sedatives (opiates) o Systemic effects include bradycardia/heart block, pericardial effusions, coagulation abnormalities, seizures, respiratory depression, hyponatremia o Prognostic factors: hypotension, bradycardia, resp failure, refractory hypothermia • Treatment- cover for concomitant adrenal insufficiency while awaiting lab results o Start with IV thyroxine repletion until sure that bowels are working o T3 is more potent than T4 but may worsen heart disease, arrhythmias o Early T3 may stave off need for mechanical ventilation o Judicious fluid management, early antibiotics o Opiates will linger, avoid whenever possible ICU delirium

Diagnosis Confusion assessment method (CAM) 1. Acute onset Is there acute behavior change from baseline and does it fluctuate during the day? 2. Inattention Does the patient have difficulty focusing, easily distractible 3. Disorganized thinking Does the patient ramble, unclear or illogical flor of words 4. Altered consciousness For example, vigilant, lethargic, stupor, or coma Diagnosis requires presence of 1 AND 2 plus either 3 OR 4 The Intensive Care Delirium Screening Checklist (ICDSC) has high agreement with CAM

Delirium Prevention • Nothing has been shown to reliably prevent delirium, but you can reduce the incidence: Orientation protocol- clocks, calendars, windows, etc Cognitive stimulation Physiologic sleep- data supports ear plugs, noise reduction Early mobilization, limited restraints Visual and hearing aides Avoid problematic medications Manage medical issues – volume depletion, hypoxemia Treat pain • Current evidence does not support using medications to prevent delirium in ICU or postoperative settings

Management • Treatment of medical conditions: o Fluids and electrolytes o Infections o Organ failure – uremia, hypoxemia, etc o Hypoglycemia • Drug toxicity – thought to contribute to 30% of all cases of delirium, even when levels are “therapeutic” o Classic examples are lithium and digoxin • Withdrawal- namely alcohol and sedatives • Thiamine deficiency and Wernicke encephalopathy- older patients with nutritional deficiency • Managing agitation o Nonpharmacologic interventiosn such as addressing noise, light, windows, and restraints have been shown to improve clinical outcomes of frail patients. o Physical restraints should be a last resort. o Neuroleptics to treat severe agitation – data support reduces severity and duration, not incidence § Best data is for quetiapine as add-on treatment to as-needed haloperidol o When pain is an issue: data supports more rapid improvement with morphine versus haloperidol • Hypoactive delirium- similar management to the above; some data for low dose methylphenidate improving alertness

Hyperactive delirium is less common in older patients and usually alternates with periods of hypoactive delirium which is less obvious to providers.

Prognosis Mortality – one and six month mortality is 14 and 22%, respectively, even after adjusting for confounders Persistent cognitive dysfunction- after 2 years, only 1/3 of patients live independently Course of Alzheimer disease – deterioration proceeds at twice the rate compared with pre-hospitalization

Courtesy of Drs. Phil Lamberty and Bryan McVerry

Approach to ICU Sedation Key Principles • Focus on minimal drug necessary to achieve comfort o Reduce time on vent o Reduce ICU LOS o Promote functionality o Reduce delirium • Start minimization process as soon after intubation as possible/safe • Goal directed o Riker 4 default § Recognize that will not necessarily work for all comers • EtOH withdrawal • Need for paralytic • Start with pain relief based focus o Fentanyl drug of choice o Supplement with longer acting to minimize infusion • Benzodiazepine use o Useful when indicated o Bolus when needed o Supplement with longer acting enteral agent if needed/effective o Avoid infusion • Utilize short acting non-benzodiazepine meds for continuous infusion when possible o Propofol o Dexmedetomidine o Ketamine o Benzodiazepine last resort • Daily interruption when continuous drips required to assess ongoing need o Regular attempts at de-escalation if patient does not meet automatic sedation interruption criteria • Implement as bundle intervention o Cannot do in isolation though sedation minimization is key component of bundle as all else flows from wakefulness o ABCDE § Awakening § Coordination • SBT § Delirium Monitoring/Management § Early Mobilization • does not necessarily equate to early ambulation • ASSESS YOUR PATIENT’S NEEDS BEFORE DOSE ADJUSTMENT o Attempt to discern and fix underlying reason for agitation o Don’t forget about delirium prevention/treatment • Frequent reassessment o Patient response o Bedside nurse support

Courtesy of Dr. Rachel Givelber

Fatigue Mitigation

1. Fatigue: tiredness, reduced motivation, need to expend increased effort to perform a task effectively and without error a. Accumulates with increasing work duration and intensity b. Affected by quantity and quality of sleep c. Affected by time of day that work occurs (relative to circadian time) 2. Cognitive domains affected by sleepiness: attention, working memory, mood, executive functioning. Fatigued people have POOR INSIGHT into impairment 3. Individual variability

4. Multiple adverse effects on residents associated with prolonged shift work: needle sticks, car crashes, self-reported medical errors; objectively observed medical errors.

HEMATOLOGIC EMERGENCIES Benign Heme Emergencies Malignant Heme Emergencies Autoimmune hemolytic anemia Hypercalcemia TTP Hyperleukocytosis Sickle cell crisis Hyperviscosity Acute tumor lysis syndrome Acute cord compression Superior vena cavae syndrome

Acute cord compression • Lung ca > Breast ca > Prostate ca • Thoracic spine > Cervical spine > Lumbar spine • 90% pain; 75% weakness; 50% loss of bladder/bowel function • Treatment: XRT + IV Dex + surgery (if able) best outcomes

Tumor lysis syndrome • More common: high-grade lymphoma (Burkits) or acute leukemia (ALL) • Tumor lysis Labs: ↑ uric acid, ↑ K, ↑ Phos, ↓ Ca • Clinical tumor lysis = Tumor lysis labs + one of the following: o Cr > 1.5, Arrythmia, Seizure, or Death • Prophylaxis and Treatment: o IVF o Allopurinol o Rasbirucase

Hypercalcemia • Etiologies o PTH-rP (80%): Sq cell CA (lung, Head & Neck), RCC, Bladder, Breast, Ovarian o Osteolysis from bone mets (20%): Multiple myeloma, Breast, Lung o Excess Vit D production from malignant cells: least common • Sx: lethargy, confusion, nausea, constipation, polyuria, polydipsia, arrhythmias (bradycardia, short QT, cardiac arrest) • Treatment (for Ca > 12-14): o IVF o Calcitonin o Pamidronate o Zolendronic acid o Steroids o Furosemide (only use on euvolemic patients)

Superior vena cavae syndrome • Etiologies o Non-malignancy: thrombosis, fibrosing mediastinitis, post-radiation fibrosis o Malignancy: lung ca, lymphoma (diffuse large B-cell) • Initial treatment: Airway management • Definitive treatment: XRT, chemo, endovascular stenting

HEMATOLOGIC URGENCIES Neutropenic fever Transfusion reaction DIC AML w/o hyperleukocytosis Bleeding diathesis

Hemoptysis

Massive Hemoptysis- ranging from 100 mL to 600 mL over 24 hours. Life threatening bleeding- usually >500 mL of blood over 24 hours or a rate of >100 mL/hour.

Causes of Hemoptysis Airway Parenchymal Bronchitis and *bronchiectasis Almost any infection – *Tb, fungal, bacterial, viral Bronchovascular fistula (aortic aneurysm, trauma, surgery, Exotic infections – anthrax, Y. pestis, tularemia, *P stent complication) westermani *Bronchogenic carcinoma Rheumatic – amyloid, Goodpasture, Bechet, GPA, SLE, APLA Dieulafoy – subepithelial bronchial artery Idiopathic pulmonary hemisiderosis Metastatic cancer Coagulation Disorders Foreign body Medications – anticoagulant and antiplatelet Trach erosion into innominate artery (low placement) DIC Pulmonary Vascular Thrombocytopenia Heart failure, mitral regurgitation, congenital disease Von Willebrand disease Pulmonary embolism Leptospirosis PVOD One case series of embolization for hemoptysis: 40% CF/bronchiectasis, 14% metastatic disease, 12% lung cancer, 7% fungal infection. Most common etiologies *bolded

Remember that blood from the upper GI tract can be expectorated and mimic hemoptysis- called “pseudohemoptysis”

Diagnosis 1. CXR reveals the site of hemoptysis is almost half of cases and the case in ~35%. 2. CT is preferable for bronchiectasis and carcinomas. Bronchoscopy is better for mucosal abnormalities such as bronchitis, Kaposi, small papillomas, etc • Study of 50 patients with hemoptysis, normal CXR: CT diagnostic in 30% and bronchoscopy in 10%. 3. Recurrent hemoptysis with normal CT and bronchoscopy – most common etiology here is upper airway source or use of anticoagulants. Recurrence in the remainder happens in about 20%.

Management of Massive Hemoptysis First position the patient bad lung down, establish an airway, ensure hemodynamic stability, and then try to control the bleeding. • Identification of side of bleeding can be difficult – patients can often tell you which side it’s coming from and physical exam and CXR may help. • Try to place an 8.0 ETT. You can place in the mainstem of the nonbleeding lung to protect this good lung. Combine this with balloon tamponade or bronchial blocker placement. • Double lumen tubes are another option – try to get a left-sided double-lumen tube- long lumen terminates in the left main and shorter lumen terminates in the distal . This avoids RUL occlusion.

Bronchoscopy is often going to be your first choice in the ICU • Endobronchial blocker. See video < https://www.youtube.com/watch?v=Tru-vVO6s3w> • Iced saline lavage – cool 1L of saline ahead of time (put in a bunch of 50-60cc syringes). Lavage bleeding source with 50cc aliquots of cold saline. Average volume in one case series was 500mL per patient. • Topical epinephrine [1:20,000]

Arteriography and Embolization • Use when there is persistent hemoptysis despite bronchoscopy and correction of coagulopathy. • Anterior spinal artery arises from a bronchial artery in 5%- embolization may result in paraplegia (1%) Idiopathic

The main thing you have to do when considering IPF is to rule out other causes of interstitial lung disease.

History Physical Exam 50-60 years old Coarse bibasilar at end inspiration Most have a smoking history • Can be unilateral especially early Several months of dyspnea and cough End inspiratory squeaks are traction bronchiectasis Systemic symptoms are rare (fever, myalgias, etc) Clubbing in 50-75%

Radiology If the H&P is as above and the CT chest has these three features, then it is likely IPF 1. Peripheral, bibasilar predominant reticular opacities 2. Honeycombing 3. Traction bronchiectasis

However, there are a few exceptions to the above- as experts you should be aware: • Honeycombing is essential to making a UIP diagnosis, but is sometimes absent • Up to 30% of UIP diagnosed by biopsy have other features on CT chest than listed above • Ground glass opacities can be present in IPF! But should not be the predominant feature

So, if I’m pretty sure it’s IPF, do I need labs? Usually the answer is no. See the ILD handout for details on serologies. A few things to keep in mind: 1. ANA >1:40 is present in up to 25% of biopsy proven UIP 2. Positive rheumatoid factor is present in about 15% 3. Up to 70% a people with anti-synthetase syndrome can present with a UIP pattern of fibrosis

When do I recommend a biopsy? If with the above, you are not confident in an IPF diagnosis then get a biopsy. It’s important to get this right because IPF has a prognosis worse than most cancers. But usually you can spare them the morbidity of a biopsy.

Ok. So they have IPF. What can I tell them to expect? • FVC declines about 150 – 200 cc per year – this means • Acute exacerbations are unpredictable – this they can expect a slow decline in functioning means consider early transplant referral • “If I take 100 people with IPF, about 20 of them will be dead in 5 years”

And then they say, “aren’t there some medicines or something?” For mild to moderate IPF, meaning DLCO 45-65% predicted, I would have a discussion about the pros and cons of medication. Here’s what you need to know: • Nintedanib is a multiple tyrosine kinase blocker and mediates elaboration of fibrogenic growth factors (PDGF, VEGF, FGF). It slows the rate of decline in lung function. Don’t give to cirrhotics. And it interferes with CYP3A4 and increases risk of bleeding on anticoagulation. • Pirfenidone is an antifibrotic that inhibits TGF-beta stimulated collagen synthesis; blocks fibroblast proliferation in vitro. Also slows the rate of decline in lung function and possibly a survival benefit in a pooled analysis.

Now they are in the hospital with an acute exacerbation of IPF. So now what? Know that mortality is about 50% and probably higher if they end up on mechanical ventilation – approaching 100% in some studies. Can try the following: • Rule out infection and give 1-2 grams of solumedrol daily for 3-5 days- know that evidence for this is lacking • Very limited data on protocol with pheresis and IVIg- patients that respond to this (and the above meds) probably have an underlying, undiagnosed connective tissue disease Approach to Interstitial Lung Disease

History Physical Exam Allergic and asthma – Fibrosis sounds like coarse, velcro-like crackles Nasal polyps – EGPA (churg-strauss) High pitched inspiratory – bronchiolitis (HSP) Medications – amiodarone, anti-TNFα, nitrofurantoin Clubbing is nonspecific, usually in advanced fibrosis Smoking – RBILD, DIP, EG PAH, cor pulmonale (edema, loud P2, RV heave) Exposures – asbestos, silica, birds, etc Extrapulmonary – rashes, Raynauds, arthritis, muscle weakness/pain, nailfold capillary

ILD that may have obstructive PFTs • • LAM/tuberous sclerosis • Hypersensitivity • Eosinophilic granuloma • Combined pulmonary fibrosis emphysema

Clinical Pearl: Look at old imaging and PFTs to determine the time course and progression of disease!

Radiology Classic UIP pattern that indicates IPF and requires no further workup: 1. Bilateral, subpleural reticular opacities in a basilar predominance 2. Traction bronchiectasis 3. Honeycombing Other typical radiographic patterns of ILD • Balanced hilar adenopathy- sarcoidosis • Pleural plaques and septal lines – • Centrilobular nodules – hypersensitivity pneumonitis, eosinophilic granuloma, sarcoidosis • “Atoll sign” – airspace disease at the end of an airway with central clearing – COP • Cysts – EG, LAM, Sjogren

Clinical Pearl: If you have a classic UIP pattern and no inkling of autoimmune disease, you can call it IPF. We still recommend some screening serologies to help with prognosis and rule out myositis.

Serologies Screening serologies that I get on almost everyone ANA – get excited with titer >1:80; pattern matters, i.e., nucleolar important, homogenous not so much RF- pretty nonspecific but can clue you in that something is afoot CK, aldolase, myositis panel, Jo-1: 70% of anti-synthetase syndrome presents with ILD and negative ANA ESR and CRP- these are not helpful and I do not get them Disease specific serologies that I only get if pretest probability is high ccp- specific marker for RA, get hand XR as well if suspicion is high ssA/ssB, immunoglobulins: Sjogren, IgG f seronegative Sjogrens, IgG subclasses for IgG4 disease Scl 70, centromere, PM-1: scleroderma and the scleroderma/myositis overlap syndrome ANCA- order with suspicion of vasculitis: GPA, EGPA, MPA; interpretation can be difficult dsDNA, smith, RNP- SLE and its overlap syndromes, RNP is helpful if dsDNA and smith are negative

Clinical Pearl: If the CT is not classic UIP fibrosis and/or you suspect autoimmune disease based on history, exam, serologies- try to biopsy something to get an actual diagnosis.

VATS TBBx NSIP Sarcoidosis COP Hypersensitivity pneumonitis Eosinophiic pneumonia Lymphangitic carcinomatosis

Liver Failure

Differential Diagnosis A Acetaminophen, hepatitis A, autoimmune, Amanita phallodes, adenovirus B Hepatitis B, Budd-Chiari C Hepatitis C, CMV, cryptogenic D Hepatitis D, drugs E Hepatitis E, EBV F Fatty infiltration, acute fatty liver of pregnancy, Reye’s syndrome G Genetic – Wilson disease, hemochromatosis H Hypoperfusion, HELLP, HSV, heat stroke, hemophagocytic lymphohistiocytosis I Infiltration by tumor

Physical Exam Hepatic encephalopathy is the hallmark of acute liver failure and has four grades: • Grade I – mild confusion, slurred speech, disordered sleep; mild asterixis • Grade II – lethargy, moderate confusion • Grade III – stupor, incoherent speech, sleeping; asterixis is the most prominent • Grade IV – coma, unresponsive to pain; in 75%; posturing present

Subclinical seizures are thought to occur in ~30% and are difficult to detect clinically

Laboratory Pearls • Elevated INR is part of the definition of acute liver failure and must be present (INR >1.5) • Aminotransferases should be markedly elevated (acutely) • Decreasing aminotransferases may indicate recovery or worsening with loss of hepatocyte mass – don’t be fooled! • Bilirubin and INR are the most important to monitor, only give FFP if really needed

Despite elevated INR – 20% are hypocoaguable, 45% normal, 35% hypercoaguable! (via thromboelastography)

Management • Have a low threshold to send patients to a liver transplant center. Only 40% of patients with acute liver failure will spontaneously recover. • Use hepatic encephalopathy for triage: Grade I on the floor, Grade II – IV in the ICU

Some disease- specific treatments N-acetylcysteine Obvious role in acetaminophen toxicity; there may be some role in non-acetaminophen liver failure as well; low threshold to administer, risks are minimal Hepatitis B Consider lamivudine; give to transplant candidates to prevent post-transplant recurrence Amanita phalloides Early charcoal improves survival; consider silibinin (milk thistle extract) and penicillin G Budd-Chiai TIPS, surgical decompression, thrombolysis HSV Acyclovir for 7 days Wilson disease Will generally require transplant; plasma exchange with FFP to remover copper as a temporizing measure Autoimmune hepatitis Trial of steroid not unreasonable (prednisone 40-60 mg daily); be weary of infection Acute fatty liver of pregnancy Emergent delivery

1-page TICU tips David T. Huang, MD, MPH May 2018

Neuro

1. Hepatic encephalopathy is like ileus – something caused it! 2. Cirrhotics get NMS too 3. Golytely a good hepatic enceph tool

Cardiovascular

1. Know “usual” blood pressure 2. Investigate “normal” CI 3. Watch for the crump – even w/ minor stress 4. Love, fear, + respect lactate!

Pulm

1. OK to tap belly/chest w mild-mod coagulopathy 2. Check more ABGs when Bili > 20 3. Drain /hydrothoraces slowly, then speed up

GIB

1. Intubate suspected variceal bleeding pre-EGD 2. Transfuse to ~8 3. Tell GI + IR to talk directly to each other, while you stabilize pt 4. Hey GI, what’s rebleed plan? 5. Balloon tamponade? – remember 50/50! (50 cm in, 50 cc air – take Xray!)

Renal

1. Cirrhotics get drug/sepsis/etc-induced AKI too 2. Carefully err on side of more volume 3. Dialysis may not be a good idea…

Infection

1. Infection likely worsens liver function, and portal HTN, per se 2. TICU handshake = ascites tap 3. Treat ~ as if transplant pt! 4. Intubation a 2-step procedure (Tube, then lung specimen)

Approach to Lung Cancer I - Screening

Some Lung Cancer Fun Facts • There are more lung cancer deaths than breast, prostate, and colon combined • 80% are nonresectable on presentation and 50% are dead within 1 year • It takes about 10 years of smoking cessation to get your cancer risk down to ~5%

Causes of Lung Cancer Smoking Second hand smoke Occupational exposures Air pollution Radiation Diet and nutrition

Occupational Agents Associated with Lung Cancer- it’s on the boards! Arsenic Asbestos (multiplicative risk for cancer with smoking) Chromium Nickel Radon Vinyl Chloride

Most common genetic abnormalities Cancer Mutation Incidence Squamous cell p53 60-70% Adenocarcinoma KRAS in smokers 10-30% EGFR kinase domain in nonsmokers 10-40% Small cell c-MET overexpression 13%

The best evidence of effective screening is a reduction in mortality, not prolonged survival. Higher survival rates in the screened population is due to earlier detection- the classic “lead time bias”.

Bias in Screening Lead time bias Disease detected earlier but death is not delayed Length bias Screening preferentially detects slowly progressive disease Overdiagnosis bias Screening detects disease that would not otherwise be clinically evident

National Lung Screening Trial (NSLT) of low dose CT scan • 53,000 participants, 148,000 exams, 59 sites in 28 US states • 20% reduction in mortality; 3 fewer deaths per 1,000 people over an average of 6.5 years of follow up • 24% with abnormal result and 96% of those were false positives • 2.5% had an invasive test, 1.9% had a biopsy, and 0.4% had an adverse outcome

Whom do I screen? Age 55-75 Smoking history of at least 30 pack years Asymptomatic Current smoker or has quit within the last 15 years

Check out the very awesome Solitary Pulmonary Nodule Risk Calculator: https://www.uptodate.com/contents/calculator-solitary-pulmonary-nodule-malignancy-risk-brock-university- cancer-prediction-equation

Lung Cancer II – Staging and Treatment

There are many online sites to help with learning this, such as http://www.radiologyassistant.nl/en/p42459cff38f02/lung-cancer-new-tnm.html

Fleischner Society Guidelines 2017 Nodule Type Size (mm) Follow up (months) Solid <6 No follow up, optional CT at 12 months for high risk 6-8 CT at 6-12 months then 18-24 >8 CT, PET, or biopsy at 3 months Ground glass <6 No routine follow up ≥6 CT at 6-12 months, then every 2 years until 5 years Mixed <6 No routine follow up ≥6 CT at 3-6 months, then annually until 5 years Multiple Solid ≥6 CT at 3-6 months, then 18-24 months for high risk Multiple Ground glass ≥6 CT at 3-6 months, if stable repeat at 2 & 4 years

PET scanning • Avoids futile thoracotomies in ~20% (detects non-resectable disease) • False Positives: granulomatous disease (sarcoid), rheumatoid nodules, • False Negatives: tumors <1cm, low-grade BAC, carcinoid

When performing bronchoscopy, EBUS, Navigational, whatever... you really need to get enough tissue to do molecular studies. Survival is better for targeted therapy vs non-targeted therapy.

Lung Cancer Paraneoplastic Phenomena Syndrome Marker Cancer Hypercalcemia Bony mets (usually), PTHrP squamous SIADH Hyponatremia, urine and serum osm Small cell Lambert-eaton Voltage gated calcium channel Ab Small cell Limbic encephalitis/nonconvulsive status Anti-Hu Small cell Hypertrophic osteoarthropathy Clubbing, PET with diffuse uptake Dermatomyositis and Polymyositis Muscle weakness, CK, aldolase

Courtesy of Dr. Matt Morrell

Disease specific criteria for listing for lung transplantation

Chronic obstructive pulmonary disease BODE index of at least 7 or at least 1 of the following: • FEV1 < 20% predicted and either DLCO < 20% predicted or homogenous distribution of emphysema

• History of recurrent exacerbations with associated (pCO2 > 50mmHg) despite aggressive medical management • Pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy Idiopathic pulmonary fibrosis Histologic or radiographic evidence of UIP and any of the following: • A 10% or greater decrement in FVC during 6 months of follow-up • A decrease in pulse oximetry <88% during a 6-minute walk test • Honeycombing on high-resolution CT of the chest • A DLCO <39% predicted Cystic fibrosis

• FEV1 <30% predicted or rapidly declining lung function • Pulmonary hypertension • Increasing oxygen requirements

• Baseline hypercapnia (pCO2 >50mmHg) Pulmonary Hypertension • Persistent NYHA class III or IV symptoms on maximal medical therapy • Low or declining 6-minute walk • Failing therapy with intravenous epoprostenol or equivalent • Cardiac index <2L/min/m2 • Right atrial pressure >15mmHg

Contraindications for transplantation:

Relative Absolute History of HIV, Hep C or B Recent or active malignancy BMI >35 or <18 Active drug use, cigarette or alcohol abuse Age >70 Severe neurologic or psychiatric disease Presence of end organ damage (dual organ Non-compliance transplant?) Prior thoracic surgery or pleurodesis Absent social support Mechanical support (ventilation/ECMO) Severe deconditioning High level of HLA antibodies

Studies required for transplant workup:

CXR PFTs ECHO V/Q scan Barium Swallow

CT chest 6 minute walk R/LHC Serologies HLA Antibodies Neurocritical care – Acute Traumatic Brain Injury

Glasgow Coma Sale Eye opening Verbal response Motor response 1 No eye opening None None 2 Painful stimuli Incomprehensible sounds Extension to central pain 3 Verbal command Inappropriate words Withdrawal to central pain 4 Spontaneous Confused Withdrawal to pain 5 Oriented Localizing pain 6 Obeys commands *Give the best score for each category. 8 or less is severe brain injury * severe injury is GCS <8 and carries a 30% risk of death

Guidelines recommend CT head in TBI patients with GCS 14 or lower. Evolution of CT findings is common and often does change management. Don’t hesitate to repeat CT if things change or even routinely

General Management Issues in the ICU Blood pressure management • Avoid SBP <90 • For ischemia target SBP 140-180 Intracranial pressure management ICP monitoring indications: • GCS ≤ 8 AND abnormal CT with mass effect • Consider if age > 40, posturing, SBP <90

General management: Advanced management • Elevated head of bed to 30 degrees • First- consider CSF drainage if ICP >20 • Optimize neck vein drainage (loosen • Mannitol 1g/kg q4-6h- monitor serum osmolality neck brace!) • – can reduce ICP but also leads to • Avoid , reasonable to vasoconstriction- goal pCO2 30-40 track CVP • Sedation – Propofol is first line both for ICP reduction and neuroprotective effects Seizures • Incidence is ~10%, up to 30% with severe TBI • Short term ppx to reduce early seizures- 7 days of phenytoin, valproate, orkeppra Temperature management • Maintain normothermia – fever worsens outcomes • Therapeutic hypothermia (32-35 C) is not recommended outside of clinical trials Glucose management • Hyper- and hypoglycemia are bad • Hemostasis • Coagulopathy common, up to 30% • Correct medication associated coagulopathy – antiplatelet, warfarin

Hypoxia (PaO2 <60) and hypotension (SBP <90) have been found in 50 and 30% of patients, respectively, and associated with poorer neurologic outcomes (OR ~2 for both). Non-CF Bronchiectasis

Clinical Features Chronic productive cough Recurrent pulmonary infections Hemoptysis Recurrent rhinosinusitis Dyspnea Wheezing Weight loss fatigue

Differential Diagnosis Postinfectious Congenital Immunodeficiency Pseudomonas, haemophilus Primary ciliary dyskinesia Hypogammaglobulinemia Tuberculosis Alpha 1 antitrypsin HIV Aspergillus (ABPA) Trocheobronchomegaly (Mounier Kuhn) Job syndrome (HIV, measles, flu) Cartilage deficiency (Williams-Campbell) Chronic granulomatous disease Sequestration Cancer/chemotherapy Toxic inhalation/aspiration Rheumatic Other Chlorine RA IBD: UC & Crohn’s Smoke/fire SLE Young’s syndrome Heroin overdose Sjogren’s Yellow nail syndrome Foreign body/obstruction Relapsing polychondritis Constrictive bronchiolitis

Etiology by location focal Broncholithiasis Congenital bronchial atresia Endobronchial neoplasm/foreign body Mucous plugging Upper lung Cystic fibrosis Post-tuberculosis Sarcoidosis Central/upper ABPA RML MAI Immotile cilia syndrome RML syndrome Lower lung Aspiration hypogammaglobulinemia UIP with traction Alpha 1 antitrypsin (rarely)

Make that diagnosis • Bacterial and mycobacterial sputum culture • Exclude CF with sweat test (<40 is normal) • Immunoglobulins o Can also do nasal PD, semen analysis • ANA, RF, ssA/ssB • Primary ciliary dyskinesia – screen with nasal NO (low) • Bronchoscopy, GI evaluation o Carinal or nasal biopsy with electron micro

Management Pearls • DNAse- not used because trial data showed increased exacerbations and FEV1 decline • Corticosteroids- use only for ABPA • Antibiotics for exacerbation- try to base on prior culture data, cover pseudomonas, 1-2 week duration Core Conference Series: Numerical Concepts in Clinical Study Interpretation

Type I and Type II error in Clinical Trials “Truth” Clinical Benefit No Benefit

Trial “Positive” “Correct” Type I error Result “Negative” Type II error “Correct”

The “p-value” = probability of type I error—the probability of finding benefit where there is no benefit. “α” The power = 1 - probability of type II error—the probability of finding no benefit when there is benefit. “1-β” The sample size a function of the study design, effect size, and acceptable type I and type II error.

Sensitivity, Specificity, PPV, NPV, and Likelihood Ratios in Diagnostic Testing “Truth” Disease + Disease - True False “Positive” Test Positive Positive Result False True “Negative” Negative Negative

�� �� ���� = ���� = �� + �� �� + ��

�� �� ��� = ��� = �� + �� �� + ��

���� 1 − ���� ��+= ��−= 1 − ���� ����

Sensitivity, specificity, and likelihood ratios are inherent to the test; PPV and NPV depend on specificity, sensitivity, and disease prevalence

Relative Risk Difference vs. Absolute Risk Difference Absolute Number N N Relative Risk Mortality Risk Needed to Alive Dead Reduction Reduction Treat Study 1 Treatment 80 20 0.20 0.05 1-(0.20/0.25)=0.20 1/ARR=20 N=200 Control 75 25 0.25

Study 2 Treatment 980 20 0.02 0.01 1-(0.02/0.03)=0.33 1/ARR=100 N=2000 Control 975 30 0.03

Greater relative risk reduction ≠ “better” treatment! Diagnostic Testing

Example: DDimer for VTE—low risk population 1000 pts VTE Yes No DDimer Positive 56 536 592 Negative 4 404 408 60 940 1000

�� �� ���� = = ���� = = �� + �� �� + ��

�� �� ��� = = ��� = = �� + �� �� + ��

���� 1 − ���� ��+= = ��−= = 1 − ���� ����

Example: DDimer for VTE—high risk population 1000 pts VTE Yes No Positive 263 410 673 DDimer Negative 17 310 327 280 720 2000

�� �� ���� = = ���� = = �� + �� �� + ��

�� �� ��� = = ��� = = �� + �� �� + ��

���� 1 − ���� ��+= = ��−= = 1 − ���� ����

Relative vs. Absolute Risk

Absolute Number Relative Risk N Total N Dead Mortality Risk Needed to Reduction Reduction Treat Prostate Cancer Screen 72,952 214 0.0030 Screening Control 89,435 326 0.0036 Low VT Low VT 432 134 0.31 for ARDS Control 429 171 0.40

Diagnostic Testing

Example: DDimer for VTE—low risk population 1000 pts VTE Yes No DDimer Positive 56 536 592 Negative 4 404 408 60 940 1000

�� 56 �� 404 ���� = = = 0.93 ���� = = = 0.43 �� + �� 60 �� + �� 940

�� 56 �� 404 ��� = = = 0.09 ��� = = = 0.99 �� + �� 592 �� + �� 408

���� 0.93 1 − ���� 1 − 0.93 ��+= = = 1.63 ��−= = = 0.16 1 − ���� 1 − 0.43 ���� 0.43

Example: DDimer for VTE—high risk population 1000 pts VTE Yes No Positive 263 410 673 DDimer Negative 17 310 327 280 720 2000

�� 263 �� 310 ���� = = = ~0.93 ���� = = = 0.43 �� + �� 280 �� + �� 720

�� 263 �� 310 ��� = = = 0.39 ��� = = = 0.95 �� + �� 673 �� + �� 327

���� 0.93 1 − ���� 1 − 0.93 ��+= = = 1.63 ��−= = = 0.16 1 − ���� 1 − 0.43 ���� 0.43

Relative vs. Absolute Risk

Absolute Number Relative Risk N Total N Dead Mortality Risk Needed to Reduction Reduction Treat Prostate 1-(0.0030/0.0036) 1/ARR= Cancer Screen 72,952 214 0.0030 0.0006 =0.17 1667 Screening Control 89,435 326 0.0036 Low VT Low VT 432 134 0.31 0.09 1-(0.31/0.40)=0.23 1/ARR=11 for ARDS Control 429 171 0.40

Obstructive Sleep Complications of Sleep Apnea (aka: why this is important) Daytime function and cognition Daytime sleepiness, inattention, exacerbation of cognitive deficits, increased errors and accidents Motor vehicle crashes 2-3 times more common in OSA Cardiovascular HTN, PAH, CAD, heart failure, CVA • Unclear whether treatment improved mortality; see SAVE study in NEJM 2016 Metabolic syndrome Independent of obesity, OSA is a risk for incident diabetes Nonalcoholic fatty liver Again seems to be independent of obesity; 2-3 fold increase in risk Perioperative complications Respiratory failure, cardiac arrest, and ICU transfer All-cause mortality AHI >30 has a 2-3x increase; more in women; not present in untreated mild OSA

Risk factors for OSA Age Plateaus around the sixth to seventh decade Gender 2-3x more common in males; gap narrows in menopausal women Obesity This is the strongest risk; 10% increase in weight confers a 6x OSA risk Craniofacial, upper airway Short mandible, wide craniofacial base, tonsillar/ hypertrophy

Medical Conditions Associated with Increased OSA Prevalence Pregnancy Asthma, COPD, IPF CHF CVA and TIA ESRD Acromegaly Hypothyroidism Polycystic ovary syndrome

A note on screening questionnaires: not adequately tested as a screening tool for asymptomatic patients and are not recommended for diagnosis. They tend to have a high false positive rate and thus are more useful to rule out OSA when the score is low. For example, the STOP-Bang questionnaire has a sensitivity and specificity of 84 and 56% for AHI >5 and a sensitivity and specificity of 93 and 43 for AHI >15.

So for whom should I perform diagnostic testing? • Basically anyone with excessive daytime sleepiness • In the absence of excessive daytime sleepiness, if the patient snores and works in a “mission-critical” profession (airline pilots, bus drivers, truck drivers) or has two additional features of OSA • For patients who do not snore and do not have daytime sleepiness, consider testing high risk groups like PAH, resistant HTN, secondary polycythemia.

Diagnosis – need one of the following two conditions: 1. Five or more obstructive events (, , or respiratory effort related arousals) per hour of sleep with one or more of: sleepiness, gasping or , , comorbidity (HTN, mood, CAD, CVA, CHF, AFib, DM II) 2. 15 of more obstructive events per hour of sleep regardless of symptoms or comorbidities

Differential –These are other conditions that cause excessive daytime sleepiness Periodic limb movements Jerks in arms and legs fragment sleep Shift workers These workers get 7 hours per week less sleep than non-shift workers Narcolepsy Daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis Upper airway resistance Considered a type of OSA, not many apneas of hypopneas, rather syndrome respiratory effort related arousals; common in thin women with craniofacial abnormalities Central sleep apnea No respiratory effort Primary snoring Most patients who snore do not have OSA GERD Can causes choking and dyspnea and may actually improve with NIV! Occupational Lung Disease – inhalation of crystalline silica in quartz, granite, sandstone – the most widespread pneumoconiosis in the US – occupations include mining, quarrying, drilling, sandblasting • Simple Silicosis – upper lobe, small rounded opacities, centrilobular and perilymphatic nodules • Complicated Silicosis – confluence of silicotic nodules into large opacities – this evolves into progressive massive fibrosis – “angel wing” appearance • 10% of silicosis will have UIP fibrosis • Hilar and mediastinal adenopathy is common - Calcium salt deposits lead to eggshell calcification • Tuberculosis is found in 25% due to toxic effect of silica on alveolar macrophages • Acute silicosis – usually in sandblasters – looks like alveolar proteinosis on imaging with ground glass and crazy paving • Erasmus syndrome – association of occupational silica exposure with development of scleroderma

Coal worker’s pneumoconiosis – silica free coal dust particles that reach the alveoli – looks similar to silicosis but the pathology is distinct. • Upper lobe small, rounded, opacities, that can develop into progressive massive fibrosis • 10-40% with UIP fibrosis and honeycombing – associated with bronchogenic carcinoma • Caplan syndrome – coal worker pneumoconiosis with rheumatoid arthritis

Talcosis– exposure to ceramic, paper, plastics, rubber, paint, cosmetics • Similar appearance to silicosis – upper lobe opacities, bases are spared • Often contaminated with amphibole asbestos fibers – will get pleural plaques • Don’t confuse with talc granulomatosis which is from crushing and injecting pills

Hard Metal Pneumoconiosis – produced by compacting tungsten carbide with cobalt called sintering. • Manifested by interstitial fibrosis and asthma, sometimes obliterative bronchiolitis • Pathology is alveolar macrophages and multinucleated giant cells – giant cell pneumonia

Asbestos-related diseases – primary exposure in mining and milling, secondary exposure with insulation, brakes, shipbuilding, construction, textiles • Pleural plaques – most common manifestation, usually on parietal and diaphragmatic pleura; rarely associated with restrictive physiology • Benign asbestos – 10-12 years after exposure, exudative and unilateral • Diffuse pleural thickening – starts unilateral in the base and progresses to bilateral; can lead to pleurogenic fibrosis or retractile pleuritic with restrictive physiology • Malignant mesothelioma- latent period of 30-45 years; pleural thickening > 1cm • Asbestosis – lower lobe fibrosis, think septal lines; seen in up to 1/3 of exposed patients • Bronchogenic carcinoma – usually lower lobe adenocarcinoma, also consider rounded

Berylliosis – granulomatous lung disease; beryllium is a lightweight metal used in dental, computer, nuclear weapons, nuclear reactor , and aerospace industries • Imaging: early is ground glass, later is perilymphatic small nodules, mediastinal adenopathy in 25% • Pathology looks like sarcoidosis with noncaseating granuloma • Acute looks like noncardiogenic pulmonary edema

Hypersensitivity pneumonitis – inhalation and sensitization to agricultural dusts, bioaerosols, microorganisms, or reactive chemicals • 34% birds; 21% hot tub (mycobacteria); 11% farmer lung (actinomycetes); 25% no cause identified • Imaging hallmark is centrilobular ground glass nodules; mosaic attenuation, bases usually spared • Chronic hypersensitivity – fibrosis tends to start lower and progress to upper regions, endstage is severe upper lobe scarring and distortion.

Noxious Fumes – nitric acid, sulfur dioxide, chlorine gas, ammonia, phosgene • Acute lung injury, noncardiogenic pulmonary edema, asthma, delayed-onset obliterative bronchiolitis Palliative Care in the Intensive Care Unit

Four Parts to a Family Meeting Words and phrases to try 1. Get what they family knows • “What have you heard? What have other doctors and • Gets you on the same page nurses been telling you?” • lets you know whether or not they already know the • “What have you talked about with your family?” bad news • “What have you read online?” • Follow up with “Has anyone talked with you about what the future may look like?” 2. Deliver the headline • “I’m worried that…” • The headline is a succinct, clear message- usually this • “She will always require someone to take care of her- is the bad news to bath her, feed her. She will not be able to walk, • When there is uncertainty, acknowledge it and then will spend most of her time in the bed” say what you can- put in terms of ADLs • “He will likely require machines for the rest of his life” 3. Expect and attend to emotion • Name- “I’ll bet you are feeling scared and helpless • Emotion is good, it lets you know the family heard right now. This is all so sudden.” your headline. • Understand- “I can’t imagine what it like seeing your • Remember your NURSE statements dad like this.” • Respect- “You have done such a great job caring for your mom.” • Support- “We will be here with you through the whole process” • Explore – “Tell me more about that.” 4. Make a recommendation • “If your dad could sit here with us, what do you think • The family is the expert in the patient, their lived he would say about all this?” experience, and their values • “Has he ever thought about being really sick or filled • You are the medical expert and the family wants your out a living will.” medical recommendation on what makes sense • “Given everything you’ve told me about your mom, I think we should…”

Communicating Prognostic Uncertainty • Even when surrogates rate communication highly, they are often inaccurate about prognosis • Families have a perceived need to remain optimistic and that’s ok • Uncertainty is bet dealt with by acknowledging the uncertainty and still giving what you think the future will look like • “Hope for the best and plan for the worst”

Conflict • Conflict over life-sustaining therapies in the ICU is exceedingly common – over 50% in most studies • Recognize conflict early and then ask yourself 3 questions: 1. What is their story – Why is this loving family member saying something that does not make sense 2. What is our common ground – This is usually the patient. Refocus the conversation on the patient 3. How can we work together • Give them some time – more than half the time withdrawal takes more than a day and “stuttered” withdrawal is associated with increased satisfaction • Propose a time limited trial – be clear on how long and how we know if it is working

If conflict persists, consider a palliative care consult – it can be very helpful to have a skilled, impartial third party Diagnostics

Light’s Criteria Two-test rule Three-test rule Pleural protein:serum protein > 0.5 Pleural cholesterol > 45 Pleural fluid protein > 2.9 Pleural LDH:serum LDH >0.6 Pleural LDH > 0.45 upper limit Pleural cholesterol > 45 Pleural LDH > 2/3 upper limit Pleural LDH > 0.45 upper limit

Some basic cutoffs Tuberculous effusion protein is > 4.0 Cholesterol >250 is chyliform, LDH > 1000 – empyema, rheumatoid longstanding effusion Protein > 7 – think multiple myeloma TAG > 110 is a PJP has LDH ratio >1; very low protein Very low glucose (less than 60) rheumatoid Esophageal rupture Empyema Malignant Lupus Tuberculous

Some more obscure pleural fluid tests Urinothorax – pleural: serum creatinine >1 (usually 1.7) Peritoneal dialysis – pleural:serum glucose >1 – pleural:blood hematocrit >0.5 CSF – beta-2 transferrin

Pleural eosinophilia Pneumothorax (including catamenial) Hemothorax Pulmonary infarction Benign asbestos effusion Parasitic disease Fungal – coccidio, crypto, histo Malignancy (absence of eos does not rule out) Drugs

Always Atelectasis Due to increased negative intrapleural pressure CSF leak Surgery, trauma, ventriculopleural shunts Heart failure Diuresis may make this appear exudative On the right, should have ascites as well Hypoalbuminemia Rare Nephrotic Bilateral and subpulmonic Peritoneal dialysis Acute and large 48 hours after initiating dialysis Urinothorax Ipsilateral obstructive uropathy, i.e., a stone

Some selected (there are a lot…) Infectious Pneumonia, Tb, hepatic and splenic abscess/infarction, hepatitis, esophageal rupture Iatrogenic CVC migration (s/p Fontain), drug-related, RFA of lung nodules Malignancy Carcinoma, Mesthelioma, Leukemia, Mult. Myeloma and Waldenstrom’s CTD SLE, RA, MCTD, EGPA, GPA, FMF Endocrine Hypothyroidism, ovarian hyperstimulation Lymphatic Malignancy, chylothorax, yellow nail syndrome, LAM, lymphangiectasia Abdominal Pancreatitis, Meigs’ syndrome, Malignant ascites, Subphrenic abscess, Other Trapped lung, benign asbestos effusion, PE, Radiation therapy, Sarcoidosis, post cardiac injury

When you still do not have a diagnosis: 1. Revisit the history with special attention to drugs, exposures, PE, Tb, and comorbidities 2. Time course helps – some last for weeks to months (parapneumonia, Tb, postcardiac injurt) and others last for years or forever (yellow nail, lymphangectasia, trapped lung, malignancy) 3. Consider trapped lung with history of pneumonia, pneumothorax, surgery, hemothorax, RA, Tb, malignancy 4. If still unsure- get a CT (PET has an emerging role here) and consider pleural biopsy Pneumonia

Pneumonia is a clinical diagnosis: fever, dyspnea, sputum production. Airspace opacities on CXR can be a lot of things (as you know) and some studies say CXR has a 30% false negative rate compared with CT.

Some fun facts on culture data in pneumonia: • Sputum cultures positive in ~60% (as long as sputum • Blood cultures positive in only 16% is adequate. 60% of these are strep • Urine strep antigen positive in 50% of those with • Bronchoscopy helpful in about 50% of confirmed Strep pneumoniae patient who do not make sputum. Again… pneumonia is a clinical diagnosis.

So what’s up with procalcitonin? You will probably get a question about this on your boards. Know that in a Cochrane meta-analysis use of procalcitonin decreased antibiotic exposure from 8 to 4 days without increase in mortality. Low level supports viral or non-bacterial etiology. Use is not guideline supported however..

Risk Stratification. There are a number of tools out there. You should know the PSI and CURB-65. PSI is the gold standard however it’s complicated and needs a calculator. CURB 65 30 day Mortality C - Confusion 1 = 0.7% U – Urea (BUN >20) 2 = 2% R – respiratory rate >30 3 = 9% B – blood pressure, systolic <90, diastolic <60 4 = 15% Age > 65 years 5 = 40% Score of 3 or higher usually merits ICU admission.

Treatment. Note here that treatments are highly influenced by local resistance patterns and the dementia of local antibiotic stewardship programs. In general go for: Ceftriaxone P Azithromcyin O Levofloxacin Cefotaxime L clarithromycin R moxifloxacin Ceftaroline U Ertapenem S Amp-Sulbactam

A note on tigecycline because it may be on your boards. Tigecycline has a black box warning for increased mortality with hospital acquired pneumonia, in particular ventilator associated pneumonia. So only use it if fluoroquinolone or beta-lactam is not an option.

Concern for multidrug resistant Pseudomonas or other MDR GNRs – like CF, bronchiectasis, severe COPD- it is not unreasonable to double up with something like pip/tazo + levofloxacin. Just know that there is absolutely no data to support this practice.

What about steroids? It’s kind of controversial but a recent meta-analysis showed a modest mortality benefit in hospitalized patients with more severe pneumonia. If you’re going to do it, pick more severely ill patients, be wary of those that may have or Aspergillus, and make a note of risks for adverse events like GI bleeding, neuropsychiatric illness, immunocompromised patients, and pregnant women.

And finally, a note about treatment duration. A meta-analysis of 15 RCTs showed no difference in less than 7 days versus more than 7 days. In fact, in the more than 7 days group there was a signal of harm with increased antibiotic side effects. So, less is more people. Give patients 72 hours to respond to your therapy and if they do, you can stop after another couple of days.

HCAP does not exist anymore because there is no data that nursing home residence, hemodialysis, etc increases the risk for MRSA and Pseudomonas pneumonia. The 2016 HAP/VAP guidelines are on your website for you but are mostly expert consensus-type recommendations. Preoperative Pulmonary Evaluation Postoperative pulmonary complications are the most costly of major postoperative medical complications and result in the longest length of stay.

Significant complications that adversely affect the clinical outcome Atelectasis Hypoxemia Infection Exacerbation of COPD or asthma Respiratory failure (mechanical ventilation >48 hours after surgery or unplanned reintubation) The rate of postop pulmonary complications across all surgery was 6.8 % in one systematic review

Patient-related risk factors • Age – independent risk factor for every decade over 50; even healthy older adults have post-op pulmonary risk (unlike cardiac surgery) • COPD – OR 2.4 for all complications; no absolutely prohibitive level of pulmonary function, most severe obstruction surgical mortality is 5-6%; must weigh against risks and benefits of surgery • Smoking – RR 1.7, risk is greater with more than 20 pack years, risk decreases with at least 4 weeks of smoking cessation • OSA – many patients preparing for surgery have undiagnosed sleep apnea and should be screened • Pulmonary hypertension – even mild and moderate and regardless of etiology; i.e., hip replacement mortality OR is 3.7 • Heart Failure – OR is about 3 • ASA class >2 has OR of 4.8 for pulmonary complications (that’s “severe systemic disease” or worse)

Asthma and obesity are not risk factors for post-op pulmonary complications

Procedure-related risk factors • Surgical site is most important and inversely related to distance from diaphragm – upper abdominal OR is 20 and lower abdominal OR is 8. (An exception is laparoscopic cholecystectomy.) • Duration – less than 2 hours has 8% complication rate while greater than 4 hours has a 40% rate • Anesthesia – this is controversial but existing data suggests lower risk with regional anesthesia compared with general. One large systematic review showed 40% decrease in pneumonia and 60% decrease in post- op respiratory depression with epidural or spinal vs general

Preoperative risk assessment • Most important is a history and physical with particular attention to the above factors • If concerned for sleep apnea, administer the 4 question STOP questionnaire • Candidates for lung resection should have preoperative PFTs; sometimes a quantitative VQ scan

Pulmonary Function Testing should not be part of routine preoperative testing, including abdominal and other high risk surgery with the exception of lung resection. Get PFTs if it will change preoperative management. For example, if the patient has COPD and you are not sure if they are at baseline. If the patient has unexplained dyspnea and could have heart or lung disease or deconditioning.

Other routine testing that does not help • ABG – the exception is a pCO2 >45, but this risk is not prohibitive and you should already know about it • CXR – very unlikely you will find anything that will change preoperative management

CPET is helpful in two settings: 1. Patients with abnormal PFTs to assess the safety of lung resection 2. Unexplained dyspnea in non-cardiopulmonary surgery – can predict survival and overall complication rate. Distance on a 6 minute walk gives comparable numbers.

There are several postoperative pulmonary risk calculators out there. I like the Arozullah respiratory failure index because it predicts the incidence of postoperative respiratory failure, which is what we mostly care about. (Arozulla AM, et al. Ann Surg 2000; 232:242 – This article among others is on your website)

Here is a different calculator that is online and easier to use (this is from the CHEST paper on the website): https://www.qxmd.com/calculate/calculator_261/postoperative-respiratory-failure-risk-calculator

Courtesy of Dr. Rivera-Lebron

PULMONARY EMBOLISM

Epidemiology • 90% achieve complete resolution • 30% recurrence within 10 yrs • 4-5% of acute PE develop CTEPH

Diagnosis • Use clinical decision rues (Wells or Geneva) to categorize patients into a pre-test probability: PE Likely or PE Unlikely. PE likely gets at CTA. PE unlikely then gets PE rule out criteria (PERC rule). If PERC neg, nothing else to do. If PERC positive, then do D- dimer. • CTA is gold standard for diagnosis • Echo is complementary and provides prognostic info • BNP and Trop are useful for prognostic info

Classification High risk (Massive) = hemodynamic compromise (SBP < 90 for > 15 min) Intermediate risk (Submassive) = HD stable but signs of RV strain by CT, Echo or biomarkers Low risk = no HD compromise or RV strain

Treatment • NOAC is AC of choice for VTE w/o cancer • Lovenox if AC of choice for VTE w cancer • Duration of AC for Provoked PE is 3 mo • Duration of AC for Unprovoked PE is indefinite (until risk of bleeding is > risk of recurrence) • Low risk PE, with no major comorbidities or contraindications to AC, good compliance can be treated out of the hospital • Single Subsegmental PE, without DVT, asymptomatic and low risk of recurrence does not need to be AC • Systemic tpa only indicated in High risk (massive) • Catheter-directed tpa reverses RV strain quickly, but no mortality benefit reported yet • IVC Filter only indicated in patients unable to tolerate AC Pulmonary Function Testing Interpretation

Clinical Presentation Recommended Testing Dyspnea • Spirometry before/after bronchodilator, volumes, DLCO • Ambulatory pulse oximetry Cough • Spirometry before/after bronchodilator • Consider Methacholine challenge Asthma • Spirometry before/after bronchodilator • Consider Methacholine challenge COPD • Spirometry before/after bronchodilator, oximetry • Consider lung volumes and DLCO in initial evaluation Suspected ILD • Spirometry, volumes, DLCO, oximetry Neuromuscular disease, diaphragmatic weakness • Upright spirometry, volumes • Max inspiratory and expiratory force

For initial, diagnostic PFTS, ask the patient to hold their bronchodilators so that bronchodilator response can be assessed. Hold short acting for 4 hours and long acting for 12 hours.

Lung Volumes and Capacities

Spirometry: forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and their ration (FEV1/FVC). • Normal ratio is >70; other normal are >80% of predicted in general • Supine spirometry to evaluate diaphragm dysfunction: supine decrease in VC by 25% unilateral and 50% bilateral Post-Bronchodilator: significant with increase in FEV1 more than 12% and 0.2 liters Lung Volumes: vital capacity (VC), functional residual capacity (FRC)- this is the end of a tidal breath, residual volume (RV), expiratory reserve volume (ERV), inspiratory capacity (IC), total lung capacity (TLC) • Decreased vital capacity alone may be due to air trapping in severe obstruction. You can see air trapping when the FRC or RV is increased >120% DLCO: Restriction, Reduced DLCO Obstruction, Reduced DLCO Isolated decrease in DLCO Intrinsic disease: ILD, fibrosis Emphysema Pulmonary vascular disease, PAH, Extrinsic restriction, i.e., obesity, Normal in other obstructive disease CTEPH DLCO is normal or slightly reduced Maximal Inspiratory Pressures: MIP and MEP- used to follow patients with neuromuscular disease • Neuromuscular disease pattern: increased RV, normal FRC, low MIP and MEP, low MVV

Obstructive and Restrictive Flow Volume Loops

In obstructive disease, forced expiratory volume in the first second is decreased (FEV1). Expiratory flow in the latter two-thirds of expiration are effort independent and vary directly with elastic recoil of the lung and inversely with airway resistance. In COPD elastic recoil is decreased due to loss of lung parenchyma and airway resistance is increased due to secretions, bronchospasm, or loss of small airways.

Upper Flow Volume Loops

B: intra- and extra-thoracic masses, adenopathy, fixed airway stenosis C: , tracheomalacia, vocal cord abnormalities, i.e., paradoxical vocal fold motion D: introthoracic tracheomalacia, bronchogenic cysts, tracheal masses, i.e., malignancy

Approach to pulmonary function test interpretation

Spirometry

Normal ratio Low ratio: Normal ratio Obstruction Low FVC: Restriction Clinical asthma/ chronic cough? Bronchodilator Confirm with lung volumes Negative: COPD Positive: Check for reduced FEF 25-75% vs asthma asthma Methacholine challenge DLCO DLCO Isolated DLCO Low: Normal: Low: Normal: decrease: pulm ILD extrinsic – emphysema asthma/COPD vascular disease obesity, NMD Pulmonary Hypertension

Pretest Probability Assessment via Echocardiography (some numbers are rounded for ease of use) Probability ESC/ERS 2015 guidelines recommend TRV Older 2009 guidelines and ISHLT use PASP of PH Low TRV < 2.8 m/s PASP <35 and TRV <2.8 Medium TRV ~ 3 – 3.5 m/s PASP and TRV and in-between low and high + other PH signs on echo High TRV~3 – 3.5 with other PH signs on echo PASP > 50 and TRV > 3.5 TRV > 3.5 m/s What are “other signs of PH on echo” ? • RV:LV basal diameter ratio > 1.0, flattening of the septum • PA diameter > 25 • IVC > 21 mm with decreased inspiratory collapse

Who to screen for pulmonary hypertension – high risk groups Systemic sclerosis Congenital heart disease HIV HHT, family history of HHT, other heritable etiologies Portopulmonary hypertension Sickle cell disease

If you have a medium to high risk of pulmonary hypertension on echocardiography 1. Determine if there is left heart disease sufficient to explain the pulmonary hypertension 2. If there is no left heart disease or insufficient left heart disease, consider the following work up: • Chronic lung disease evaluation with PFTs, CT chest, 6 minute walk; overnight oximetry/PSG if needed • Venous thromboembolism evaluation with VQ scan; rare cases may require angiography 3. Consider HIV and serologic testing 4. If one of these etiologies is identified, you do not necessarily need a RHC but it may be indicated, especially in mixed disease or to assess for treatment effect

Primary Therapy for Pulmonary Hypertension (AKA – treat the underlying disease) • In all patients, consider the following: diuretics, oxygen, anticoagulation, digoxin (particularly in group 3 with COPD and biventricular failure), exercise • Anticoagulation seems beneficial in idiopathic PAH, not in CTD-associated PAH (Khan MS, et al. Circulation. 2018; 11) A special note on oxygen in Group 3 PH – the only modality with proved mortality benefit • PaO2 < 60 on oxygen for 15 hrs/day - decreased 5 year mortality but only after 500 days of therapy (lancet 1981) • NOTT showed improved 3 year mortality in continuous oxygen vs nocturnal oxygen (Ann Int Med 1980)

Broad Review of Drug Therapies – This is mostly for Group 1 PAH Calcium channel blockers – use for those who are vasoreactive on RHC (mean PAP decreases at least 10 and to a value less than 40 mmHg). Nifedipine has been shown to increase 5 year survival (Rich S, et al. NEJM 1992) Prostacyclin agonists – epoprostenol, treprostinil, selexipag • Epoprostenol improves hemodynamics, functional capacity and survival in idiopathic PAH, but no known survival benefit in other types of Group 1 - Consider for idiopathic, CTD, , HIV, congenital heart disease Endothelin receptor antagonists – bosentan, macitentan, ambrisentan - improved exercise capacity, dyspnea, and hemodynamics (not survival); adverse effects are hepatotoxicity and peripheral edema • Note: ambrisentan is associated with disease progression and hospitalizations in patients with IPF PDE5 inhibitors – sildenafil, tadalafil, vardenafil – improves functional class for group 1, no role in lung disease, benefit in left heart disease “unclear” according to Cochrane review 2019 Guanylate cyclase stimulant – riociguat – benefit in inoperable CTEPH, maybe benefit in group 1 (Ghofrani HA. NEM 2013)

Combination therapy with tadalafil plus ambristentan shows decreased hospitalizations and increased exercise capacity (Galie N. NEJM 2015) Pulmonary Rehabilitation

Benefits – What you can tell your patients they will get out of pulmonary rehabilitation: Mortality- meta-analysis suggests decreased mortality in patients receiving rehab after COPD exacerbation Exercise capacity- meta-analysis 65 RCTs shows improved capacity compared with community-based care Quality of life – same meta-analysis shows improvement based on chronic respiratory questionnaire Health care utilization- uncontrolled studies suggest decrease in hospital stay by 23 days/year/patient; other controlled studies are less clear, showing little to no decrease Comorbidities – preexisting functional disability and osteoporosis result in poorer outcomes from rehab; CAD did not adversely affect likelihood of improved exercise tolerance and quality of life Frailty. In one study, those who met criteria for frailty found that pulmonary rehabilitation experienced reduced dyspnea, improved exercise performance, and most no longer met frailty criteria. **These benefits decline over time and the degree of improvement tends to decrease with successive programs.

Main indication for pulmonary rehabilitation is COPD with GOLD category B (FEV1 >50%), C (FEV1 <50%), and D (more symptoms with COPD assessment test score >10).

What about other lung diseases? Interstitial lung disease- increased exercise tolerance, decreased dyspnea, improved QOL, but less than in COPD Bronchiectasis- improved walk distance and fewer exacerbations Cystic fibrosis – consider infection control issues Asthma- pre-exercise bronchodilators may reduce exercise-induced bronchoconstriction Pulmonary hypertension- concern for syncope and sudden death; submaximal exercise appears safe

Exercise capacity measurements • 6 minute walk – mean improvement in 6 min walk after pulmonary rehab is 107 meters. • Shuttle walk (patient walks back and forth between two cones) – mean improvement is 81 meters • CPET- when dyspnea etiology is unclear- can determine intensity of training workload to target

Components of Pulmonary Rehabilitation Endurance training- the most common- benefits thought to be due to true training effect with skeletal muscle adaptation, reduction in lactic acidosis and ventilation • Arm or leg ergometer for 20-30 min at 60% of max work rate; usually associated with Borg score of 4-6 • Most evidence is for lower extremity exercise; upper extremity exercise is derived from leg training data Interval training- better tolerated than continuous with greater adherence to the program and similar improvements Strength training- lower oxygen consumption and MV with less dyspnea; seems additive to endurance training Benefits of breathing retraining such as yoga and diaphragmatic breathing, ventilator muscle training, transcutaneous neuromuscular electrical stimulation, Tai Chi, flexibility training are being studied and have less clear benefits Education – smoking cessation, oxygen therapy, nutrition, physical activity, medications, health maintenance (vaccines) • Education is not an effective substitute for exercise training- in multiple trials education alone is same as control Advance care planning is an accepted component of pulmonary rehabilitation Psychological Support- one trial showed improved depression scores independent of changes in QOL and dyspnea

Maintenance Programs- one multicenter trial of 143 patients with COPD showed marginal but significant differences between the maintenance and control groups in BODE index and six-minute walk distance up to two years, but the benefit vanished after that time. No mortality difference over 3 years.

Pulmonary Vasculitis A number of vasculitic processes can involve the lungs, we are mostly dealing with GPA/Wegner’s, microscopic polyangitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss).

Granulomatous with Polyangiitis (GPA, Wegner’s) – small vessel vasculitis Extra-Pulmonary Organ Involvement Joints- myalgias, arthralgias, arthritis Nervous system – mononeuritis, cranial neuropathies, hearing loss, tinnitus, opthalmoplegia Eyes – conjunctivitis, episcleritis, uveitis Cardiac – pericarditis, myocarditis, conduction system Skin – vesicular, purpura; subcutaneous nodules Also- GI, GU, parotid, thyroid, liver, breast

Pulmonary Manifestations Chronic rhinosinusitis – pain; purulent, bloody discharge; hearing loss, nasal perforation • May be present without other manifestations for weeks, months before progressing to vasculitic disease • Key difference vs EGPA is that EGPA has nasal polyposis and is less likely to have nasal perforation Tracheobronchial disease –stenosis, inflammatory pseudotumors, malacia, TE fistula • Subglottic stenosis in up to 50%- may be the sole manifestation and require tracheostomy Pulmonary nodules – cavitation in 25-50% Interstitial disease – fibrosis and honeycombing – commonly a UIP pattern; ILD most common with MPA Alveolar hemorrhage – presenting ~25%, commonly associated skin, renal, and neurologic involvement Pulmonary artery stenosis – rarely, seen on CTA, PA pressures may not be elevated

Over 90% of GPA or MPA with lung and renal involvement are cANCA (PR3) positive. Minority will have pANCA (MPO). Persistently elevated ANCA is associated with relapse.

Biopsy is important because need to exclude infection and metastatic disease affecting the lung • In general you want a surgical lung biopsy – not recommended in DAH or ILD. • Nasal and sinus biopsies are very low yield- usually do not show vasculitis

Treatment Induction: usually cyclophosphamide (more Maintenance: usually azathioprine or rituximab, experience) or rituximab (less toxicity); for mild again- if no renal disease may try MTX disease without renal involvement- may try MTX

Eosinophilic Granulomatosis with Polyangitis (EGPA, Churg-Strauss) Three Phases of disease: • Prodromal – atopy, , asthma • Eosinophilic – peripheral eosinophilia, eosinophilic infiltration of lung and GI tract in particular; this is the triad of pulmonary opacities, asthma, and eosinophilia that presents prior to systemic vasculitis (true ~40%) • Vasculitic – medium and small vessels; associated with constitutional symptoms

EGPA Clinical Manifestations Asthma – in 90% and precedes vasculitis by 8-10 years Neurologic – usually mononeuritis – up to 75% Upper Airway – nasal polyposis; looks like aspirin Renal – common, biopsy shows necrotizing exacerbated glomerulonephritis Skin –subcutaneous nodules on extensor surfaces, GI – abdominal pain, bleeding, diarrhea- may biopsy shows granulomas precede vasculitis Cardiac – due to high eosinophilic infiltration Myalgias and arthritis are less common Increased thromboembolic risk Eosinophilic lymphadenopathy in ~40%

EGPA Diagnostic Criteria: need 4 or more of the following (sensitivity 85%, specificity 99%) Asthma Migratory or transient pulmonary opacities >10% eosinophils Paranasal sinus abnormality Mononeuropathy or polyneuropathy Biopsy showing extravascular accumulation of eosinophils Sarcoidosis

There are three forms of sarcoidosis to consider: 1. Spontaneous remission- clinically inactive and usually requires no treatment 2. Transiently or chronically active disease- treatment to prevent granulomas and organ damage 3. Relapsing and remitting- treatment to prevent disease relapses. We often fail to recognize this form and it is this form that often insidiously progresses and leads to end organ damage.

Sarcoidosis organ involvement (can affect any organ) Lung 95% Erythema nodosum 8% Skin 16% Spleen 6% Lymph node 15% Neurologic 5% Eye & liver 11% Cardiac 2% (prob underestimated)

A word about ACE level: ACE level is useful for following disease activity. However, it has poor sensitivity and insufficient specific (almost 10% false positives; diabetes has a high ACE), thus is not used for diagnosis.

I need a biopsy I don’t need a biopsy Biopsy the most accessible lesions- skin, nodes, certain Stage I asymptomatic disease, just monitor ocular lesions Next choice is lung parenchyma (transbronchial yield Classic Lofgren’s- fever, EN, arthralgias, bilateral ~75%%) and/or intrathoracic nodes (EBUS) hilar adenopathy Exclude other noncaseating granulomatous disease, i.e. fungal and mycobacterial, before calling sarcoidosis and treating as such. Don’t be the guy who gives steroids to histoplasmosis.

Triad of CD4:CD8 >4, lymphs >16%, TBBx with noncaseating granuloma has 100% PPV for sarcoid vs other ILD and 80% PPV for sarcoid vs all other disease

Corticosteroids for Sarcoidosis Pros Cons Rapid improvement in symptoms Toxicity limits long term dosing Short term radiographic improvement Dose required for chronic disease is too high Effective in most organs Dose too high to prevent relapsing-remitting disease

Methotrexate for sarcoidosis Pros Cons Clinical trial data showing efficacy as a steroid- Slow onset of action- may take 2-6 months for full effect sparing agent Relatively low doses control inflammation and Variable oral bioavailability prevent relapses Well-tolerated Very rare side effect of hypersensitivity pneumonitis within 6 weeks on starting Effective in most organ systems (?CNS and Liver toxicity rarely develops after cumulative dose of 3 liver) grams (which is about 2-3 years)

Antimetabolite, steroid-sparing therapy for sarcoidosis Level of evidence Common toxicity Rare toxicity Methotrexate Double blind, placebo Nausea, leukopenia, Pneumonitis, teratogenic controlled trials hepatotoxicity, “washed out” feeling Azathioprine Case series and Leukopenia, nausea Hepatotoxicity, reports pancreatitis, skin cancer Leuflunomide Double blind, placebo Leukopenia, hepatotoxic, Pneumonitis, teratogenic, controlled trials alopecia neuropathy Mycophenolate Case series Nausea, diarrhea Skin cancer Core Conference: Sepsis Update

List of the Strong Recommendations based on Moderate/High Quality Evidence in SSC Guidelines 2016 Antibiotics Antibiotics ASAP and within 1 hour for sepsis and septic shock Empiric broad-spectrum antimicrobials to cover all likely pathogens AGAINST routine combination therapy (i.e. 2 GNR agents) in neutropenic sepsis/bacteremia Volume Crystalloids as resuscitation fluid of choice (rather than colloids) Expansion AGAINST use of hydroxyethyl starches Use transfusion threshold of Hgb <7.0 in absence of AMI, severe hypoxemia, hemorrhage AGAINST use of EPO for anemia AGAINST use of AT-III Vasopressors Target MAP>65 with vasopressors if needed Norepinephrine as vasopressor of choice AGAINST low dose dopamine for renal protection Mechanical Lung protective ventilation: Vt 6cc/kg, Pplat <30 Ventilation and Prone positioning for P:F<150 Sepsis-induced AGAINST high-frequency oscillatory ventilation ARDS Conservative fluid management in absence of tissue hypoperfusion AGAINST B-agonists in absence of bronchospasm AGAINST routine use of PA catheters Use a weaning protocol including daily SBTs Glucose Protocol with target <=180 Control DVT PPX Use something, and LMWH>UFH unless contraindicated Nutrition AGAINST early TPN where enteral feeding possible or before 7 days AGAINST IV selenium or glutamine Goals of Care Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate

Beyond the Guidelines

Diagnosis -What’s in a name?: Sepsis-3 vs. “good old SIRS”; what do we do without a gold standard?

Treatment -Protocolized sepsis resuscitation: -The trials: PROCESS, PROMISE, ARISE: “failure” of the bundle or improvement in usual care? -The meta-analysis: PRISM: protocolized care increased costs without improving outcomes

-Real-world impact of care protocols: Rory’s Regulations in NY State: antibiotics help, but what about fluids?

-The Federal Government enters the fray: The SEP-1 Bundle

-How much fluid should I give?: Enough but not too much!

-The Magic Bullet?: Hydrocortisone/VitaminC/Thiamine

Epidemiology -Long-term outcomes: among previously independent patients with severe sepsis, 1/3 die; of the survivors, 1/3 are not independent at 6 months -Major driver of readmissions Approach to Shock 1. Airway, breathing, circulation – establish airway, IV access, send some labs, start with an IVF bolus 2. Perform targeted history, physical, bedside US 3. Perform life-saving intervention if needed 4. Support hemodynamics with continued IVF and/or vasopressors

Classification of Shock Cardiogenic Cardiomyopathy Arrthythmogenic Mechanical • MI • Atrial and ventricular • Valvular insufficiency (severe) • CHF exacerbation tachyarrhythmias • Valve/chordae rupture • Cardiomyopathy of sepsis • Bradyarrhythmias – heart block • Septal wall defect • Myocarditis • Atrial myxoma • Drugs (BB) • Free wall rupture Obstructive Pulmonary Vascular Mechanical • PE with RV strain • Tension pneumothorax • Severe PAH • Hemothorax • Pulmonic or tricuspid valve obstruction • Tamponade • Air embolism • Constrictive pericarditis • Restrictive cardiomyopathy • Intrinsic PEEP • Abdominal compartment syndrome Distributive – Septic vs non-septic Non-septic • Inflammatory – burns, pancreatitis, post-bypass, post-arrest, amniotic and fat embolism • Neurogenic – brain injury, spinal cord injury, neuro-axial anesthesia • Anaphylactic – allergic reaction (food, meds, insect bite), exercise or heat induced • Other – adrenal insufficiency, thyrotoxicosis, myxedema coma, heavy metal poisoning, toxic shock syndrome Hypovolemic – hemorrhagic vs non-hemorrhagic Non-hemorrhagic • GI losses – vomiting, diarrhea • Skin losses – heat stroke, burns • Renal losses – diuretics, salt-wasting nephropathy, hypoaldosteronism • Third space losses – postop, intestinal obstruction, pancreatitis, cirrhosis

Shock Type Cardiac output PCWP Hypovolemic ↓ ↓ Cardiogenic ↓ ↑ Obstructive ↓ Normal or ↑ Distributive ↑ ↓ or normal

Fluids and Pressors • A good fluid bolus is about 30 cc/kg – then check for response (exam and hemodynamic changes) • First line pressor = norepinephrine (alpha 1>beta 1) • Second line: Epinephrine (beta 1>beta 2>alpha 1)- God’s own catecholamine! • Add to NE: Vasopressin (AVP analog; may upregulate beta 1 receptors) • Phenylephrine AKA water (alpha 1)- use when tachyarrhythmias are a problem • Dopamine (dose dependent effects: 5 mg = dopa, 10 mg = beta 1, 15 mg = alpha 1) • Dobutamine (beta 2 then beta 1)- probably will need NE underneath to offset fall in peripheral vascular resistance

Toxicology

Airway Tips • When intubating- use rocuronium. Do not use succinylcholine in case of cholinergic toxicity • In salicylate poisoning, avoid intubation. The hyperventilation is beneficial and difficulty to replicate. • If a patient is compensating for a metabolic acidosis, i.e., toxic alcohol, and begin to tire or have a seemingly normal pCO2, then intubate.

Toxidrome Exam Pupils Discerning Examples Features Sympathomimetic Hyperalert, Dilated Wide pulse Cocaine, amphetamines, ephedrine, hallucinations, pressure, caffeine, theophylline hyperthermia, hyperreflexia, seiure tachycardia Anticholinergic Agitation, Dilated Dry skin and Antihistamines, TCA, Parkinson hallucinations, mucous meds, phenothiazines delirium, fever, membranes, (chlorpromazine, Compazine) tachycardia, flushing, urinary hypertension retention, picking Hallucinogenic Hallucinations, Dilated Nystagmus PCP, LSD, psilocybin, MDMA agitation, synesthesia, fever, tachycardia Opioid CNS depression, Constricted Pulmonary edema, Heroin, fentanyl, methadone apnea, bradycardia track marks Sedative Confusion, stupor, Varies BZD, barbiturates, alcohols, coma zolpidem Cholinergic Confusion, coma, Constricted Salivation, Pesticides (organophosphates), bradycardia, diaphoresis, nicotine, physostigmine, bethanechol hypothermia incontinence, diarrhea, fasciculations Serotonin Confusion, agitation, Dilated Tremor, myoclonus, SSRIs, meperidine, syndrome hyperthermia, clonus, diaphoresis, dextromethorphan, TCAs, MAOIs tachycardia trismus, rigidity

Testing Tips • Always check for acetaminophen and salicylates- difficult to diagnosis and treatments should be implemented early • Rapid drugs of abuse screens are immunoassays that have some false positives and negatives • Comprehensive screening is mass spectrometry and takes longer- this rarely leads to management changes

Toxin Antidote Cyanide (nitroprusside) Hydroxocobalamin (vit B12) IV 5 grams (or thiosulfate) Methemoglobinemia Methylene blue IV 2mL/kg Digoxin Digoxin Fab IV 2-5 vials Calcium channel blocker 10% Calcium chloride IV 20mL Insulin IV 0.5-1 units /kg with dextrose Local anesthetic 20% Intralipid bolus IV 1.5 mL/kg Sodium channel blocker (anti-arrhythmic, TCA, Sodium bicarbonate IV 100 mL antihistamines, cocaine) Cholinergic Atropine IV 2 mg- double every 3-5 min as needed