The Ohio State University College of Medicine

Med 2 Integrated Pathway

Lecture Handouts September 9 – September 26, 2008
Block Leader: James N. Allen, M.D. 201 Heart & Lung Research Institute 473 W. 12th Ave. Columbus, OH 43210 Phone: 614-293-4925 email:

Pulmonary 2008-2009 Course Packet Table of Contents
Title Introduction CPC Instructions Lectures: Structure, Function & Ventilation – Dr. J. Allen Histology of the Respiratory System – Dr. Hitchcock O2 and CO2 Transport - Dr. J. Allen Diffusion – Dr. B. Allen Arterial Blood Gases - Dr. J. Allen Chest Radiology - Dr. King Blood Flow & Metabolism – Dr. Haden Ventilation & Perfusion – Dr. Haden Examination and Diagnostic Testing - Dr. J. Allen Mechanics – Dr. B. Allen Pulmonary Hypertension - Dr. Haden Pulmonary Embolism - Dr. Ali Control of Ventilation – Dr. Essig Sepsis and Acute Respiratory Distress Syndrome - Dr. O'Brien Respiratory Failure - Dr. Hoffmann Asthma - Dr. B. Allen Anti-Asthma Medications - Dr. Fertel Pleural Disease - Dr. Hitchcock Upper Airway Disorders - Dr. McCallister COPD - Dr. Diaz Pathology of Pneumonia – Dr. Hitchcock Lower Respiratory Infections in Adults – Dr. Schaffernocker Lower Respiratory Infections in Children – Dr. Powell Lung Cancer - Dr. Hitchcock Lung Cancer - Dr. J. Allen Interstitial & Occupational Lung Disease - Dr. Hitchcock Immunologic and Rheumatologic Lung Disease - Dr. Weiland Inhalational and Occupational Lung Disease - Dr. Essig Interstitial Lung Disease - Dr. J. Allen Chest Emergencies – Dr. Essig Infant Lung Diseases – Dr. B. Allen Childhood Lung Diseases – Dr. B. Allen Approach to Cough – Dr. Wood Approach to Dyspnea – Dr. J. Allen Cystic Fibrosis and Bronchiectasis - Dr. B. Allen Page 1 4 6 8 16 18 20 26 30 31 32 37 38 39 46 47 52 58 59 67 74 80 87 94 102 103 111 117 125 130 139 145 151 156 160 163 171

Date 9-9-08 9-9-08 9-9-08 9-10-08 9-10-08 9-10-08 9-11-08 9-11-08 9-11-08 9-12-08 9-12-08 9-12-08 9-15-08 9-15-08 9-15-08 9-16-08 9-16-08 9-17-08 9-17-08 9-17-08 9-18-08 9-18-08 9-18-08 9-19-08 9-19-08 9-19-08 9-22-08 9-22-08 9-22-08 9-23-08 9-23-08 9-23-08 9-24-08 9-24-08 9-24-08

2008 MED II Respiratory Module – Introduction
Date: Time: Faculty: Email: September 9, 2008 8:30 am James Allen, MD; Division of Pulmonary & Critical Care Medicine

This module will cover the physiology, pathology, pharmacology, histology, radiology, and clinical diseases encountered in pulmonary medicine. In order to teach you, we have assembled an interdisciplinary group of faculty: Physiology – Drs. James Allen, Elizabeth Allen, Douglas Haden, and Roy Essig Radiology – Dr. Mark King Pathology – Dr. Charles Hitchcock Pharmacology – Dr. Richard Fertel Adult Pulmonary & Critical Care Medicine – Drs. James Allen, Naeem Ali, Jennifer McCallister, Doug Haden, Philip Diaz, James O’Brien, Roy Essig, Jeffery Weiland, Karen Wood, Troy Schaffernocker, and Stephen Hoffmann Pediatric Pulmonary – Dr. Elizabeth Allen Pediatric Infectious Disease – Dr. Dwight Powell We have adopted the educational techniques of concept building and repetition in order to enhance learning and retention. In this regard, for most major classes of disease, we will start with a normal physiology lecture, followed in about a day by a pathophysiology lecture, followed in about a day by clinical case presentations in a lecture setting (usually with “live” patients who will discuss their diseases and permit questions from you), followed in about a day by small group case studies. For some disease topics, we deleted the clinical case presentations in the lecture setting or we deleted the small group case studies (for time constraints, not because any of these topics are less meritorious). The lectures will have any required reading listed on their handouts. Most readings will be available on texts that are on-line through the Health Sciences Library website. There is one text that is required for the module that is not available on-line from the library: Respiratory Physiology: The Essentials by John B. West. Because physiology is historically the most difficult part of the respiratory module, it is essential that you acquire a copy of the text in order to assimilate the material. The most recent version is the 8th edition (2008) that has the advantage of coming with an access to the on-line version of the book. The 7th edition will work fine for your purposes but does not have the on-line access. On line, you will find the cases for the small group sessions. They are created in PowerPoint format. These cases were created exclusively for use by students at the Ohio State University College of Medicine. Many of the pathology images are used with permission of Dr. Edward Klatt from his internet collection “WebPath” which can be found on the internet at:

Page 1 of 177 Dr. Klatt has stipulated that these images be used only for educational purposes by Ohio State University medical students and not be disseminated elsewhere. The case studies also include discussion points in the “notes” section of the PowerPoint slides. These discussion points were designed to assist the faculty members leading the small group case study sessions, however, because these points may also be useful for your review, they are included in the student copies of the case studies, also. In order to optimize your learning, I recommend that, when possible, you review the cases prior to the small group sessions but not read the discussion points until after the sessions. On September 24, 2008, your small groups will present CPCs (clinical pathologic conferences) where you will be given 3 clinical cases and you will be asked to work through it to arrive at a diagnosis. Your small group’s findings will be presented to a faculty member during the CPC and the faculty member will reveal the actual diagnosis (these will be modeled after the weekly CPCs published in the New England Journal of Medicine). These cases will represent a pulmonary disease not discussed in detail in the regular lectures and small groups. It will be your group’s responsibility to work through the cases and to educate yourselves about the disease in question. The final exam will be on September 26, 2008. Exam questions will test didactic knowledge and your ability to integrate concepts from multiple lectures. An example of the first type of question is: Hilar adenopathy with diffuse reticulonodular pulmonary infiltrates are most common in: 1. 2. 3. 4. Sarcoidosis Idiopathic pulmonary fibrosis Emphysema Pneumococcal pneumonia

Correct = 1 An example of the second type of question is: A 35 year old woman is brought to the emergency room after being found unconscious at a shopping mall. No medical history is available. On exam, she is unresponsive, blood pressure 110/70, heart rate 114, and respiratory rate 24 with clear lungs to auscultation. A chest x-ray is normal. An arterial blood gas reveals: pH 7.14, pCO2 15, pO2 90, HCO3 10, and SaO2 98%. Laboratory studies include sodium 140, potassium 5.4, chloride 100, serum CO2 12, creatinine 2.5, BUN 40.

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The measured osmolarity is 300 and calculated osmolarity 296. Which of the following diseases is most likely based on these laboratory findings: 1. 2. 3. 4. 5. Ethylene glycol intoxication Renal tubular acidosis Diabetic ketoacidosis Heroin overdose Histoplasmosis pneumonia

Correct = 3 Test questions may be based on materials presented in lectures, small group discussion sessions, handouts, CPCs, or required textbook readings. This module is fairly short (less than 3 weeks) and there is a large amount of information covered. It is important to keep up with the materials presented since each day builds on materials from previous days. It is especially important to focus on physiology during the first week in order to be able to apply the concepts presented in the physiology lectures to the more clinically-based lectures later in the module. Our goal for this module is for you to have a solid foundation of knowledge in the normal respiratory system as well as the common disease processes that you will encounter in MED III and MED IV. Please call or email us with any questions about the lecture materials and at the end of the module, give us feedback about what was particularly effective or ineffective about the module as it pertains to your learning. Additionally, there will be review sessions most evenings at 6:30 (location to be announced) when I will be available for questions about the coursework.

Jim Allen, M.D. Professor of Internal Medicine Division of Pulmonary and Critical Care Medicine September, 2008

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CPC Instructions
As clinicians, we learn the most from the patients that we care for. The CPC (Clinical Pathological Conference) has a long tradition in American medicine for teaching fellow physicians about interesting or unusual clinical cases. In a CPC, the salient features of a patient’s presentation are presented and a discussant (who does not know what the correct final diagnosis is) discusses the case including the differential diagnosis, the test that he/she proposes was used to establish a final diagnosis, and what the final diagnosis most likely was. In a way, it is like a detective game of figuring out what is wrong with the patient. CPCs are presented weekly in the New England Journal of Medicine and reading through one or two CPCs in the journal is a great way to prepare yourself for your Med II pulmonary module CPC. When practicing physicians are faced with a difficult case that they have not encountered before, they turn to the medical literature to help them sort out the case. Medical education does not stop with medical school and residency, it is something we do constantly our entire professional career. The CPCs we will use in the Respiratory Module will help teach you how to teach yourself. For the CPCs, each of the 8 small groups will be broken into 3 subgroups. Each subgroup will be responsible for preparing one of three CPCs to the entire small group (with a faculty preceptor present). Therefore, you will be responsible for teaching yourselves about the diseases involved in the CPCs. Each of the 3 CPCs will take 30 minutes. Plan on 5 minutes for the faculty preceptor to introduce the case, 15 minutes for the subgroup to discuss the case, 5 minutes for the faculty preceptor to discuss what the diagnosis actually was, and 5 minutes for questions from the other students. Do not procrastinate your preparations for the CPCs. You will want to be spending much of the last week of the module studying for the exam so try to get as much of the work done during the first and second weeks of the module. You should start meeting with your subgroup at the beginning of the module to organize your approach to the CPC. When presenting your CPC, you can just verbally present your findings, use Powerpoint, use handouts, or use the whiteboard. You will be the teachers for these exercises, so use the medium that you feel will best teach the rest of your small group the information that you wish to convey. In past years, the subgroups that have been most effective have used innovative and interesting ways to present their findings, usually using Powerpoint presentations. Be creative and incorporate x-rays, pathology images, and physical examination images that you encounter in your literature review into your presentation. You will not be graded on whether you get the CPC right but the final exam will contain questions about the diseases involved in the CPCs, so it will be up to your subgroup to educate the rest of your small group about the disease. Remember though, you only have fifteen minutes to present your findings and proposed diagnosis.

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As a general guide, use the following timetable to help you organize yourselves: September 10 Meet with other members of your subgroup after your regular small group session to organize your subgroup. Designate a group leader to moderate your meetings and a presenter who will present your subgroups findings at the CPC on September 24th. Individual students should review the cases and develop his/her own differential diagnosis. Use standard references to help you (UpToDate, Cecil, Harrison’s, Wikipedia, etc.). The Prior Health Sciences Library can be a great resource and there are a number of on-line resources through the library that can be valuable in your research and preparation. Subgroups should meet periodically to discuss the cases and develop the subgroup’s differential diagnosis. Subgroups should prepare their presentations using verbal presentation, handouts, and/or powerpoint slides. The designated presenter from each subgroup will present the subgroup’s findings to the rest of the small group.

September 10-15

September 16-19 September 20-23 September 24

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Physiology 1: Structure and Function; Ventilation
Date: Time: Faculty: Email: September 9, 2008 9:00 am Jim Allen, MD; Division of Pulmonary & Critical Care Medicine

Required Reading: West, John B.: Respiratory Physiology: The Essentials. Chapters 2 & 2. Lippincott, Williams, & Williams. 2008.

1. Describe the differences between the conducting zone and the respiratory zone of the lung. Define the different airway structures and alveoli. 2. Distinguish between the alveolar acinus, the alveoli, the respiratory bronchiole and the terminal bronchiole. Describe the relative sizes of these structures. 3. List the tissues that comprise the alveolar wall. 4. Describe the mechanisms that the lung uses to eliminate dust and debris. 5. Distinguish the bronchial and pulmonary circulations. 6. List the pressure of oxygen and carbon dioxide in air, arterial blood, venous blood, and tissue cells. Memorize the atmospheric pressure at sea level, the percent nitrogen in air, and the percent oxygen in air. Describe the mechanisms that the lung uses to eliminate dust and debris. 7. Be able to calculate the partial pressure of oxygen in the alveoli. Know the normal value for the respiratory exchange ratio (R). 8. Know the meaning of the following symbols used in pulmonary medicine (see Appendix A from West): C, F, P, Q, R, S, V, A, D, E, I, L, T, a, c, v. 9. Given the barometric pressure, be able to calculate the PO2. 10. List the normal values for tidal volume and dead space. 11. List the major accessory muscles of inspiration. Describe the muscle contractions that result in inspiration. 12. Show the derivation of the lung volumes including TLC, FVC, FRC (TGV), RV, and tidal volume. 13. Define hyperventilation and hypoventilation. Describe the relation between ventilation and PCO2.

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14. Differentiate anatomic and physiologic dead space. 15. Define minute ventilation and alveolar ventilation. 16. Explain why ventilation is greatest in the lower portions of the lung 17. Describe the physiology of the cough.

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Pulmonary Histology
Date: Time: Faculty: Phone: Email: September 9, 2008 10:00 – 10:50 Charles L. Hitchcock, M.D., Ph.D., Department of Pathology 081 - Heart and Lung Research Institute Office 247-7469

Learning Objectives: 1. Recognize the structures that distinguish the various regions of the upper and lower airway systems that conduct air. 2. Given a microscopic image of the respiratory mucosa, correlate the cellular and acellular components with their function. 3. Given a microscopic image of the alveolar wall, define the function(s) of the components that make up the alveolar septum. 4. What are the roles of the respiratory mucosa and alveolar macrophages in the immune response? 5. What is the significance of the dual blood supply of the lungs? Learning Resources: 1. Gartner, L.P. and Hiatt, J.L., Color Textbook of Histology, 3rd Edition, Saunders, Philadelphia. Chapter 15, Respiratory System, pp 343-364. 2. Gartner, L.P. and Hiatt, J.L. (2006) Color Atlas of Histology, Lippincott, Williams & Wilkins, Philadelphia, Chapter 12, Respiratory System, pp 235-254. 3. Ogilvie, R.W. (2006) Histology: Independent Study Exercises, MUSC Press, Charleston, SC, Unit 15, Respiratory Tract & Lung, pp 329-354. I. OVERVIEW A. Structures 1. The respiratory system is divided into a conducting portion and a respiratory portion. 2. The conducting portion includes: a. Extra-pulmonary - nasal cavities, pharynx, larynx, trachea, and primary bronchi

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b. Intra-pulmonary bronchial tree consisting of bronchi, distributing bronchioles, and terminal bronchioles. 3. The respiratory portion includes: respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli. B. Functions 1. The conduction portion of the respiratory system conditions the air by filtering, warming, and humidifying it. 2. The main function is the exchange of gases between the blood and the air. 3. The respiratory system is a key organ in both innate and adaptive immunity. II. CONDUCTING PORTION A. Respiratory Epithelium 1. This is a pseudostratified ciliated columnar epithelium. Five different cell types, each resting on the prominent basal lamina, line airways of the respiratory system. 2. Ciliated columnar cells, making up about 30% of the cells, are tall slender cells with a basal nucleus and apical cilia and microvilli. The wave-like motion of the cilia moves mucus and entrapped particles toward the nasopharynx for elimination. The alignment of the apical basal bodies of the cilia gives rise to a horizontal staining density on the apical surface. Their neoplastic transformation gives rise to adenocarcinoma. a. Kartagener syndrome is an autosomal recessive disorder resulting in defective cilia motility – primary cilia dyskinesis – due to defects in dynein protein in the cilia. The syndrome is also characterized by the presence of situs inversus, chronic sinusitis, and bronchiectasis. b. Patients have a history of chronic respiratory infections. Men are infertile due to immotile sperm arising from abnormal dynein in their flagella. 3. Goblet (mucus) cells, making up about 30% of the lining epithelial cells, are non-ciliated cells that extend from the basal lamina to the lumen. They secrete mucin that humidifies the air, keeps the surface moist, and entraps inspired particles. Their neoplastic transformation gives rise to adenocarcinoma. 4. Brush cells are columnar cells with microvilli on their apical surface. Their numbers are few (<3%) in the epithelium. They have been considered to be sensory cells or goblet cells that have secreted their mucin. Their neoplastic transformation most likely gives rise to adenocarcinoma.

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5. Basal cells that comprise about 30% of the epithelial cells, and are attached to the basal lamina, but do not reach the lumen. They are the committed stem cells that the replace other epithelial cells. Changes in their differentiation give rise to squamous metaplasia and squamous cell carcinoma. 6. Small granule cells (Kulchitsky cells) are neuroendocrine-like cells that are distributed along the basal portion of the respiratory epithelium. They contain electron dense granules that contain a variety of peptides that include antidiuretic hormone, serotonin, somatostatin, calcitonin and other neuropeptides. Their neoplastic transformation gives rise to typical and atypical carcinoids (well and moderately differentiated neuroendocrine carcinomas), small cell carcinoma (poorly differentiated neuroendocrine), and large cell neuroendocrine carcinoma. B. Nasal Cavity and Paranasal Sinuses 1. Provide a large surface area for conditioning inspired air. Olfactory mucosa on the roof of the nasal cavity and superior concha. C. Pharynx and Larynx 1. The nasopharynx is lined by respiratory epithelium. In contrast, stratified, non-keratinized, squamous epithelium lines the oral pharynx and the laryngeal pharynx. 2. The larynx is responsible for phonation and for preventing solids and liquids from entering the trachea. a. The larynx is a rigid tube due to the presence of the thyroid and cricoid hyaline cartilages. b. The epiglottis, with its fibroelastic cartilage, covers the laryngeal opening. c. The intrinsic muscles, skeletal muscle innervated by the inferior laryngeal nerve, link the thyroid and cricoid cartilages. Muscle contraction leads to modulation of the voice. 3. The larynx is divided into three regions: a. Supraglottis that includes the epiglottis, false vocal cords, and ventricles. b. The glottis includes the true vocal cords and the commissures. c. The subglottis lies between the true vocal cords and the bottom margin of the cricoid cartilage. 4. The pharyngeal surface and part of the lingual surface of the epiglottis, as well as the true vocal cords, are lined by non-keratinized stratified squamous epithelium.

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a. Respiratory epithelium lines the remaining mucosal surfaces of the larynx. D. Trachea 1. The tube-like trachea extends approximately 10 cm long from the larynx to its bifurcation into the two primary (extrapulmonary) bronchi. 2. Four layers make up the tracheal wall. a. The mucosa contains respiratory epithelium that sits on a prominent basal lamina, loose connective tissue, and lymphatic tissue. b. The submucosa contains denser connective tissue and mucus and serous secreting glands. c. C-shaped hyaline rings form the cartilaginous layer. These 16-20 Cshaped rings prevent the collapse of the tracheal lumen. The trachealis muscle and fibroelastic tissue fill in the open portion, posterior portion adjacent to the esophagus. These rings can undergo ossification with age. d. Adventitia is the peripheral loose connective tissue layer of the trachea. E. Bronchi 1. The trachea divides to form right and left (extrapulmonary or primary) bronchi. The right bronchus is wider and significantly shorter than the left bronchus. Upon entering the lungs the bronchi are called the intrapulmonary bronchi. 2. The airways within the lung undergo unequal dichotomous branching. a. The right bronchus divides into three lobar bronchial branches while the left divides into two lobar bronchial branches. b. The left lung is further divided into eight bronchopulmonary segments and the right lung into ten of these segments. Each is supplied by a segmental bronchus (i.e. tertiary bronchi). c. The segmental bronchus and lung parenchyma that it supplies make up a bronchopulmonary segment. Each segment has its own blood supply and connective tissue septa. This subunit arrangement facilitates surgical resection. d. The segmental bronchi further divide into smaller subsegmental bronchi that are subsequently continuous with bronchioles. e. Branching of the pulmonary arteries follows that of the airways as they travel together.

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3. The wall of the bronchus decreases in diameter with each branching from approximately 1 cm to 5mm or less. a. Respiratory epithelium lines the mucosa. With airway segmentation there is a decrease in the epithelial height accompanied by a decrease in the numbers of basal cells, brush cells, and neuroendocrine cells. b. The lamina propria of the pulmonary airways – bronchi and bronchioles – contains three layers – lamina lucida, lamina densa, and lamina reticularis. It is the lamina reticularis, found only in adults, that thickens in patients with asthma and other inflammatory airway conditions. c. The submucosa has two smooth muscle layers with a spiral orientation running in opposite directions. Their contraction would compress the lumen like ringing out a wet cloth. The submucosa also contains seromucus glands, nerves and ganglia, lymphoid tissue, and irregularly shaped hyaline cartilage plates. d. The adventitia contains loose connective tissue that is continuous with the accompanying branch of the pulmonary artery. F. Bronchioles 1. Bronchioles are a direct continuation of a small subsegmental bronchus and represent the 10th-15th generation dichotomous branching. Each bronchiole supplies air to a pulmonary lobule. 2. Bronchiole range from 5 – 1 mm in diameter and decrease in size with further branching to yield terminal bronchioles that in turn give rise to the respiratory bronchioles. 3. The initial pseudostratified columnar epithelium changes to simple ciliated columnar epithelium and even simple cuboidal epithelium in smaller bronchioles. The occasional goblet cells seen in larger bronchioles are replaced by Clara cells in the smaller bronchioles. a. Clara cells are non-ciliated columnar cells whose apical dome contains secretory granules. They secrete a surfactant component and a Clara cell secreting protein that is protective of the bronchiolar epithelium. They also detoxify inhaled toxins. They also serve as the reserve cell for the bronchiole epithelium. b. The walls lack cartilage and glands. The lamina propria contains a thin layer of loose connective tissue rich in elastin. Surrounding this is a helical layer of smooth muscle controlled by the parasympathetic nervous system. The loose connective tissue of the outer layer contains elastic fibers that radiate out to connect with other airways and accompanying pulmonary artery branches.

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III. RESPIRATORY PORTION A. Respiratory Lobule and Acinus 1. The respiratory lobule is a 1-2 cm in size area separated by an interlobular septum. a. Each lobule contains a terminal bronchiole and its distal acini (respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli). Each lobule contains 3 – 10 acini. 2. The respiratory acinus is considered to be the functional unit of the lung. a. It consists of the respiratory bronchiole and all of its branches - alveolar duct, alveolar sacs, and alveoli. This concept is important to understanding the types of emphysema. 3. Terminal bronchioles are the most distal portion of the conducting system of airways. a. The lining epithelium consists of Clara cells and some ciliated cuboidal epithelial cells. b. The narrow lumen is surround by loose connective tissue and one or two layers of smooth muscle. c. Elastic fibers radiate out connecting the terminal bronchioles with other bronchial tree members. 4. Respiratory bronchioles serve as a transition between the conducting airways and the primary site for gas exchange. a. The lining epithelium contains both ciliated cells and Clara cells. The wall is interrupted by outpocketing of alveoli were the cuboidal epithelium is replaced by Type I pneumocytes. 5. Alveolar ducts, lined by alveoli, do not have their own walls and as they branch out they end in alveolar sacs with their clusters of alveoli. a. Loose connective tissue intra-alveolar septa support the alveolar ducts. b. A smooth muscle cell acts as a sphincter, controlling the opening of an alveolus to an alveolar duct. c. Elastic fibers tend to tie everything together. They ramify with fibers the various components of the lobule. B. Alveolus 1. Gas exchange between the air and the blood takes place in the 200,000,000300,000,000 alveoli of the lungs.

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2. The alveoli are at the terminus of the respiratory bronchiole via the alveolar ducts and alveolar sacs. An alveolar septum separates each of the 0.2 mm sacs from each other. The septum contains lining cell, a capillary, and loose connective tissue that contains elastic fibers. 3. Alveolar pores (pores of Kohn) traverse the thin wall between adjacent alveoli. These small, 7 - 9 μm in diameter, apertures are located in spaces between the capillaries of the alveolar wall. They can provide for collateral air circulation that would tend to prevent alveolar collapse when peripheral branches of the bronchial tree become obstructed. 4. The surface of the alveolus in contact with the air is lined by type I and type II alveolar cells (pneumocytes) and the occasional brush cell that are held together by tight junctions. a. Type I pneumocytes are squamous cells that make up approximately 95% of the alveolar surface area. b. Type II pneumocytes are cuboidal in shape and are interspersed among the type I cells. 1) They bulge into the airspace and are concentrated at septal junctions. 2) Although close in number to the Type I cells, their cuboidal shape allows them to only comprise about 5% of the surface area of the alveoli. 3) They function as secretory cells whose lamellar bodies represent the storage form of the phospholipids and proteins found in surfactant. Contents of the lamellar bodies are released into the alveolar space by means of exocytosis. 4) Surfactant forms a monomolecular layer over the alveolar epithelium, and functions to reduce the surface tension at the cell-air interface. 5) Lack of surfactant can result in alveolar collapse during exhalation. This is a problem in premature infants whose lungs are not sufficiently developed to produce surfactant. 5. The thin blood-air barrier is the site of gas exchange. This barrier, averaging 0.5 μm in thicknessμm, is made up by the layer of surfactant, type pneumocytes, epithelial basal lamina, endothelial basal lamina, and endothelial cells. Two or more alveoli may share the same capillary.

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IV. OTHER COMPONENTS A. Respiratory System As An Immune Organ 1. The respiratory epithelium’s lining of mucus secretions from goblet cells and submucosal glands serves as a barrier to invading organisms. It also contains enzymes that help to break down entrapped material. 2. The cilia propel filtered and entrapped material toward the oropharynx where it is swallowed or spit out. 3. IgA secreted by plasma cells in the lamina propria and submucosa is secreted into the mucosa lining. 4. Tonsil and lymphoid aggregates with the mucosa and submucosa of the airways are critical components of the adaptive immune response to inhaled antigens. 5. Lymphoid aggregates are found throughout the lung parenchyma within the septal connective tissue. 6. Alveolar macrophages crawl along the surface of the alveoli just under the surfactant layer. a. Parenchymal lung diseases are mediated, in large part, by their secretion of mediators, reactive oxygen species and proteolytic enzymes in response to inhaled allergens, inert particles, and organisms. B. Pleura 1. The pleural cavity – the space between the surface of the lungs and the thoracic cage – is lined by a continuous two serous membrane. The visceral pleura covers the lungs and the parietal pleura lines the inner surface of the thoracic cage. 2. The pleura is lined by mesothelial cells that overlie a layer of connective tissue that contains collagen and elastic fibers. 3. The pleural cavity between these two layers contains a thin film of lubricating fluid that reduces the friction between the lung surfaces and the thoracic walls that could occur during respiratory movements. C. Pulmonary Circulation 1. The lungs have a dual blood supply of arteries and veins. a. Pulmonary arteries arise from the heart and function in gas exchange. b. Bronchial arteries arise from the thoracic aorta and intercostal arteries and provide nutrients to the lungs.

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Physiology: O2 and CO2 Transport
Date: Time: Faculty: Email: September 9, 2008 11:00 am James Allen, MD

Required Reading: West, John B.: Respiratory Physiology: The Essentials. Chapter 6. Lippincott, Williams, & Williams. 2008.

Physiology Lecture: Mechanisms of O2 and CO2 Transport 1. Define the 2 mechanisms by which O2 is carried in whole blood. 2. Distinguish between % oxygen saturation (SaO2), oxygen content (CaO2) and PO2. Define what normal PO2, SaO2 and CaO2 are in the arterial blood. Be able to draw an oxyhemoglobin dissociation curve with either % Hb saturation or O2 content on the Y axis. 3. Know the approximate normal Hb in males and females. Given the constant for the reaction of Hb with O2 and the % saturation, be able to calculate the content of arterial oxygen in the blood. 4. Distinguish the differences in the behavior of the reaction between O2 and hemoglobin above and below a PO2 of 60 mm Hg. Identify how this influences the loading of O2 at the lungs and the unloading of O2 at the peripheral cells. 5. Describe the pathophysiologic mechanism of carbon monoxide poisoning, methemoglobinemia, sickle cell anemia, and cyanide poisoning. Be able to diagnose and treat carbon monoxide poisoning and methemoglobinemia. 6. Distinguish the effects of anemia and carbon monoxide poisoning on the O2 content, the PO2 and the O2 saturation of the arterial blood. 7. Define the primary factors influencing delivery of O2 to metabolizing cells. Distinguish the potential influences of capillary PO2, diffusion distance, mitochondrial or cell PO2, velocity of blood flow and metabolic rate. 8. List the common factors that shift the oxyhemoglobin dissociation curve to the right and left. Describe the consequences of rightward vs. leftward shifts on oxygen delivery to the peripheral tissues and oxygen uptake at the lungs, respectively. 9. Identify conditions that increase and decrease red blood cell DPG.

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10. 11.

Define the role of myoglobin in tissue oxygen metabolism. List the three primary mechanisms for CO2 transport in the blood and define the relative significance of each. Memorize the CO2 hydration reaction and the role of carbonic anydrase. Define how PCO2 affects the acid base status of the blood and the levels of HCO3- and H+. Memorize the normal pH and normal PCO2 of arterial blood. Define the term “mixed venous blood” and what the PCO2 and PO2 values are for mixed venous blood. Compare and describe the differences in the shape of the oxyhemoglobin dissociation and the CO2-blood dissociation curves. Determine how the shapes of the curves differentially affect the arterial-venous PO2 and PCO2 differences. Discuss what role the red blood cell plays in CO2 transport and H+ buffering. Determine how CO2 loading and unloading affect O2 carrying capacity of Hb. Contrast this with the influence of O2 on CO2 carrying capacity of whole blood.




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Date: Time: Faculty: Email: September 10, 2008 8:30 am Elizabeth Allen, MD

West Physiology Chapter 3: Diffusion 1. 2. Define diffusion. Memorize Fick’s law, and be able to use it to predict how alterations in the lung tissue or gas might affect rates of diffusion. 3. 4. 5. 6. 7. 8. 9. Know what characteristic of CO2 and O2 explains their greatly different rate of diffusion. Distinguish between diffusion limitation and perfusion limitation. Identify which gas is considered to be an example of a “perfusion limited” gas, and why. Identify which gas is considered to be an example of a “diffusion limited” gas, and why. Identify circumstances under which oxygen transfer becomes diffusion limited. Identify circumstance under which oxygen transfer is perfusion limited. Describe how diffusion capacity is measured by the single breath CO method.

10. Know the relationship between diffusion capacity, rate of CO uptake and alveolar CO pressure. 11. Know the 2 steps of oxygen diffusion that affect diffusion capacity. 12. Identify factors that can affect the lung’s diffusion capacity.

West Physiology Chapter 7: Mechanics 1. Know which muscles are involved in inspiration and expiration – both at rest and during active breathing. Identify which muscles are the “main” muscles of inspiration or active expiration. 2. 3. Know how the diaphragm affects the thorax shape, and how it is innervated Know what the term “compliance” means, and what factors can increase, or decrease, lung compliance. 4. 5. Know what cells make surfactant, what its key component is, and what it does for the lung Explain how and why the area of “best lung ventilation” shifts depending on whether the lung is normally inflated – or partially deflated. 6. Understand what is different about “uninhibited” chest wall versus lung movement, and what that has to do with functional residual capacity (FRC.) 7. 8. Describe the 3 types of air movement seen in the airways – and where each is likely to occur. Memorize Poiseuille’s law and use it to predict how airway resistance changes depending on changes in the airway.

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Know where in the airways resistance is highest, and why the answer to this question is NOT the smallest airways.

10. Know how lung volume, smooth muscle constriction, and air characteristics, affect airway resistance. 11. Know what causes airway smooth muscle constriction, or relaxation. 12. Understand why the equal pressure point limits exhalation, and under what circumstances this limitation occurs “earlier” in exhalation. 13. Know the relative amount of work required for normal inhalation versus exhalation. 14. Know what “breathing strategies” patients use to reduce work in disease states, and why it’s important that they develop these strategies.

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Acid-Base and Arterial Blood Gases
Date: Time: Faculty: Email:
Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Calculate the A-a gradient. Calculate the anion gap. Know the normal values for pH, PCO2, HCO3, anion gap, and A-a gradient. Understand buffering using the Henderson-Hasselbach equation. Identify the four main acid base disturbances by analyzing the arterial blood gas. List the common causes of each of the four main acid base disturbances. Distinguish anion gap metabolic acidosis from non-anion gap metabolic acidosis. List the common causes of anion gap and non-anion gap metabolic acidoses. Distinguish chloride responsive from chloride non-responsive metabolic alkalosis. List the common causes of chloride responsive and chloride non-responsive metabolic alkaloses. Apply compensation rules to distinguish simple from mixed acid-base disturbances. Solve common acid-base problems and create differential diagnoses base on the results of arterial blood gas measurements, anion gap calculations, and osmolar gap calculations. 13. Describe the clinical use of pulse oximetry and pitfalls of its use in carbon monoxide poisoning and methemoglobinemia. 14. Given the PCO2 and PO2 while a patient is breathing room air, be able to calculate the A-a gradient.

September 10, 2008 9:30 AM James Allen, MD; Division of Pulmonary & Critical Care Medicine

Required Reading West, John B.: Respiratory Physiology: The Essentials. Chapters 6 & 10. Lippincott, Williams, & Williams. 2008.

I. Introduction A. Lungs and kidneys work in concert to maintain a narrow range of pH in the blood (7.35-7.45). B. Lungs 1) Major role in minute-to-minute control of pH by changes in alveolar ventilation. a) Alveolar ventilation determines the partial pressure of CO2 in the blood by changes in the total minute ventilation (Remember that minute ventilation is determined by the alveolar volume and dead space volume). b) PaCO2 = k x Rate of CO2 production Alveolar ventilation c) An increase in PaCO2 by 5 mm Hg can result in a two-fold increase in minute ventilation. 2) Excrete 10 mEq of carbonic acid per minute or > 10,000 mEq per day. 3) During exercise acid excretion can increase to 40,000 mEq per day. 4) Carbonic acid is also known as a volatile acid because it can be converted to CO2 that is eliminated by the lungs.

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C. Kidneys 1) Renal tubular cells are important in maintaining proper pH by secreting or retaining bicarbonate (HCO3-) in exchange for hydrogen ions (H+). 2) Excrete 100 mEq fixed acids per day. 3) Fixed acid refers to endogenous acid production mainly from combustion of glucose and fatty acids. 4) Unlike the immediate ventilatory response to acid-base disturbances, the renal response slowly evolves over 24-72 hours. II. pH A. The body’s major buffering system is the carbon dioxide-bicarbonate system. 1) Hydrogen ion formed from metabolically produced acids is converted to water and carbon dioxide by carbonic anhydrase. 2) The pH results from solution of carbon dioxide in the blood and the dissociation of carbonic acid. H2CO3 ↔ H+ + HCO3B. Henderson-Hasselbach equation: pH = pKA + log[HCO3] [H2CO3] In the plasma, the equilibrium of carbon dioxide and carbonic acid favors carbon dioxide. The solubility coefficient for carbon dioxide is 0.03 mL/dL/mm Hg. Therefore: pH = pKA + log[HCO3] 0.03 x PaCO2 Substituting in known values, pKA of carbonic acid 6.1, bicarbonate concentration 24 mEq/L, and partial pressure of carbon dioxide 40 mmHg. pH = 6.1 + log 24/0.03 x 40 = 6.1 + log 20 = 7.4 B. Homeostasis 1) From the Henderson-Hasselbach equation, as long as the ratio of bicarbonate to carbon dioxide remains equal to 20, the pH will be 7.40. 2) Bicarbonate concentration is mainly determined by the kidneys. 3) Partial pressure of CO2 is determined mainly by the lungs. 4) Primary respiratory disturbance a) Aberration in volatile acid excretion resulting in an abnormal level of carbon dioxide. 1. Respiratory acidosis occurs if carbon dioxide cannot be excreted and thus PaCO2 is elevated. Kidneys compensate by retaining HCO3. 2. Respiratory alkalosis occurs if carbon dioxide is over excreted and thus PaCO2 is decreased. Kidneys compensate by excreting HCO3. 5) Primary metabolic disturbance a) Aberration in fixed acid excretion resulting in an abnormal serum bicarbonate level.

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1. 2.

Metabolic acidosis determined by a decreased HCO3 level. Lungs compensate by increasing minute ventilation and thus alveolar ventilation to “blow off” CO2. Metabolic alkalosis determined by an increased HCO3 level. The lungs compensate by decreasing minute ventilation to retain CO2.

III. Arterial Blood Gases A. Normal values pH (7.35-7.45; average = 7.40) PaCO2 (36-44 mmHg; average = 40) PaO2 (80-100mmHg) age dependent. Your PaO2 decreases with age and can be calculated by the following formula: [104 – (age x 0.4)] HCO3- (22-26 mEq/L; average = 24) SaO2 (95-98%) B. Evaluating arterial blood gases. 1) Look at the pH first---alkalemia is present if the pH is > 7.45 and an acidemia is present if the pH is < 7.35. 2) Next look at the PaCO2 and HCO3 to determine the primary disturbance. For the purpose of blood gas interpretation, use 40 mmHg as the normal value for PaCO2 and 24 mEq/L for HCO3. 3) Let’s say the pH is < 7.35 (acidemia)----Primary process is respiratory acidosis if PaCO2 is > 40 mm Hg or metabolic acidosis if the HCO3 is < 24 mEq/L. 4) Let’s say the pH is > 7.45 (alkalemia)----Primary process is respiratory alkalosis if PaCO2 is < 40 mm Hg or metabolic alkalosis if the HCO3 is > 24 mEq/L. IV. Respiratory Acidosis A. Definition 1) If an acidosis is present by pH and the PaCO2 is elevated, then a primary respiratory acidosis exists. As the PaCO2 increases, the renal tubules are stimulated to excrete H+ and retain HCO3-. 2) Note: There are two categories for primary respiratory disturbances, acute and chronic, because the kidneys take several days to fully compensate. Therefore, there are different degrees of compensation depending on when the blood is sampled. B. Etiologies 1) Central nervous system depression (drug overdose). Depressed respiration. 2) Neuromuscular disorder (ALS, muscular dystrophy, Guillian Barre syndrome). Inability to move the thoracic cage or diaphragm. 3) Thoracic cage abnormalities (severe kyphoscoliosis). 4) Obstructive lung disease (asthma, COPD). Airflow limitation can impair CO2 elimination by increasing dead space ventilation. 5) Obesity hypoventilation syndrome. 6) Myxedema coma (severe hypothyroidism). Central nervous system depressant. C. Compensation 1) Acute respiratory acidosis (less than 2-3 days). For every 10 mmHg ↑ in the PaCO2 the HCO3 ↑ by 1 mEq/L 2) Chronic respiratory acidosis (greater than 2-3 days). For every 10 mmHg ↑ in the PaCO2 the HCO3 ↑ by 3.5 mEq/L

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V. Respiratory Alkalosis A. Definition 1) If alkalosis present by pH and the PaCO2 is low, then a respiratory alkalosis is present. As the PaCO2 decreases, the renal tubules are stimulated to excrete HCO3in exchange for H+. B. Etiologies 1) Anxiety/pain. 2) Sepsis. 3) Central nervous system (stroke). 4) Aspirin overdose. 5) Chronic liver disease. 6) Pulmonary embolism. 7) Pregnancy. 8) Hyperthyroidism. C. Compensation 1) Acute respiratory alkalosis For every 10 mmHg ↓ in PaCO2 the HCO3 ↓ by 2 mEq/L 2) Chronic respiratory alkalosis For every 10 mmHg ↓ in PaCO2 the HCO3 ↓ by 5 mEq/L VI. Metabolic Acidosis A. Definition 1) If pH indicates an acidosis and the HCO3 level is low then a metabolic acidosis is present. The drop in pH stimulates chemoreceptors to increase the minute ventilation. 2) Results when excess fixed acids are ingested or produced. 3) Note: Metabolic acidoses are separated into gap and non-gap acidosis. a) The anion gap can be calculated by the following formula: Na+ - (Cl- + HCO3-) = anion gap b) Sodium is the primary cation in the extracellular space and bicarbonate and chloride are the primary anions. The sum of chloride and bicarbonate is less than the sodium concentration. The extra anions that are needed to maintain electrical neutrality are not routinely measured serum electrolytes. These extra anions are referred to unmeasured anions or the anion gap. Extra negatively charged particles such as acids, like lactic acid or ketones, will increase the anion gap, indicating a metabolic acidosis. The normal anion gap is 12. c) The presence of an elevated anion gap (> 12) always indicates the presence of a metabolic acidosis. B. Etiologies 1) Anion gap acidosis a) Ketoacidosis (diabetic, starvation, alcohol). b) Lactic acidosis (sepsis). c) Uremia (renal failure). d) Certain poisonings---methanol, ethylene glycol.

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i. These can be suspected if there is an increase in the osmolar gap ii. Osmolarity = 2(sodium) + glucose/18 + BUN/2.8 + ethanol/4.6 iii. Normally the measured Osm. - calculated Osm. < 10 iv. If the osmolar gap is > 10, suspect methanol or ethylene glycol e) Aspirin/salicylate toxicity. 2) Non-anion gap acidosis a) Diarrhea (loss of bicarbonate through the colon). b) Renal tubular acidosis (loss of bicarbonate through the kidneys). c) Acetazolamide (carbonic anhydrase inhibitor). d) Total parenteral nutrition (infusion of excess acid). e) Pancreas transplant (plug the new pancreas into the bladder, lose bicarbonate in the urine). C. Compensation 1) Last 2 digits of the pH = PCO2 (easy to calculate) 2) PaCO2 = 1.5(HCO3) + 8 ± 2 (harder to calculate) VII. Metabolic Alkalosis A. Definition 1) If pH indicates the presence of an alkalosis and the HCO3 is elevated, then a metabolic alkalosis is present. 2) Results from loss of acidic bodily fluids, excess alkali ingestion (antacids), or excess renal retention of bicarbonate. 3) Note: Metabolic alkaloses are separated into chloride responsive and unresponsive based on the urine chloride level. Chloride responsive metabolic alkalosis results from loss of body fluids and responds to intravascular volume expansion (intravenous replacement of fluid) with sodium chloride solution. Chloride unresponsive due to problem with HCO3 homeostasis so does not respond to fluid replacement. B. Etiologies 1) Chloride responsive (urine Cl- < 10) a) Vomiting. b) Nasogastric suctioning. c) Diuretic use. 2) Chloride unresponsive (urine Cl- > 10) a) Exogenous steroids b) Cushing’s syndrome c) Hyperaldosteronism d) Bartter’s syndrome C. Compensation 1) For every 10 mEq/L ↑ HCO3 the PaCO2 ↑ by 6 mmHg VIII. Hypoxemia A. Causes: i. Low alveolar PO2 ii. Hypoventilation iii. High altitude iv. Reduced inhaled oxygen (FiO2) v. Diffusion impairment vi. Interstitial lung disease vii. Pulmonary edema viii. Emphysema

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ix. Shunt x. Intra cardiac shunt xi. Intra pulmonary shunt B. The A-a gradient (Alveolar-arterial oxygen gradient) i. This is a way of assessing oxygenation adjusted for changes in ventilation (PCO2) ii. A-a gradient = [150 - (5/4 x PCO2)] - PO2 iii. Normal = 4 + (age ÷ 4) 1. Therefore, normal for a 20 year old = 8 and for an 80 year old = 24 2. An increase in the A-a gradient indicates abnormal: a. Shunt b. Ventilation-perfusion mismatch c. Diffusion limitation in the lung

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Date: Time Faculty: September 10, 2008 10:30 am Mark A. King, M.D. Associate Professor of Radiology

Objectives: 1. 2. 3. 4. 5. Correctly identify air, water (soft tissue) and calcium density on a chest radiograph. Explain the summation sign and identify an example on a chest radiograph. Correctly identify the silhouette sign on a chest radiograph and explain why it occurs. Know when a lateral decubitus radiograph might be used in clinical practice. Correctly identify typical examples of lobar pneumonia (and identify which lobe is involved), pneumothorax, and pleural effusion.

The Chest Radiograph Systematic evaluation of the chest radiograph should include attention to the bones and soft tissues, the hila, the mediastinum, the heart, and finally the lungs and pleura. Systematic evaluation is important because it is common that more than one abnormality is present on a CXR, and often incidental findings, those we are not looking for or expecting, are the most important findings. If one is searching only for one abnormality, once it is found, the search is over without complete evaluation of the radiograph. The standard views for conventional chest radiography include: 1. PA (posterior-anterior): The film is against the chest wall, the photons enter from posterior and travel in an anterior direction through the patient to the film. 2. AP (anterior-posterior): The film is against the patient’s back, and the photons enter from an anterior direction and travel posteriorly through the patient to the film. Used almost exclusively for portable examinations in patients who cannot be transported to the radiology department. 3. Lateral: The film is (usually) against the left side of the patient, photons enter from the right side. 4. Lateral decubitus: The patient is placed on his/her side (either right or left) with film behind the patient. Done to take advantage of gravity, especially to detect fluid in the pleural space. 5. Oblique: Can be done with film in front of, or behind the patient; the patient is obliquely oriented with respect to the film. Not used very often these days: this view has been mostly replaced by CT. 6. Apical lordotic: Film behind the patient, beam enters from the anterior direction and travels posteriorly through the patient; the patient “leans back” against the film for this exam. This is used to improve visibility of the lung apices. As is the case with the oblique radiograph of the chest, this view has also been mostly replaced by CT.

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Normal Anatomy: We will go through normal anatomy in class. Always try to keep in mind that it is important to think of the anatomy you are seeing in a three-dimensional way: the chest radiograph is a twodimensional representation of a three-dimensional structure. Radiographic Densities: On a chest radiograph, four basic densities are visible: air (black), bone/calcium (white), fat (dark gray) and soft tissue/water (very light gray to white). Of course, these densities are all relative: they relate to the efficiency with which the tissue in question attenuates, or for lack of a better term, absorbs, the x-ray photons. If all the photons make it to the film (such as is the case with air), the film is exposed and turns black. If the photons encounter calcium in bone, many photons are absorbed and don’t make it to the film, and the film is relatively unexposed, and remains clear (then, when it is shown using a white light source, it appears white). Water is more efficient at absorbing the x-ray photons than is fat, so water appears “whiter” than fat does. The degree to which these differences are apparent is a function of image contrast, which is altered by altering the energy of the photons delivered. The physics is complicated, and you don’t need to know any of it (unless you decide to become a radiologist), so I won’t clutter your minds with it. Just try to remember that, in order of decreasing efficiency in attenuating x-ray photons, the components of the chest are represented as follows: bone (most opaque/white), soft tissue/water, fat, then air (least opaque, most black). Understanding these different densities is crucial to being able to interpret a chest radiograph. Recognizing differences in opacity, or optical density, between two structures is how one differentiates structures that are adjacent to one another. If two contiguous structures are equally opaque, it is not possible to tell where one ends and the other begins. Fortunately, in the chest, the lungs are relatively “black” (when filled with air) and the thoracic organs are relatively “white” (composed mostly of water), so that the lungs outline, or highlight, the solid organs of the thorax. When the lungs become filled with fluid (pneumonia, aspiration, drowning, pulmonary hemorrhage, etc), or with material that has the same radiograph density as fluid (such as a lung cancer), the lung turns white in that region and is said to be “opacified”, or “opaque”. If this occurs in alveoli that are contiguous with a normal soft tissue structure (fluid density), the margin between the two structures is obscured: this is called the “silhouette sign”. The silhouette sign is a useful tool for detecting and localizing lung disease on a chest radiograph. The Lungs: As mentioned earlier, the lungs are radiolucent (dark) relative to other structures in the thorax. Pulmonary artery branches and veins are visible as branching gray-white structures; bronchi, except for the main bronchi, are generally not visible except in disease states. Most of the diseases affecting the lung cause abnormally increased opacity: pneumonia, pulmonary edema, interstitial lung disease, and a variety of other pathologic processes cause increased opacity in the lung. When the lung fills with fluid (of any kind), two radiological signs may be observed:

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1. The silhouette sign (mentioned above) 2. Air bronchogram: This occurs when air-filled (patent) bronchi are surrounded by fluidfilled alveoli. The bronchus is visible as a dark gray tube surrounded by opaque lung tissue. It is generally not possible to diagnose a specific etiologic agent when pneumonia is seen on a chest radiograph. In fact, it may be difficult to differentiate pneumonia from lung cancer on a chest radiograph. Knowledge of the clinical findings and the patient’s history is important when trying to assign a specific likely etiology to a chest radiographic abnormality. Emphysema, vascular obstruction, and air trapping are examples of processes that cause abnormally decreased opacity in the lung. In emphysema, there is less tissue per unit volume in the lung (alveolar atrophy); in vascular obstruction (such as acute pulmonary embolism), there is less soft tissue density per unit lung (decreased blood flow in a given volume of lung); in diseases that cause air trapping, there is more air (radiolucent) per unit lung volume. The Heart and Mediastinum: There are a couple of facts one needs to know regarding the heart and mediastinum on chest radiographs: 1. On the frontal view of the chest made in the postero-anterior projection, the transverse diameter of the heart should not exceed the maximum transverse diameter of the thorax. If it does, the heart is likely pathologically enlarged. 2. On the frontal view of the chest, the right heart border is the right atrium; the left heart border is the left ventricle. 3. On the lateral view, the anterior portion of the heart is the right ventricle, and the posterior portion of the heart is the left atrium. 4. The medial edge of the right lower lobe is superimposed over the spine, and parallels the esophagus and azygous vein. This anatomic region is bordered by a pleural reflection and is called the azygoesophageal recess. On the frontal view of the chest, it is a window into the middle mediastinum (remember: it is an air/soft tissue interface) and middle mediastinal masses are visible on the frontal film if they cause a convex bulge in the outline of this recess. 5. On the frontal radiograph, the azygous vein should measure no more than 12mm in diameter. If larger, the patient may have abnormally enlarged lymph nodes in this region. The Pulmonary Hila: The hila are difficult to evaluate, and even experienced chest radiologists may misinterpret structures in the hila. A couple of facts regarding the hila are helpful for identifying the normal hilum and for recognizing abnormalities of the hilum: 1. On the frontal view, the density of the two hila should be essentially the same. If one hilum appears more opaque than the contralateral hilum, a mass should be suspected. (See “summation sign”).

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2. On the lateral view, the right pulmonary artery appears more opaque than the left pulmonary artery, because of the fact that the RPA crosses the mediastinum from left to right before branching and turning to descend into the lower lobe; the course of the LPA is relatively vertical as it ascends from the pulmonary outflow tract, then descends into the left lung. It is seen in profile, so its radiographic density is less than that of the RPA, which is seen en face. 3. Hilar masses cause convex bulges in the normal contour of the hilum. It takes a great deal of experience to feel comfortable with diagnosing hilar masses, unless they are large and cause obvious contour abnormalities. The Pleura: The lung is surrounded by the visceral pleura, and the chest wall is lined internally by the parietal pleura. The intervening space contains a small amount of fluid that is dispersed throughout and, as a result, the layers of the pleura are adherent. The lung therefore adheres to the chest wall, essentially, and occupies the thoracic volume. The “relaxed” volume of the lung, however, is only about the size of a fist. If air makes it way into the pleural space, the lung loses its adherent contact with the parietal pleura, and the lung pulls away from the chest wall (pneumothorax). If excess fluid collects in the pleural space (pleural effusion, or hydrothorax), it usually collects in the most dependent portion of the pleural space. This causes blunting of the normally sharp lateral and posterior costophrenic sulci.. Pleural fluid may also be “loculated”: this is diagnosed when a pleural fluid collection occurs in a location that is not dependent, and often indicates an inflammatory pleural fluid collection (could mean infection, or bloody effusion). Pleural thickening by soft tissue masses (such as in spread of malignancy to the pleura), may look exactly like a loculated pleural fluid collection: it is a pleural abnormality that occurs in a nondependent location, and is often localized. Summary: The chest radiograph is an indispensable tool for evaluating the patient with suspected pulmonary disease. Understanding fundamental principles of thoracic anatomy, physiology, and pathology is important when interpreting a chest radiograph.

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Blood Flow & Metabolism
Date: Time: Faculty: Email: September 11, 2008 8:30 am Douglas Haden, MD

Objectives for Pulmonary Circulation Lecture 1. Name the primary differences between the underlying anatomical and physical characteristics of the pulmonary circulation vs. the systemic circulation. 2. Describe the source(s) of nutrient blood flow to the bronchi and lung parenchyma. Describe how blood flow leaving this system can influence the final PO2 in the arterial blood. 3. Given a set of hemodynamic values from a cardiac catheterization, calculate the mean pulmonary artery pressure and pulmonary vascular resistance. 4. List thee primary factors that affect the passive resistance of the pulmonary circulation. 5. Compare what makes up the “transmural pressure” across the pulmonary vascular wall in the extrapulmonary and intrapulmonary vessels. 6. List at least 2 primary vasomediators in the pulmonary vasculature that are sometimes used clinically. 7. Compare total pulmonary blood flow in apex of the lung vs. the lung bases in the upright position and how this might change in the supine position. Define what is meant by the “Dependent Region” of the lung. Describe the different “lung zones” based upon the relative vascular and alveolar pressures.

8. Recognize the Starling Equation for fluid movement across the lung (or any other vascular bed). Define oncotic pressure, osmotic pressure, permeability coefficient and reflection coefficient. Be able to determine the direction of fluid movement from one compartment to another when changes occur in capillary hydrostatic pressure, pleural pressure, interstitital or alveolar protein concentration, lung fluid permeability.

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Ventilation & Perfusion
Date: Time: Faculty: Email: September 11, 2008 9:30 am Douglas Haden, MD

Objectives for Ventilation-Perfusion Lecture 1. Given a clinical case presentation the student will correctly identify the cause of hypoxemia. 2. Given the values from an arterial blood gas, the student will correctly calculate an alveolar-arterial oxygen difference and recognize whether it is normal or abnormal. 3. Recognize the source of the physiological alveolar-arterial oxygen gradient 4. Given a clinical case presentation the student will correctly describe the ventilation-perfusion inequality and it’s effect on gas exchange 5. The student will be able to describe the different types of shunt

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Examination & Diagnostic Testing
Date: Time: Faculty: Email: September 11, 2008 10:30 AM James Allen, MD; Division of Pulmonary & Critical Care Medicine

Objectives: By the end of this lecture and the associated small group case studies, you should be able to: 1. Utilize information from patient’s histories in order to generate differential diagnoses of pulmonary conditions. 2. Associate a description of patients’ physical examination findings with common lung diseases including pneumonia, pleural effusion, interstitial lung disease, pulmonary edema, asthma, upper airway obstruction, and chronic obstructive lung disease. 3. Analyze pulmonary function test results and use patterns of obstruction, restriction, and reduced diffusing capacity to diagnose common lung diseases covered in this module. 4. Correctly choose procedures in pulmonary medicine in order to facilitate diagnosis in common clinical settings. Specific procedures include: methacholine challenge testing, ventilation perfusion scan, thoracentesis, mediastinoscopy, video-assisted thorascopic surgical biopsy, bronchoscopy, pulmonary angiography, CT scan, PET scan, chest x-ray, and pulmonary artery catheterization. 5. Recognize flow volume loop patterns of upper airway obstruction, asthma, restriction, and normal individuals. 6. Compare different tests of oxygenation including overnight oximetry, 6-minute walk test, and high altitude hypoxia simulation test. Optional Reading: 1. Harrison’s Principles of Internal Medicine – 17th Ed (2008); Chapter 245: Approach to the patient with disease of the respiratory system; David Lipson, Steven E. Weinberger. 2. Harrison’s Principles of Internal Medicine – 17th Ed (2008); Chapter 246: Disturbance of respiratory function; Steven E. Weinberger, Ilene Rosen. 3. Harrison’s Principles of Internal Medicine – 17th Ed (2008); Chapter 247: Diagnostic procedures in respiratory disease; Scott Manaker, Steven E. Weinberger. I. Examination of the Pulmonary Patient A. Signs and Symptoms 1) Note duration, timing, character, severity, ameliorating and exacerbating factors, associated symptoms. 2) Most common symptoms a) Dyspnea or shortness of breath. i) Tachypnea—rapid respiratory rate. Distinguished from dyspnea. ii) Hyperventilation---increased VA so hallmark is low PaCO2 distinguished from tachypnea. iii) Orthopnea---dyspnea in recumbent or supine position. iv) Platypnea---dyspnea in upright position. v) Paroxysmal nocturnal dyspnea. b) Cough c) Chest pain i) Pleuritic ii) Non-pleuritic

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d) Hemoptysis---coughing up blood. 3) Most common signs a) Tachypnea b) Adventitial or abnormal breath sounds. B. History 1) Tobacco usage described in pack-years (number of packs per day x years smoked). 2) Illicit Drug use. 3) Occupational or other exposures. 4) Hobbies or home environment. 5) Travel history. 6) Family history. 7) Co-existing or previous diseases 8) Symptom specific questions: a) Duration b) Frequency c) Severity d) Quality e) Exacerbating factors f) Relieving factors g) Associated factors C. Physical Examination 1) Key features---inspection, palpation, percussion, and auscultation. 2) Normal breath sounds a) Examples on the internet at: i) ii) b) Vesicular---heard over small airways, duration of inspiration > expiration. c) Bronchovesicular---heard over large airways, duration of expiration = inspiration. 3) Abnormal breath sounds a) Crackles = rales i) Brief discontinuous sound heard during inspiration. ii) Congestive heart failure, pulmonary fibrosis and pneumonia. b) Wheezes = rhonchi i) High or low-pitched musical sound, more continuous, heard during inspiration, expiration or both. ii) Asthma and COPD c) Other

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ii) iii) iv)

Bronchial – abnormal – more expiratory than inspiratory and more “tubular” or “hollow”. Indicates an underlying consolidation Egophony---hear a nasal “aaa” with stethoscope when patient says “eee” over an area of consolidation. Whispered pectoriloquy----whispered sounds accentuated through a stethoscope over consolidation. Rubs---friction sound during inspiration and expiration, inflamed pleural surfaces rubbing together.

II. Pulmonary Function Tests A. Spirometry 1) Vital capacity (VC)---maximum volume of air that can be inspired or expired Equal to IRV + VT + ERV. 2) Forced vital capacity (FVC)---volume of air measured after a maximal inspiration then forcefully exhaled completely. Slightly less than VC measured during slow exhalation. 3) Forced expiratory volume in one second (FEV1)---volume of air exhaled in the first second of a FVC maneuver. Normally about 80% of the FVC. 4) FEV1/FVC----low ratio seen in obstructive lung disease. A normal ratio depends on the patient’s age and race, for example an FEV1/FVC ratio of less than 78% may define obstruction in a young individual but the FEV1/FVC ratio cut-off may be 72% in an older individual. For convenience during this module, we will use 75% as the cut-off to define obstruction. The overwhelming majority of pulmonary function testing machines will incorporate calculations to calculate the appropriate normal value for the FEV1/FVC ratio. For convenience during this module, we will use 75% as the cut-off to define obstruction. Reversible airflow is defined as a 12% improvement in the FVC or FEV1 after an inhalational challenge with a β2 agonist such as albuterol. B. Lung Volumes 1) Residual volume (RV)---volume of air left in the lungs after a maximal expiration. a) Cannot empty the lungs completely. b) Cannot be measured directly with a spirometer. 2) Functional residual capacity (FRC)---volume of air in the lungs after a normal tidal volume breath. a) Cannot be directly measured with a spirometer; requires additional equipment. b) Methods: 1. Helium dilution. 2. Body plethysmography (most commonly used by PFT labs). c) Elevated levels indicate airtrapping (can be seen in asthma, COPD or emphysema). d) Airtrapping results in ↑ FRC, defined as > 120% of predicted. 3) Total lung capacity (TLC)---the sum of all lung volumes. a) VT + IRV + ERV + RV = RV + VC = TLC b) TLC less than 80% of predicted indicates restrictive lung disease.

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Elevated TLC is indicative of hyperinflation and can be seen in asthma, COPD, and emphysema, defined as TLC > 120% predicted.

C. Diffusing Capacity (DLCO) 1) A measure of the ability of a gas to move across the alveolar-capillary membrane. 2) Dependent on solubility and molecular weight of the gas, surface area and thickness of the membrane and transit time. Main determinant of diffusion rate is the partial pressure gradient for the gas across the membrane. 3) Measure of diffusing capacity using carbon monoxide (CO) (most commonly used in clinical practice) a) CO diffuses readily. b) Binds avidly and reversibly with hemoglobin thus there is virtually no increase in the partial pressure. Therefore, the amount of CO in the circulation is dependent on the properties of the alveolar-capillary membrane itself plus the amount of available hemoglobin. c) Uptake of CO is diffusion limited (as opposed to perfusion limited), therefore, gas of choice for measuring diffusing capacity. d) Gas mixture of CO and He with known concentration, patient breath holds for 10 seconds, CO diffuses and He does not, rate of CO disappearance is calculated from the concentration of CO in exhaled gas. e) Normal value for single breath DLCO = 25 ml/min/mmHg. 4) Measure of diffusing capacity using nitrogen (rarely used in clinical practice). a) Nitrogen does not bind with hemoglobin, dissolves in plasma, so partial pressure of gas increases resulting in back pressure, limiting further uptake of nitrogen. b) Amount of nitrogen in circulation depends on the rate of blood flow. Thus nitrogen is perfusion limited. c) Single breath nitrogen wash-out. 5) Clinical factors affecting DLCO. a) Age--- DLCO decreases with age. b) Size of lungs----gender, body size. c) Interstitial lung disease---- DLCO ↓ due to increased thickness of interstitium. d) Emphysema--- DLCO ↓ due to loss of surface area. e) Pulmonary embolism--- DLCO ↓ due to blocked blood flow. f) Hemoglobin--- DLCO ↓ with anemia due to less binding availability, DLCO ↑ with polycythemia. g) Alveolar hemorrhage--- DLCO ↑, inspired CO binds with blood in alveoli, acting as a reservoir so more CO available for transfer. Pulmonary Function Test Patterns in Lung Disease FVC ↓ or normal ↓ ↓↓ Normal FEV1 ↓↓ ↓↓ ↓ Normal FEV1/FVC < 75% < 75% > 75% Normal TLC Normal or ↑ ↑ < 80% Normal DLCO Normal ↓ ↓ ↓

Asthma/COPD Emphysema Pulmonary Fibrosis Pulmonary Embolism

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Additional features: 1) Hyperinflation can be seen in emphysema. 2) Airtrapping (↑ FRC) and ↑ RV due to inability to fully exhale air seen in asthma and emphysema. 3) Neuromuscular disorders or problems with the thoracic cage results in restriction. Differentiated from interstitial lung disease by ↑ RV and normal DLCO. IV. Radiographic Testing A. Standard PA and left lateral chest x-ray. B. Computed Tomography of the chest/Spiral CT. C. Ventilation perfusion scan. D. Pulmonary angiography. V. Invasive Testing A. Bronchoscopy. B. Thoracentesis/Pleural biopsy. C. Mediastinoscopy D. Thoracotomy E. Video Assisted Thoracoscopic Surgery (VATS)




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Mechanics Date: Time: Faculty: Email: September 12, 2008 8:30 am Elizabeth Allen, MD

West Physiology Chapter 7: Mechanics 1. Know which muscles are involved in inspiration and expiration – both at rest and during active breathing. Identify which muscles are the “main” muscles of inspiration or active expiration. 2. 3. Know how the diaphragm affects the thorax shape, and how it is innervated Know what the term “compliance” means, and what factors can increase, or decrease, lung compliance. 4. 5. Know what cells make surfactant, what its key component is, and what it does for the lung Explain how and why the area of “best lung ventilation” shifts depending on whether the lung is normally inflated – or partially deflated. 6. Understand what is different about “uninhibited” chest wall versus lung movement, and what that has to do with functional residual capacity (FRC.) 7. 8. Describe the 3 types of air movement seen in the airways – and where each is likely to occur. Memorize Poiseuille’s law and use it to predict how airway resistance changes depending on changes in the airway. 9. Know where in the airways resistance is highest, and why the answer to this question is NOT the smallest airways. 10. Know how lung volume, smooth muscle constriction, and air characteristics, affect airway resistance. 11. Know what causes airway smooth muscle constriction, or relaxation. 12. Understand why the equal pressure point limits exhalation, and under what circumstances this limitation occurs “earlier” in exhalation. 13. Know the relative amount of work required for normal inhalation versus exhalation. 14. Know what “breathing strategies” patients use to reduce work in disease states, and why it’s important that they develop these strategies.

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Pulmonary Hypertension
Date: Time: Faculty: Email: September 12, 2008 9:30 am Douglas Haden, MD

Objectives for Pulmonary Hypertension Lecture 1. Given measurements obtained from pulmonary artery catheterization, the student should be able to calculate mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) and diagnose the presence of pulmonary hypertension. 2. Given a clinical vignette, the student should be able to correlate the most likely cause of pulmonary hypertension (e.g. left heart disease, lung disease) with results from pulmonary artery catheterization.

3. The student should be able to identify the common histopathological findings observed in patients with pulmonary arterial hypertension (PAH). 4. The student should be able to relate the molecular pathogenesis of pulmonary arterial hypertension to the pharmacological mechanisms of currently available drug therapies.

5. Given a history suggestive of pulmonary arterial hypertension, the student should be able to recognize key findings on physical examination and suggest appropriate diagnostic testing.

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Thromboembolic Disease
Date: Time: Faculty: September 12, 2008 10:30 am Naeem A. Ali, MD 201d DHLRI, 473 W 12th Ave Columbus, OH 43210 293-4925, 293-4799


Learning objectives: by the end of this lecture and the associated small group case studies, you should be able to: 1. List the major risk factors for venous thromboembolism. 2. List the components of Virchow’s triad. 3. Given a clinical vignette, recognize the signs and symptoms of deep venous thrombosis and of pulmonary embolism. 4. Given a clinical vignette, choose appropriate diagnostic tests for deep venous thrombosis. 5. Compare and contrast diagnostic studies used to diagnose pulmonary embolism including ventilation perfusion scans, pulmonary angiography, D-dimer, and CT angiograpy. 6. Given a clinical vignette, recommend appropriate treatment for patients with venous thromboembolism based on thromboembolism severity and results of diagnostic tests. 7. Recommend strategies to prevent venous thromboembolism in at-risk patient populations. Learning resources: 1. Harrison’s Principles of Internal Medicine 2. Recent review articles: a. V Tapson, “Acute Pulmonary Embolism”, N Engl J Med. 2008 Mar 6;358(10):103752. b. Bates SM, JS Ginsberg, “Clinical Practice: Treatment of deep-vein thrombosis”, N Engl J Med. 2004 Jul 15;351(3):268-77. 3. Valuable Website: Outline: Definitions: • Deep Vein- veins that reside predominantly in the interior of the extremities. Usually are associated with corresponding arteries. • Pulmonary embolism- any lesion that has physiologic effects on the lung after traveling through the systemic veins and then pulmonary arteries to lodge in the small subsegmental pulmonary arteries. • Thromboembolism- Any pulmonary embolism thought to result from clot formed outside of the lung. • Massive pulmonary thromboembolism- Any pulmonary embolism that presents acutely with life-threatening respiratory or circulatory failure.

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Massive DVT- Any DVT that results in venous obstruction to the extent that limb threatening ischemia results

Epidemiology: Prevalence About 500,000 people suffer from thromboembolic disease on a yearly basis Primary Cause of death in 50,000 Cause of death annually for 150,000-200,000 people Incidence 0.1% overall (Kearon, et al, Semin in Vasc Med, 1 (1), 2001, 7-25) 2/3 are DVT only 2/3 are first events Incidence with increasing age (Kearon, et al, Semin in Vasc Med, 1 (1), 2001, 7-25) 1% all patients >60yo 0.03% Age 40 0.1% Age 60 0.26% Age 80 Gender (Kearon, et al, Semin in Vasc Med, 1 (1), 2001, 7-25) Age association is stronger for men North American Studies suggest worse outcome/incidence in men Scandinavian, British studies suggest worse outcome/incidence in women Ethnic groups (Kearon, et al, Semin in Vasc Med, 1 (1), 2001) In the US African Americans at greater risk for idiopathic DVT compared to whites Hispanic, Asian and Pacific Islanders at less risk for idiopathic DVT compared to whites Non-whites more likely to have fatal VTE events than whites Seasonal variation Higher in winter months, but controversial Pathophysiology: Virchow’s Triad 1. Vascular injury a. Endothelial disruption-localized injury from needle stick or cellular injury b. Vasculitis-diffuse endothelia injury from inflammatory cells (Behcets) 2. Venous stasis a. Local-immobilization, resolving DVT, Pregnancy b. Systemic-Congestive heart failure 3. Hypercoagulability a. Idiopathic-unrecognized state after testing and history b. Inherited-abnormalities like Factor V Leiden or Prothrombin gene mutation c. Acquired- Antiphospholipid antibody syndrome or pregnancy

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Risk Factors: Table 1: Initial VTE event Risk Factor Inherited Conditions o ATIII Deficiency o Prot C or S Deficiency o Factor V Leiden (Hetero:Homozygous) o Prothrombin Gene Mutation Acquired Conditions o Surgery or Trauma o History of Previous VTE o APL Antibodies o Cancer o Age o >50 o >70 o Pregnancy o OCP o HRT Other o Hyperhomocysteinemia
Adapted from N Engl J Med 2004;351:268-77

Estimated Relative Risk for VTE 25 10 5:50 2.5 5-200 50 2-10 5 5 10 7 5 2 3

Table 2: Recurrent VTE Risk Factor AT III Prot C or S Deficiency Factor V Leiden o Heterozygous o Homozygous Prothrombin Gene Mutation APL Antibody Hyperhomocysteinemia
Adapted from N Engl J Med 2004;351:268-77

Prevalence (%) 1 3 20 2 5 5 10-25

Relative Risk for Recurrence
after cessation of therapy

1-3 1-3 1-4 4 1-5 2-4 1-3

Clinical Presentation: Up to 40% of patients presenting with symptoms of DVT have a simultaneous PE. (JAMA; 271:223-5) DVT: Classic- Typical site of nidus for thrombus formation in DVT is the lower extremity venous sinuses of the calf muscle. Symptoms are usually pain warmth or swelling of the affected extremity. Other sites include the pelvic veins or subclavian vein in special circumstances. Other- Can be asymptomatic, especially after major surgery (i.e. hip arthroplasty)

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Pulmonary thromboembolism: Classic- Pleuritic chest pain and dyspnea If symptomatic, most frequent symptoms (Arch Intern Med 1986; 146:961-7): (1) chest pain (88%) (2) dyspnea (84%) (3) cough (53%) (4) hemoptysis (30%) Other- Less often near-syncope, chest pressure, hypotension (weakness), respiratory failure Setting clinical suspicion: • Required to interpret diagnostic study results (imaging) • Difficult to do for inexperienced clinicians • Aided by prediction scores (Wells prediction score, most common) Wells VTE prediction score: Variable DVT symptoms and signs PE as likely or more likely than other Dx • After assessing Hx, CXR, ECG, labs HR> 100 bpm Immobilization or Surgery in last 4 wks Previous VTE Hemoptysis Cancer Total score: • <2.0 low pretest probability • 2.0-6.0 intermediate pretest probability • >6.0 high pretest probability Dichotomized score: • ≤ 4.0 PE unlikely • >4.0 PE likely Diagnosis: DVT: Contrast Venography- considered the gold standard and consists of cannulation of a peripheral vein in the lower extremity and administration of contrast. Good for the diagnosis of both distal (calf) and proximal (femoral) DVT. Ultrasonography- Practical gold standard for the diagnosis of proximal DVT (above knee). Relies on the fact that veins are hypoechoic and can collapsed under direct pressure during visualization. (non-compressible=luminal filling defect=DVT) Score 3 3 1.5 1.5 1.5 1 1

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PE: Diagnostic testing • Pulmonary angiography- Considered the gold standard. Requires cannulation of a large vein (femoral or other) and insertion of a pulmonary artery catheter. IV contrast is injected to reveal intraluminal filling defects. Complications include bleeding risk, renal insufficiency from IV dye and transient RBBB or other arrhythmias. • Ventilation-Perfusion Scan- Using aerosolized particles that emit radiation and labeled albumin, the ventilation patterns and perfusion regions of the lung are measured and mapped over several minutes of spontaneous ventilation. The number of areas that have ventilation without a matching area of perfusion determine the presence of an abnormality. • CT Pulmonary angiography- Peripheral administration of IV contrast is coupled with rapid acquisition of CT images of the chest. Adjunctive testing • D-Dimer- A surrogate measure of clot burden. If a clot exists in the vasculature, endogenous fibrinolytic factors evolve degradation products of fibrin. These are measured in serum samples and can give rapid estimates of the pre-test probability of disease. o A study of 566 patients with suspected DVT/PE, a negative D-dimer was effective in excluding DVT/PE if the clinical suspicion was low (N Engl J Med 2003; 349:1227-35) o A negative D-dimer test in patients with cancer does not reliably exclude DVT and 21% of cancer patients with a normal D-dimer had a DVT compared to 3.5% of patients without cancer (Ann Int Med 1999; 131:417-23) • Echocardiography- Clinically used to assess the potential secondary injury to the heart with the acute pulmonary hypertension that develops after PA obstruction. May indicate a higher risk group for poor outcomes after the diagnosis of PE. Diagnostic Approach to Suspected Acute Pulmonary Embolism
Clinical suspicion Low or moderate ELISA nl No Treatment Nl or abnl Chest CTA/V Positive Negative ? ? abnl CXR nl V/Q Scan Normal Hi prob High Consider initiating Tx


No Treatment

Further tests

No Treatment


If hi clin prob continue

Adapted from: Tapson V. N Engl J Med 2008;358:1037-1052

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Interpreting the CT-angiogram (PIOPED II) CT-angiography Hi Prob (Wells>6) PPV 96% NPV 60

Intermediate (Wells 2-6) Lo Prob (Wells<2) 92 58 89 96

CT-angio+venogram Hi Prob (Wells>6) Intermediate (Wells 2-6) Lo Prob (Wells<2) PPV 96% 90 57 NPV 82 92 97 PIOPED result comparing test performance with or without CT venography: Stein P et al. N Engl J Med

Important point: Better test performance was observed when assessment for PE and DVT were used to determine treatment. Treatment: • DVT: Early anticoagulation with either Unfractionated Heparin (UFH) or LMWH is the goal. Outpatient management with LMWH, warfarin and close follow-up is acceptable in properly selected cases. Warfarin to achieve INR 2-2.5 for at least three months is the standard. This needs to be adjusted based on presenting and revealed risk factors. • Massive DVT: Extended duration Heparins in the initial phase (7-14 days) with the addition of Warfarin to achieve INR 2-2.5 for at least three months is the standard. Occasionally, thrombolytics can be added to treat vascular compromise resulting from DVT. • PE: Early anticoagulation with either Unfractionated Heparin (UFH) or LMWH is the goal. Outpatient management is not pursued because of greater morbidity and mortality. Warfarin to achieve INR 2-2.5 for at least three months is the standard. This needs to be adjusted based on presenting and revealed risk factors. • Massive PE: PE presenting after syncope or with vasopressor requiring hypotension or intractable hypoxemia may be treated with thrombolytics after a careful assessment of bleeding risk. • Special considerations to the duration of treatment o 3 months is the minimum o Transient risk factor (major surgery, etc) 3 months o Idiopathic event (no identifiable risk factor) 6 months at least o Idiopathic event (with known hypercoagulable risk factor) Idefinite o Recurrent idiopathic events Indefinite Follow-up: • Subjects are at the greatest for VTE recurrence in the first 6 months after cessation of therapy. • Subjects should get all indicated preventive health screenings after a diagnosis of VTE as cancer incidence appears increased in those with idiopathic VTE. No additional screening test not otherwise indicated by symptoms, age, gender or exposures are necessary.

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Prevention: Primary prevention: • Incidence of DVT high in medical & surgical patients (range = 15% of medical patients to 40-70% of hip surgery patients [Chest 1989; 95:37S - 51S]) • Perioperative low dose heparin reduces fatal PE by 2/3 in general, orthopedic, & urologic surgery (NEJM 1988; 318:1162-72) TID UFH or daily in high-risk patients Alternatives LMWH or Pneumatic compression boots or ASA Controversies: • Duration of therapy for initial VTE Some studies suggested longer duration of warfarin reduced incidence of recurrence. Longer follow-up reveals there may only be a delay in the recurrence. Exposes patient to a longer duration of bleeding risk. • Low-intensity warfarin therapy Therapy for submassive pulmonary embolism- Some authors have suggested thrombolytics may be beneficial in patients with high clot burden but without clinical signs of massive PE. PE and signs of right heart dysfunction may best characterize these patients. As a result the cardiac echo has been advocated as a test to determine if a patient is at risk for subsequent deterioration. One large study demonstrated less need for subsequent escalation of therapy after thrombolytics were given, but study design was criticized. • IVC Filter Usually clinically used in cases where there are contraindications to anticoagulation. Temporary filters have allowed filters to be used as bridge therapy during a time limited contraindication to anticoagulation (ie surgery or transient GI bleeding). Some authors have advocated as adjunctive therapy in patients without the reserve to tolerate a recurrent PE.

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Control of Ventilation
Date: Time: Faculty: Email: September 15, 2008 8:30 am Roy Essig, M.D.

Objectives 1. Define the anatomic location and the basic function of the 3 primary central controllers of respiration 2. Define the anatomic location and the function of the primary sensing system for arterial PCO2. Compare this to the primary sensing system for arterial pO2. 3. List and define the roles of 4 primary mechano-sensory receptor systems that influence respiratory rhythm generation. 4. Describe the ventilatory responses to changes in pCO2. Describe influence of modest reductions of pCO2 on ventilation vs. severe drops in pCO2. 5. Describe the ventilatory responses to changes in pO2. Distinguish the influence of modest reductions of pO2 on ventilation vs. severe drops in pO2. 6. Be able to recognize the normal responses of PaCO2 and PaO2 to exercise and describe the most recent hypothesis regarding how ventilation is controlled so carefully during exercise.

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Sepsis, Acute Lung injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS)
Date: Time: Faculty: September 15, 2008 9:30 am Jim O’Brien, MD, MSc Assistant Professor Department of Internal Medicine Division of Pulmonary, Critical Care, and Sleep Medicine 201 Davis Heart and Lung Research Institute 247-7707

Phone: Email:

Learning Objectives: 1. Given a clinical vignette, accurately identify patients with sepsis, severe sepsis and septic shock, based on American-European Consensus Conference criteria. 2. Accurately recognize the risk factors, including patient demographics and comorbidities, for sepsis and severe sepsis. 3. Accurately recognize the most common microbiological agents and sites of infection in sepsis. 4. Given a clinical vignette, recognize the initial diagnostic steps in identifying a patient with sepsis and severe sepsis. 5. Given a clinical vignette, recognize the initial therapeutic measures during the resuscitation phase for patients with severe sepsis, including timely administration of appropriate antibiotics and goal-directed resuscitation. 6. Contrast the hemodynamic effects of vasopressor agents used in septic shock. 7. Given a clinical vignette, appropriately select patients with severe sepsis for initial therapeutic efforts, including drotrecogin alfa (activated). 8. Given a clinical vignette, accurately identify patients with ALI/ARDS, based on American-European Consensus Conference criteria. 9. Accurately recognize the risk factors, including patient demographics and comorbidities, for ALI/ARDS 10. Accurately identify the common pathologic features of ALI/ARDS. 11. Accurately identify evidence-based therapies for ALI/ARDS, including lower tidal volume ventilation (e.g. 6ml/kg PBW) and conservative fluid management. Learning Resources: • Required text: o Chapter 254 – Munford, RS. “Severe sepsis and septic shock.” o Chapter 251 – Levy, BD, Shapiro, SD. “Acute respiratory distress syndrome.” • Optional, additional readings o Definitions of sepsis, severe sepsis, septic shock, ALI/ARDS

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Bone, RC, et al. “Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.” Chest 1992; 101: 1644-55. Levy, MM et al. “International sepsis definitions conference.” Crit Care Med 2003; 31: 1250-6. Bernard, GR et al. “The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes and clinical trial coordination.” Am J Resp Crit Care Med 1994; 149: 818-24. Epidemiology of sepsis. ALI/ARDS Angus, DC et al. “Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.” Crit Care Med 2001; 29: 1303-10. Martin, GS, et al. “The epidemiology of sepsis in the United States from 1979 through 2000.” N Engl J Med 2003; 348: 1546-54. Rubenfeld, GD et al. “Incidence and Outcomes of Acute Lung Injury.” N Engl J Med 2005;353:1685-93. Pathogenesis of sepsis, ALI/ARDS Hotchkiss, RS, Karl, IE. “The pathophysiology and treatment of sepsis.” N Engl J Med 2003; 348: 138-150. Ware, LB et al. “The Acute Respiratory Distress Syndrome.” N Engl J Med 2000; 342: 1334. Review on treatment of sepsis, ALI/ARDS O’Brien JM, Ali NA, Aberegg SK, Abraham E. “Sepsis:a review of epidemiology, pathogenesis and treatment.” Am J Medicine 2007; 120: 1012-22. O’Brien, JM, Abraham, E. “New approaches to the treatment of sepsis.” Clin Chest Med 2003; 24: 521-548. (reprints available from me if requested) Balk, RA. “Optimum treatment of severe sepsis and septic shock: evidence in support of the recommendations.” Dis Month 2004; 50(4): 168-213. Fan, E. et al. “Ventilatory management of acute lung injury and acute respiratory distress syndrome.” JAMA 2005; 294: 2889-96. Seminal articles on treatment of sepsis, ALI/ARDS Bernard, GR et al. “Efficacy and safety of recombinant human activated protein C for severe sepsis.” N Engl J Med 2001; 344: 699-709. Annane, D et al. “Effects of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.” JAMA 2002; 288: 862-71. Rivers, E et al. “Early goal-directed therapy in the treatment of severe sepsis and septic shock.” N Engl J Med 2001; 345: 136877. NHLBI ARDSNet. “Comparison of Two Fluid-Management Strategies in Acute Lung Injury.” N Engl J Med 2006; 354:2564-75.

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NHLBI ARDSNet. “Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.” N Engl J Med 2000;342:1301-8. SEPSIS A. Definitions 1. Systemic Inflammatory Response Syndrome (SIRS) – 2 or more of the following abnormalities: a. Tachycardia (≥90 beats/minute) b. Temperature (≥38°C or ≤36°C) c. Tachypnea (≥20 respirations/minute) d. WBC count (≥12,000/mm3 or ≤4000/mm3 or >10% immature neutrophils) 2. Sepsis = SIRS with a confirmed or presumed infectious source 3. Severe Sepsis = Sepsis with acute organ dysfunction a. Neurologic b. Respiratory c. Hepatic d. Renal e. Coagulation 4. Septic Shock = hypotension refractory to volume resuscitation due to sepsis 5. Mortality increases with more complicated sepsis a. Sepsis 7-17% b. Severe sepsis 20-53% c. Septic shock 53-63% B. Epidemiology 1. Incidence has increased by almost 9% per year since 1979 2. In 2000, there were approximately 660,000 cases of sepsis or 240 cases per 100,000 population 3. Almost 40% of these cases involved acute organ dysfunction (severe sepsis) 4. Mortality rate has decreased by approximately 10% since 1980, but because of higher incidence, mortality due to sepsis has increased a. At least the 10th leading cause of death b. Responsible for approximately 100,000 deaths per year 5. Average cost is $22,1000 per case for a national hospital cost of almost $17 billion per year C. Pathogenesis 1. Infectious agents a. Variety of infectious agents and microbiological products can be responsible. b. Gram positive organisms the most common c. Fungal organisms are increasing in importance

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d. Only about 30% of patients have a positive blood culture e. Respiratory is most common source 2. Patient factors a. Older b. Male c. Non-white d. Immunosuppression – AIDS, therapeutic e. Cancer, Cirrhosis, Alcohol abuse f. In-dwelling catheters g. Polymorphisms in genetic factors in innate immunity, cytokines, etc. D. Treatment – Supportive care 1. Antibiotics a. Start broad b. Inadequate initial antibiotics increase mortality 4-fold 2. Volume resuscitation a. May require 4-8L of crystalloid (i.e. Normal saline, lactated Ringers’) b. Inadequate resuscitation may increase mortality c. Early goal-directed therapy (EGDT) in the emergency department reduced mortality in one study (NNT=7) 1. In addition to mean arterial pressure, urine output, and central venous pressure, EGDT targeted central venous oxygen saturation (CVO2) as a measure of oxygen delivery 2. Adjustments to CVO2 required use of blood and dobutamine 3. Vasopressors Heart Rate Contractility Vasoconstriction Norepinephrine 2+ 2+ 4+ Dopamine 3+ 2+ 3+ Dobutamine 2+ 4+ 1Phenylephrine 20 4+ Epinephrine 4+ 4+ 4+ Vasopressin 113+ 4. Renal replacement therapy (dialysis) E. Treatment – Specific therapies 1. Drotrecogin alfa (activated) – recombinant form of activated protein C a. Uncertain mechanism of effect – has anticoagulant, antiinflammatory and anti-apoptotic effects b. Treatment improved survival (NNT=17) but greatest benefit was in sickest patients c. Increases risk of bleeding with almost 1% having an intracranial hemorrhage

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ALI/ARDS A. Definitions 1. Acute onset 2. Bilateral alveolar infiltrates 3. No evidence of elevated left atrial pressures 4. Hypoxemia a. PaO2/FiO2 ratio ≤ 300 = Acute lung injury (ALI) b. PaO2/FiO2 ratio ≤ 200 = Acute respiratory distress syndrome (ARDS) • Mortality increases with progression to ARDS B. Epidemiology 1. Approximately 190,600 cases of acute lung injury per year in the US 2. Accounts for 74,500 deaths 3. Accounts for 3.6 million hospital days C. Pathogenesis 1. Clinical risk factors a. Sepsis – especially pulmonary source b. Transfusions c. Ventilator management 2. Patient factors a. Older b. Polymorphisms in genetic factors in innate immunity, cytokines, etc. D. Treatment 1. Artificial ventilation – lower tidal volumes (i.e. 6 cc/kg predicted body weight) improve outcome, compared to traditional tidal volumes (i.e., 12 cc/kg predicted body weight) – NNT=12 2. Prevention of ventilator complications a. Elevation of head of bed b. Protocols for assessment of ventilator liberation c. Protocols for sedation management d. Consideration of early tracheotomy E. Treatment – Specific therapies 1. Fluid management a. In hemodynamically stable patients, keeping filling pressures low reduces time on ventilator b. Does not increase need for vasopressors or dialysis c. No significant effect on mortality.

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Respiratory Failure
Date: Time: Faculty: Email: September 15, 2008 10:30 am Stephen Hoffmann, M.D.

Objectives: Critical Care -- Respiratory Failure 1. 2. 3. 4. 5. List the mechanisms of hypoxemia Calculate a A-a gradient List the mechanisms of hypoxemia with a normal A-a gradient List the mechanisms of hypoxemia with an abnormal A-a gradient Describe various types of oxygen delivery devices

Respiratory Failure is defined as the Failure to maintain adequate oxygen and carbon dioxide homeostasis. Fundamentally it is impaired gas exchange due to failure of the respiratory system. It may acute, chronic or acute on chronic. There are two major reasons for respiratory failure. • Failure of respiratory pump resulting in ineffective ventilation • Failure of gas exchanging region (alveolar-capillary membrane) The Respiratory System is composed of many discrete anatomic structures and systems. Failure of any of them may result in respiratory failure. • CNS (medulla) • Peripheral nervous system (phrenic nerve) • Respiratory muscles • Chest wall • Lung • Upper airway • Bronchial tree • Alveoli • Pulmonary vasculature • Heart and the peripheral vasculature There are three Types of Respiratory Failure. Hypoxemic Respiratory Failure is a failure of gas exchange usually resulting in a low PaO2 and a low or normal PaCO2 along with an elevated A-a gradient. Most commonly it is due to ventilation/perfusion mismatch. Hypercapnic Respiratory Failure is a failure of respiratory pump where demand exceeds supply. It is characterized by ineffective ventilation (increased PaCO2) with normal A-a gradient. PaCO2 > 45 mmHg is present and it is frequently associated with low PaO2. Mixed Hypoxemic and Hypercapnic Respiratory Failure is very common and is the third type. Hypercapnic Respiratory Failure PaCO2 is normally maintained in a narrow range by adjusting alveolar ventilation to match CO2 production.

PaCO2 = 0.863 x Rate of CO2 Production Alveolar Ventilation

Ventilatory failure occurs when minute ventilation is unable to keep up with production of CO2 due to: depressed respiratory drive, inadequate neuromuscular competence or excessive respiratory system load.

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Resistive Loads
Bronchospasm Airway edema, secretions, scarring Upper airway obstruction OSA

Depressed Drive
Drug Overdose Brainstem Lesion Sleep Disordered Breathing Hypothyroidism

Lung Elastic Loads
Alveolar edema Infection Atelectasis


Neuromuscular Competence

Muscle Weakness
Fatigue Electrolyte Derangement Malnutrition Hypoperfusion States Myopathy

Chest Wall Elastic Loads
Pleural Effusion Pneumothorax Rib fractures/flail chest Tumor Obesity Ascites Abdominal Distention Fibrothorax

Impaired N-M Transmission Minute Volume Loads
Sepsis Pulmonary Embolus Excess Calories Phrenic Nerve Injury Cord Lesion Neuromuscular Blockers GBS Myasthenia Gravis ALS Botulism

Adapted from Murray and Nadel, 1995

Hypoxemic Respiratory Failure Hypoxemic is a failure of gas exchange usually resulting in a low PaO2. The normal alveolar oxygen tension is determined by the alveolar gas equation: • (Barometric pressure – H2O vapor pressure)FiO2 – PaCO2/Respiratory quotient o (BP – WVP)FiO2 – PaCO2/0.8 o (760 – 47)0.21 – 40/0.8 = o 150 – 50 = 100 mm Hg

It is influenced by the barometric pressure, the FIO2 and the PaCO2. Normal arterial oxygen tension decreases with age and can very roughly be estimated: • PaO2 = 104 – (age x 0.4)

The (A-a) Gradient is the partial pressure of oxygen in the alveolus minus partial pressure of oxygen in an artery (alveolar air equation minus the PaO2). • • [FIO2 * (Barometric pressure - water vapor) - (1.2*PCO2)] - PaO2 o [FIO2(760 - 47) - (1.2 * PCO2)] - PaO2 o [FIO2(713) - (1.2 * PCO2)] - PaO2 At Room Air (where is most clinically relevant): o [150 - (1.2 * PCO2)] - PaO2 = A-a Gradient

The normal A-a gradient is 8 - 12 mmHg and increases with age (roughly estimated by [Age/4 + 4]) and also increases with increasing FIO2 ( 5-7mmHg for every 10% increase in FIO2). The A-a gradient can be used to help distinguish the mechanisms of hypoxemia. The most common mechanisms of hypoxemia include: • • • • • Hypoventilation Ventilation/perfusion mismatch Shunt Decreased inspired oxygen Impaired diffusion

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Impaired Diffusion is most common with interstitial lung disease. The thickened interstitium impedes diffusion of oxygen from the alveolus to the capillary. The resulting hypoxemia is usually not significant except during states of increased oxygen demand (exercise) probably due to the combination of impaired diffusion and the decreased transit time of blood through alveolar capillaries due to increased cardiac output. Decreased Inspired Oxygen occurs at altitude. Both barometric pressure and altitude have a dramatic effect on oxygen tension. For example, Oxygen tension of inspired air: • Sea level = 150 mm Hg • Denver = 130 mm Hg • Mt. Everest = 43 mm Hg Hypoventilation (already discussed) results in hypoxemia that is always associated with hypercapnea (by definition). Remember that alveolar ventilation determines carbon dioxide tension and the normal physiologic response to increases in PaCO2 is to increase minute ventilation and thus alveolar ventilation. Ventilation/Perfusion alteration is the most common cause of hypoxemia. The adequacy of gas exchange in the lungs is determined by the balance between pulmonary ventilation and capillary blood flow. This balance is expressed as the ventilation-perfusion (V/Q) ratio. • Normal V/Q ratio ≅ 1 o Ideally, ventilation and perfusion matched for optimal gas exchange • Shunt = V/Q ratio < 1 o Pure shunt: V/Q = 0 o Perfusion of nonventilated areas • Dead space = V/Q ratio > 1 o Pure dead space ventilation: V/Q = ∞ o No perfusion to ventilated areas Clinical Situations of High V/Q (Increase Deadspace): • • • Pulmonary embolism Physiologic dead space can be seen in COPD Normal response is to increase minute ventilation o ↑ VE not very effective for correcting hypoxemia as this cannot increase already maxed alveolar oxygen tension

Clinical Situation of Low V/Q (Shunt): • • • • V/Q = 0 is represented by true right to left shunting (intracardiac defect) with venous admixture of blood. o Alveoli completely bypassed Any situation where alveoli are filled (not ventilated): o Blood, pus, water - Alveolar hemorrhage, pneumonia, CHF, ARDS Atelectasis of lung Normal physiologic response---hypoxemic vasoconstriction

The A-a Gradient reacts differently in each of these mechanisms but can help divide the causes into two main groups: • Increased A-a Gradient: o V/Q mismatch o Impaired diffusion o Pure Shunt (V/Q=0) • Normal A-a Gradient: o Decreased inspired oxygen o Hypoventilation

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Recognizing/Diagnosis of Impending Respiratory Failure Diagnosis depends upon clinical suspicion, followed by confirmation by ABGs and integrated with clinical judgment and attempts to identify a specific etiology. Requires clinical judgment and assessment by a physician at the bedside. Useful parameters include respiratory rate, mentation, pattern of breathing and patients own assessment. An arterial blood gas can be used to determine the presence of respiratory failure. – Absolute values of PaO2 and PaCO2 that define respiratory failure depend on many factors. – Generally a PaO2 < 50 - 60 torr or a PaCO2 > 50 torr represent respiratory failure. However an assessment made only by ABG is fraught with errors.

Variation in ABGs
Variation Mean 95 Percentile Range

Normal Arterial Blood Gases
AGE (Years) 20 30 40 50 60 70 80 P aO2 (mmHg) 84-95 81-92 78-90 75-87 72-84 70-81 67-79 P aCO2 (mmHg) 34-47 34-47 34-47 34-47 34-47 34-47 34-47 A – a PO2 (mm Hg) 4-17 7-21 10-24 14-27 17-31 21-34 25-38

PaO2 (mm Hg) 13 +/- 18 2 – 37

PaCo2 (mmHg)

+/- 4 0 - 12

Represents variation over a 1-hour period in 26 clinically stable ventilator dependent patients From Hess D, Agarwal NN. J Clin Monitor 1992

All values related to FIO2 = 21% at sea level Adapted from Intermountain Thoracic Society Manual, 1984 44-45

Respiratory Failure Management The three main goals in the management of respiratory failure are: • Maintain an airway • Correct the hypoxemia (Maintain oxygen saturation > 90% and remember oxygen delivery - an increase in PO2 should not be used as evidence of an increase in tissue oxygenation) and acid base status • Most importantly identify and correct the underlying problem. Oxygen Saturation & Oxygen Delivery Remember oxygen content (CaO2) is a more important management measure than PO2: CaO2 = ([Hb] * %Sat * 1.34 ml/g) + (PO2 * 0.003) Oxygen delivery the key parameter [CaO2 * Cardiac output (CO)]. PO2 is a diagnostic/evaluative measure Oxygen Delivery Devices

Those that do not provide ventilation: – Low Flow - Reservoir Devices • Nasal cannula • Simple face mask • Non/partial rebreathers – High flow delivery devices • Venturi mask • Dual regulator/Blenders – CPAP

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Those that provide ventilation: – Mechanical ventilation – Noninvasive Positive Pressure Ventilation (NIPPV) • Full face mask • BIPAP

When the patient is placed on a simple oxygen delivery device 100% oxygen is delivered from the regulator to the patient at a selected flow (usually liters per minute). The FIO2 of the oxygen reaching the lungs is a mixture of that 100% oxygen from the wall/reservoir and the oxygen entrained from the room (21% FIO2).

Low-Flow Oxygen Delivery
Device R e s e v oi r Cap a c it y (mL) 50 Oxy g e n Fl o w (L/mi n) 1 2 3 4 5 6 5-10 5-7 5-10 Appr o x i m a te FIO2 0.21-0.24 0.24-0.28 0.28-0.34 0.34-0.38 0.38-0.42 0.42-0.46 0.40-0.60 0.35-0.75 0.40-1.0

Nas al Can n ula

Simple F ace mask Mask -resevoir bag Pa r tial Rebreat her Non rebrea t her

150-250 750-1250

Estimated based on tidal volume of 500 mL, RR of 20 and I:E of 1:2 From Shapiro BA, et al 1991

High Flow Masks provide precise FIO2 at higher flows. Flow of oxygen entrains room air prior to the patient resulting in known FIO2 being delivered to the patient. Desirable in patients with chronic hypercapnea who are at risk of increased CO2 retention with increases in FIO2. Continuous Positive Airway Pressure (CPAP), does not provide ventilation but does increases FRC and can improve V/Q match. Indications include: CHF, COPD, Atelectasis, Sleep Disordered Breathing Devices that Ventilate The difference between “mechanical ventilation” and “Non-Invasive Positive Pressure Ventilation (NIPPV)” is the interface: either an Endotracheal Tube (ETT) or a face mask. NIPPV can use either a full size ventilator or a “BIPAP” machine. Selection Criteria for NIPPV • • • Respiratory distress with moderate to severe dyspnea, use of accessory muscles of respiration, abdominal paradox pH < 7.35 with PaCO2 > 45 Respiratory rate > 25 bpm

Exclusion Criteria for NIPPV • Absolute • Respiratory arrest • Cardiorespiratory instability (hypotension with impaired perfusion, serious dysrhythmia, myocardial infarction with pulmonary edema) • Uncooperative patient • Recent facial, esophageal or gastric surgery • Craniofacial trauma or burns • High aspiration risk

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• • •

Inability to protect airway Fixed anatomic abnormalities of the nasopharynx

Relative • Extreme anxiety • Massive obesity • Copious secretions • ARDS

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Date: Time: Faculty: Email: September 16, 2008 10:00 am Elizabeth Allen, MD

Asthma Objectives 1. 2. 3. 4. 5. 6. 7. 8. Describe the airway abnormalities characteristic of asthma, and their functional consequences Describe typical symptoms of asthma List common triggers of asthma exacerbations Recognize clinical patterns that are suggestive of an asthma diagnosis Describe the utility (and limitations) of tests used to assess the asthmatic patient Describe typical physical exam findings of a patient experiencing an acute asthma exacerbation Identify therapies used in the treatment of acute asthma exacerbations Correctly categorize asthma patients regarding whether they have persistent or intermittent asthma (i.e. whether they do or don’t warrant controller therapy.) 9. List commonly used controller therapies, and describe their primary mechanism and role in therapy 10. Identify reasons why asthma therapy might fail.

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Therapy of Asthma
Definition of Asthma

Normal Airway Physiology

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Cells Involved in the Asthmatic Response

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Treatment of Asthma Non-Pharmacologic Treatment

Pharmacologic Treatment


Beta2 -Receptor Agonists



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Relatively selective B2 agonists albuterol (Proventil) terbutaline (Brethine) pirbuterol (Maxair) bitolterol (Tornalate) formoterol (Foradil) levalbuterol (Xopenex) metaproterenol (Alupent) arformoterol (Brovana) salmeterol (Serevent) isoetharine

Cholinergic Blocker ipratropium bromide(Atrovent) tiotropium (Spiriva)

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Phosphodiesterase inhibitor

theophylline (Aminophylline)

Anti-Inflammatory Agents

mast cell inhibitors cromolyn sodium (Intal) nedocromil (Tilade)

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glucocorticoids beclomethasone (Beclovent) budesonide (Rhinocort) flunisolide (Aerobid) fluticasone (Flonase) mometasone (Asmanex) triamcinolone (Azmacort) prednisone dexamethasone

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Anti IgE antibody omalizumab (Xolair)

Inhibitors of the leukotriene system

Leukotriene Synthesis Inhibitor zileuton (Zyflo)

Leukotriene receptor blockers

zafirlukast (Accolate) montelukast (Singulair)

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Pleural Disease
Date: Time: Faculty: Phone: Email: September 17, 2008 8:30 – 9:20 Charles L. Hitchcock, M.D., Ph.D., Department of Pathology 081 - Heart and Lung Research Institute Office 247-7469

Learning Objectives: 1. Describe the general mechanisms underlying pleural effusions and disorders associated with different types of effusions. 2. Compare and contrast the morphologic and epidemiologic features of malignant mesothelioma and solitary fibrous tumor of the pleura. 3. Recognize the clinical presentation of a pneumothorax and compare and contrast primary and secondary spontaneous pneumothoraces as to their etiology. Learning Resources 1. Robbins Pathologic Basis of Disease, 7th Ed., pp. 766-770. 2. Harrison’s Principles of Internal Medicine, 16th Ed., ch 245. I. PLEURAL EFFSUION A. General Features 1. The pleural space normally contains up to 15 mL of serous fluid that is characterized as being acellular, clear, with low protein concentration, with a pH and glucose levels similar to that in the peripheral blood. 2. Serous fluid enters the pleural space by normal hydrostatic pressures and is absorbed by the subpleural lymphatics (parietal). Fluid may also enter the space from the abdomen (thru pores in the diaphragm). 3. Lymphatics can absorb up to a 20-fold increase in fluid. 4. An accumulation of pleural fluid (effusion) occurs in the following settings: a. Increased vascular permeability (pneumonia) b. Increased hydrostatic pressure (e.g. in congestive heart failure) c. Decreased plasma oncotic pressure (nephrotic syndrome) d. Decreased lymphatic drainage (mediastinal tumor) e. Increased intrapleural negative pressure (atelectasis)

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B. Clinical Features 1. A clinical presentation of a pleural effusion is related to the volume of fluid and its rate of accumulation. 2. It may present as dyspnea or chest pain, or it may be asymptomatic. a. “Pleuritic chest pain” is often unilateral, sharp and exacerbated by deep breathing or coughing. 3. A pleural effusion is accompanied by decreased breath sounds, dullness to percussion, decreased vocal fremitus, bronchial breathing and egophony. 4. Radiologic features vary with the amount of fluid. a. Upright radiographs show elevated hemidiaphragm(s), blunting of the costophrenic angle when volume > 250 mL, opacification (“white out”) of the hemithorax with large volumes. b. Lateral decubitus radiographs show if the fluid is free flowing. c. Ultrasound and CT are used to evaluate loculated effusions. C. Pathologic Features 1. Analysis a. Thoracentesis of 30-50 mL for testing (more is better) will be diagnostic in ~ 75% of cases; even if nondiagnostic it may exclude a number of things. i. gross appearance may be clear, cloudy/purulent, bloody, or milky. ii. pH < 7.0 may indicate esophageal rupture iii. glucose < 20 mg/dL may indicate rheumatoid effusion protein iv. cell count & differential can be used to differentiate acute from chronic inflammation. v. cytology examination helps to rule out a malignancy vi. culture for bacterial, acid fast and fungal infections b. Transcutaneous pleural biopsy – may be performed for malignancy or for culture; sometimes needed to diagnose TB. 2. Transudate vs. Exudate a. Transudative effusions are the result of increased vascular hydrostatic pressure (CHF) or decreased plasma oncotic pressure (nephrotic syndrome). b. Exudative effusions are the result of increased vascular permeability due to infections/pneumonia or trauma. c. Transudates have low protein content (< 3 g/dL) with a pleural fluid/serum protein ratio < 0.5 and a pleural fluid/serum LD ratio < 0.6

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d. Exudates have high protein content (> 3 g/dL) with a pleural fluid/serum protein ratio > 0.5 and a pleural fluid/serum LD ratio > 0.6 3. Hydrothorax is a transudate that accumulates in the pleural space. The volume may be massive. The etiologies include: a. Congestive heart failure (most common cause and it is usually bilateral). b. Nephrotic syndrome (associated with reduced plasma oncotic pressure from hypoproteinemia or salt and water retention). c. Meigs syndrome (a combination of ascites, ovarian fibroma, and a right sided only hydrothorax) 4. Hemothorax refers to blood in the pleural space. It is most often associated with trauma or a ruptured aortic aneurysm. It can also be seen in patients with hematologic disorders, malignancy, pulmonary embolus, or a collagen vascular disease (e.g. SLE). 5. Chylothorax refers to accumulation of a milky fluid (“chyle”) or lymph due to leakage from the thoracic duct. They are commonly left sided, but may be bilateral. a. Most common causes are obstruction or trauma to the thoracic duct, surgical trauma, and obstruction from metastatic disease. b. The fluid contains high triglyceride levels. 6. Empyema is a purulent, pleural exudate that complicates lung infections such as those caused by pneumococci, streptococci, and staphylococci. a. The pleural surfaces are coated by thick and shaggy fibrin layers (fibrinopurulent) that can undergo organization. Organization (i.e. wound healing) produces fibrous adhesions, localizing the pus so it cannot be drained, and eventually proceeds to encase the lung in a fibrous coat which may limit expansion. b. The exudate is creamy yellow-green with a large number of PMNs, a pH < 7.2, a glucose < 40 mg/dL, LD > 1,000, and may grow organisms when cultured. 7. Pleuritis refers to chronic inflammation of the pleura. a. Inflammatory pleural exudates rich in mononuclear cells (lymphocytes and macrophages) are seen in cases of tuberculosis, lung infarcts, lung abscesses, and bronchiectasis. b. Serofibrinous exudates are associated with collagen vascular diseases (rheumatoid arthritis, SLE), uremia, metastatic involvement of the pleura, and radiation therapy.

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8. Malignant pleural effusions are acutely exudative and bloody. a. They are the most common cause of an exudate in persons > 60 years of age. b. They are commonly seen in carcinomas of the lung and breast, and, to a lesser extent, the liver, stomach and ovaries. Lymphomas may result in an exudate. c. The diagnosis requires cytologic examination of an aspirate.

II. TUMORS OF THE PLEURA A. General 1. Metastatic tumors, mainly carcinomas of the lung and breast, are the most common tumor affecting the pleura. 2. Metastatic tumors commonly produce bloody (sanguineous) effusions, and malignant cells can be identified by cytologic examination of the pleural fluid obtained by thoracentesis. 3. Primary tumors of the pleura are classified as either diffuse or solitary lesions. Mesotheliomas are diffuse or solitary fibrous tumors are localized nodules. B. Malignant Mesothelioma 1. General Features a. Mesotheliomas are highly aggressive malignant tumors that arise from mesothelial cells that line pleural (65%-70%), peritoneal (30%), and pericardial (1%-2%) surfaces. b. Mesotheliomas are rare tumors that are most commonly associated with an occupational history of exposure to asbestos (asbestos miners, shipyard workers, textile workers, etc). c. There are approximately 2,500 new cases diagnosed per year in the U.S. in men between 50 and 70 years of age. d. They are a common cause of worker’s compensation and medicolegal litigation ( e. Long latency period from exposure to onset of the tumor (30 years and more). No relation to smoking. 2. Clinical Features a. Patients often present with progressive dyspnea, most often due to a large pleural effusion, and/or chronic chest pain. These may also be accompanied by weight loss, a nonproductive cough, fatigue, and/or fever.

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b. Imaging studies, CT with contrast being the best, demonstrate a unilateral diffuse thickening of the pleura and/or a pleural effusion. c. Diagnosis is based on an open or on a video-assisted thoracoscopy (VATS) biopsy. d. Mesotheliomas are associated with a fatal clinical course. e. Treatment may involve surgery, radiation therapy, and/or chemotherapy. The survival rate is less than 6 months for the untreated patient.

3. Pathologic Features a. Tumors are grossly characterized by diffuse thickening of the pleura with complete encasement of the lung by a thick, gray-white tumor crust. b. Mesotheliomas are histologically characterized by a proliferation of blandappearing mesothelial cells with minimal atypia that form tubulo-papillary structures. Some cases may show a biphasic or predominantly sarcomatoid (spindle cell) appearance that can be difficult to distinguish from a sarcoma. c. Mesotheliomas may be difficult to distinguish from metastatic adenocarcinoma. Special stains and electron microscopy are required for diagnosis. Abundant long, slender microvilli on the cell surface are diagnostic by electron microscopy. C. Solitary Fibrous Tumor 1. Solitary fibrous tumors are mesenchymal in origin and are not associated with asbestos exposure. 2. More than 80% have a benign clinical course, but they can grow to a size that compresses the lung and other intrathoracic structures. They are often associated with paraneoplastic syndromes – clubbing, hypertrophic osteoarthropathy, and hypoglycemia due to production of insulin-like growth factor II (IGF-II). The paraneoplastic syndromes resolve with excision of the tumor. 3. Pathologic Features a. On gross examination, solitary fibrous tumors often appear as a polypoid, pedunculated, fleshy mass attached to the pleural surface by a short pedicle. b. These tumors are histologically characterized by bland spindle cell proliferation (no mitoses or atypia) with abundant stromal collagenization.

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III. PNEUMOTHORAX A. General Features 1. Pneumothorax refers to the presence of air or gas in the pleural space that forces variable degrees of partial lung collapse. 2. Pneumothorax is a potential medical emergency. 3. Primary spontaneous pneumothoraces arise in individuals without underlying lung disease or trauma. Secondary spontaneous pneumothoraces arise in individuals with a parenchymal lung disease. B. Signs and Symptoms 1. Acute onset of shortness of breath and/or chest pain is the most common presenting feature. The chest pain may be stabbing and increases with inspiration (pleuritic). Dyspnea is more severe in patients with underlying parenchyma lung disease. 2. Cough, anxiety, and malaise and fatigue are much less common. 3. Patients often appear diaphoretic with splinting chest wall. Cyanosis may be seen in cases of tension pneumothorax. 4. Physical examination can demonstrate tachycardia, tachypnea, distant or absent breath sounds, hyperresonance on percussion, decreased tactile fremitus, and pulsus paradoxus. C. Etiologies 1. Spontaneous pneumothorax is commonly affects young adults, usually males, 20-40 years of age, without evidence of prior lung disease. It involves the rupture of one or more subpleural blebs, right lung > left lung. About half will recur. This may be seen in Marfan syndrome. 2. Traumatic pneumothorax associated with a penetrating chest wound, e.g. bullet, knife, fractured rib, or iatrogenic commonly due to a central line catheter or following a lung biopsy. a. Barotrauma is usually associated with Scuba diving where the gas within the lung rapidly expands and ruptures during rapid ascent. 3. Secondary spontaneous pneumothoraces is associated with a long ist of parenchymal lung disease that include: a. COPD – especially bullous emphysema b. Tuberculosis c. Necrotizing pneumonia d. Asthma e. Cystic fibrosis f. Cancer
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g. Interstitial lung disease h. Lymphangioleiomyomatosis (LAM) 4. A tension pneumothorax is a medical emergency caused by a valve action at the margins of a leak, trapping air under increasing pressure. This totally collapses the lung and displaces the mediastinum contralaterally. It may be encountered with mechanical ventilation or resuscitation. a. There are no breath sounds.

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Disorders of the Upper Airways
Date: Time: Faculty: September 17, 2008 9:30 am Jennifer W. McCallister, MD Assistant Professor Clinical Internal Medicine Division of Pulmonary, Allergy, Critical Care, & Sleep Medicine


1. Given a clinical vignette, accurately recognize the common symptoms of disorders of the upper airways. 2. Given a clinical vignette, accurately formulate a differential diagnosis in a patient with upper airway complaints. 3. Given a clinical vignette, decide on the appropriate test(s) to order when evaluating a patient with upper airway complaints. 4. Given a clinical vignette, accurately recognize patients in whom empiric treatment for upper airway complaints is appropriate and patients in whom additional testing is immediately warranted. 5. Describe the unified airway disease (UAD) hypothesis and when given a clinical vignette, accurately apply the principals to the selection of treatment in patients with upper and lower airway disorders. 6. Describe the basic mechanisms and inflammatory mediators of the allergic response. Upper airways • Anatomically complicated structures that extend from the airway openings at the nares and lips to the trachea • Serve numerous physiologic functions including olfaction, deglutition, phonation, coughing, and filtering, conditioning, and conveying air to the lungs Complaints related to upper airway disorders • Cough, hoarseness, pain, dyspnea, wheezing, stridor, swelling, nasal congestion, rhinorrhea, dysphagia Differential diagnosis of upper airway disorders • Neoplastic • Infectious • Allergic • Immunologic/rheumatologic • Functional • Idiopathic • Endocrine • Iatrogenic
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Rhinitis • Inflammation of nasal mucosa with characteristic nasal symptoms • Classified according to etiology and pattern of symptoms o Infectious rhinitis: Acute: viral (most common cause), bacterial Chronic: bacterial, fungal o Allergic rhinitis Acute episodic Seasonal: tree, grass, weed pollens, fungi Perennial: dust mites, cockroaches, animal proteins Occupational o Perennial non-allergic rhinitis Idiopathic (vasomotor rhinitis) o Miscellaneous Hormonal: pregnancy, hypothyroidism, etc. Drug induced: rhinitis medicamentosa (decongestant nasal sprays), antihypertensives, etc. Mechanical: deviated septum, nasal polyps, malignancy Granulomatous: sarcoidosis, Wegeners granulomatosis Allergic response • IgE mediated, requires prior sensitization • Early phase: mediated primarily by histamine • Late phase: mediated by prostaglandins and leukotrienes • Priming: continuous exposure to an allergen results in persistent nasal inflammation and symptoms with lower dose exposures • Hyperreactivity: response to nonspecific irritants Evaluation of patient with rhinitis • History: identify triggers, family or personal history of atopic disease • Physical exam: allergic salute, allergic shiners, characteristic pale, bluish color of edematous turbinates in some patients, cobblestoning of posterior pharynx Treatment of allergic rhinitis • Empiric treatment usually appropriate • Environmental measures and allergen avoidance • Antihistamines, oral decongestants, nasal ipratropium targeted at acute symptomatic relief • Mainstay (i.e. treatment of choice) for chronic symptoms: intranasal corticosteroids (ex. Flonase); addition of antihistamine and leukotriene modifiers helpful in some cases • Refer for allergist evaluation (skin testing, RAST) in patient with unclear diagnosis or inadequate response to treatment

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Sinusitis • Inflammation of one or more of the paranasal sinuses • Most commonly infectious • Classification o Acute: symptoms < 4 weeks o Subacute: (unresolved acute) symptoms from 4 to 8 weeks o Chronic: symptoms for 8 weeks or longer despite appropriate treatment o Recurrent: 3 or more episodes of acute sinusitis/year • Predisposing factors (i.e. increased risk) for sinusitis o Allergic and nonallergic rhinitis o Immunodeficiency Common variable immunoglobulin deficiency (CVID) IgA deficiency o Cystic fibrosis o Primary ciliary dyskinesia o Rhinitis medicamentosa o Anatomic abnormalities Nasal polyps Septal deviation Treatment of acute sinusitis Diagnosis generally made on basis of history & physical Decision to treat based on clinical grounds o Suspect in patients with URI persisting beyond 10-14 days o Consider antibiotics Worsening symptoms after 3-5 days Temperature > 39°C Maxillary tooth or facial pain Unilateral sinus tenderness Periorbital swelling o Avoid antibiotic therapy of uncomplicated viral URI!! 7-10 days of watchful waiting in uncomplicated case o Direct therapy at most common pathogens S. pneumoniae M. catarrhalis H. influenza Chronic sinusitis Symptoms similar but might be more subtle Evaluate for predisposing conditions Obtain imaging to include CT sinuses and osteomeatal complex Additional pathogens o S. aureus o Enteric gram negatives (ex. P. aeruginosa) o Anaerobes (Prevotella species) o Fungi

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Invasive fungal sinusitis (ex. mucormycosis) o Immunocompromised patients Diabetes Malignancy Chronic high-dose steroids o Symptoms Fever, headache, epistaxis, mental status changes o CT of sinuses with characteristic nodular mucoperiosteal thickening with focal areas of bony destruction o Aggressive surgical debridement and systemic antifungal therapy indicated (immediately!) Unified airway disease (UAD) Upper and lower airway disease may be manifestations of a single inflammatory process involving the respiratory tract Both parts of the airway should be assessed and managed accordingly Spectrum of disease o Rhinitis alone o Rhinitis and nonspecific bronchial hyper-responsiveness (BHR) o Rhinitis and asthma 80% of patients with asthma have rhinitis 50% of patients with rhinitis have asthma Both the presence and severity of rhinitis are associated with worse asthma outcomes Rhinitis is a risk factor for later developing asthma Treatment of allergic rhinitis with intranasal steroids has been shown to reduce BHR in asthmatics and improve asthma symptoms In patients with allergic rhinitis and mild asthma, daily antihistamine therapy has been shown to improve asthma symptoms, peak expiratory flow rates, and reduce rescue bronchodilator use Sinusitis is common in patients with asthma; treatment of sinusitis in these patients has been shown to improve pulmonary function, asthma symptoms, and pulmonary function (peak expiratory flow rates) Nasal polyps Inflammatory outgrowths of paranasal sinus mucosa as a result of chronic mucosal inflammation Primary symptoms o Nasal congestion o Rhinorrhea o Hypo- or anosmia Rarely (if ever) malignant No single predisposing condition Prevalence in allergic rhinitis (1.5%) similar to general population (1%) Commonly associated with: o Non-allergic rhinitis

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o Aspirin induced asthma (Samter’s triad) Nasal polyposis, asthma, aspirin sensitivity o Cystic fibrosis (CF) Always think CF in child with nasal polyps Treatment o Surgery in cases of severe obstruction or recurrent sinusitis; oral corticosteroids (ex. Prednisone) with severe obstruction or smell disturbance o Intranasal steroids as maintenance Decrease size Reduce recurrence after surgery Angioedema Self-limited, localized swelling of skin & mucosa Extravasation of fluid into interstitial spaces due to increased vascular permeability Usually benign, but may be life threatening (laryngeal involvement, anaphylaxis) Mechanisms o Mast cell mediated (90% urticaria & pruritis): Allergic (food, drugs, latex, bee stings), direct mast cell stimulation (opiates) o Kinin mediated (urticaria & pruritis usually absent) : ACE inhibitors (ex. Enalapril, captopril), C1 inhibitor deficiency Hoarseness Any change in voice quality Laryngitis o Acute Viral URI or acute vocal cord strain M. catarrhalis & H. influenza o Chronic Irritants: GERD, sinusitis, EtOH, smoking Vocal cord polyps o Result of chronic irritation Vocal cord nodules (ex. “singer’s nodules”) Vocal cord paralysis o Iatrogenic (thyroid surgery, endotracheal intubation) o Malignancy (vagus or recurrent laryngeal nerve involvement) Trauma Paradoxical vocal cord motion/vocal cord dysfunction Laryngeal cancer Hoarseness lasting > 2 weeks without firmly identifiable cause warrants otolaryngology evaluation

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Laryngeal cancer 95% cases squamous cell carcinoma Tendency to metastasize to cervical lymph nodes 4 times more common in males Risk factors o Smoking o Alcohol

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Chronic Obstructive Pulmonary Disease – “COPD”
Date: Time: Faculty: Email: September 17, 2008 10:30 AM Philip Diaz, MD 201 HLRI; 293-4925

Objectives: 1. Accurately recognize the key factors associated with the increase in COPD prevalence 2. Accurately recognize the key pathophysiologic mechanisms contributing to the disability associated with COPD. 3. Given a clinical vignette, accurately recognize the risk factors and common symptoms of COPD. 4. Given a clinical vignette, decide on the appropriate test(s) to order for diagnosing COPD. 5. Given a patient’s symptoms and the results of pulmonary function tests in a clinical vignette, accurately assess the clinical stage of COPD and therapeutic options.


Epidemiology a. Up to 30 million affected in US b. Fourth leading cause of death c. Projected to be 3rd leading cause of death by 2020


Definition a. “COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. The pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.”
Global Initiative for Chronic Obstructive Lung Disease 2006

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b. Generally involves chronic bronchitis and/or emphysema i. Chronic bronchitis – Airways disease with inflammation, mucus hypersecretion. Definition (based on symptoms) – “productive cough for at least 3 months for 2 consecutive years” ii. Emphysema – Parenchymal disease associated with destruction of alveolar walls and “disappearance” of lung tissue. Definition (based on anatomy) – “abnormal permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destructive changes of the alveolar walls, without obvious fibrosis.” iii. Note – there is considerable overlap between these entities in individual patients (as both are closely related to cigarette smoking). However, as COPD gets more severe, emphysema becomes a more prominent feature. III. Pathogenesis a. Cigarette smoke (and other noxious stimuli) activate inflammatory processes in the lung with damage to airway (chronic bronchitis) and lung parenchyma (emphysema) b. Inflammatory cells important in pathogenesis – alveolar macrophages, neutrophils, lymphocytes (esp. CD8+) c. Protease-antiprotease balance is hypothesized to be important in the development of emphysema. Cigarette smoke activates alveolar macrophages and neutrophils with subsequent secretion of proteases. Note patients with alpha-1 antitrypsin deficiency are deficient in “protective” antiproteases leading to unchecked proteolytic damage to lung tissue and premature emphysema. IV. Pathophysiology a. Airflow limitation (mainly expiratory) – two components: i. Small airways disease - inflammation, mucus secretion and luminal obstruction ii. Loss of elastic recoil – less driving pressure for expiratory flow and less “tethering’ of small airways during expiration. Instead of behaving like a “balloon” (air comes out hard and fast when you let air out of a balloon), lungs behave like a “paper bag”

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b. Increased work of breathing i. Respiratory muscles may “fatigue” ii. CO2 retention may occur in severe disease c. Ventilation-perfusion mismatch i. Hypoxemia is common, especially with exercise d. Hyperinflation i. Secondary to: decreased elastic recoil of lungs and higher functional residual capacity, airflow obstruction during expiration and increased residual volume (“trapped air”) ii. Puts respiratory muscles at mechanical disadvantage and at shorter resting muscle length – leads to respiratory muscle weakness e. Pulmonary hypertension i. Main cause – alveolar hypoxia causing pulmonary vasoconstriction ii. Contributing factors – decreased cross-sectional area of pulmonary vascular bed in emphysema; increased intrathoracic pressure transmitted to cardiac surface f. Systemic factors i. Poor nutrition ii. Deconditioning – leads to decreased oxidative capacity of skeletal muscles, earlier onset of anaerobic metabolism with subsequent greater acid load (lactic acid) and increased ventilatory demands (lactic acid converted to CO2) iii. Vicious cycle: Airflow obstruction/hyperinflation – increased work of breathing/decreased respiratory muscle strength – dyspnea on exertion – decreased activity – deconditioning – skeletal muscle dysfunction – earlier onset anaerobic metabolism – more dyspnea on exertion – more deconditioning, etc. iv. Systemic inflammation. COPD is associated with a systemic inflammatory state (e.g. increased inflammatory cytokines, oxidant stress). This is felt to be important in the pathogenesis of skeletal muscle

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dysfunction as well as associated co-morbidities (cachexia, coronary artery disease) V. Clinical Presentation a. Clinical profile i. Age – usually 40’s or older at presentation ii. Positive smoking history – at least 20 pack years (e.g. 1 pack per day for 20 years) b. Symptoms i. Dyspnea on exertion ii. Cough iii. Wheeze c. Signs i. Wheezing or decreased breath sounds on lung auscultation ii. Hyperresonance and hyperinflation (barrel chest) with more severe disease iii. Signs of pulmonary hypertension (cor pulmonale) with advanced disease – elevated neck veins, peripheral edema iv. Physical exam may be normal with mild-moderate disease d. CXR i. Flat diaphragms (hyperinflation) and enlarged pulmonary arteries (pulmonary hypertension) with advanced disease. With severe emphysema may see “bullae” – large air-sacs ii. CXR often normal in mild-moderate disease e. Pulmonary function tests i. Air-flow obstruction on spirometry is gold standard for diagnosis – decreased FEV1/FVC is sensitive (normal FEV1/FVC is ~0.70 or greater). Absolute FEV1 as a percent of predicted is better predictor of severity (e.g. FEV1 < 50% of predicted consistent with severe disease ii. Lung volumes are usually normal to increased (i.e. increased residual volume, functional residual capacity and total lung capacity) iii. Decreased diffusing capacity (indicating decreased lung surface area for gas-exchange) is reduced in emphysema

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f. Arterial blood gases i. Hypoxemia (especially with activity) common ii. CO2 retention and respiratory acidosis can develop with severe disease (FEV1 < 40% of predicted) g. *Diagnosis is based primarily on three factors: i. Symptoms (esp. exertional dyspnea and cough) ii. Smoking history iii. Spirometry – air-flow obstruction VI. Treatment a. General principles i. Most interventions do not affect mortality of natural history of disease ii. Treatment is primarily symptom based iii. Step-wise approach recommended 1. Add treatment with persistent symptoms b. Smoking cessation i. Can alter natural history of disease and slow rate of decline of lung function ii. Intervention 1. Strong (and personalized) message from physician 2. Nicotine replacement 3. Buproprion 4. Smoking cessation counseling/classes c. Pharmacologic agents i. Bronchodilators – central to symptomatic management. Inhaled delivery preferred over oral 1. Inhaled beta-agonists – albuterol (short acting), salmeterol (long acting), formoterol (long and short acting) 2. Inhaled anticholinerics – ipratroprium, tiotropium 3. Oral phosphodiesterase inhibitors – theophylline 4. May use more than one agent in individual patients ii. Anti-inflammatory agents

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1. Inhaled corticosteroids a. Indicated for patients with moderate-severe disease and frequent exacerbations of disease 2. Systemic corticosteroids a. Oral prednisone is effective for brief (1-2 week) periods when patients have an “acute exacerbation” of symptoms (usually worse dyspnea, cough and/or sputum production) 3. Generally avoid long term systemic steroids iii. Antibiotics 1. Useful for “acute exacerbations”. Often used with systemic steroids. d. Vaccination i. Influenza vaccine – good evidence for its effectiveness ii. Pneumococcal vaccine – less evidence for its effectiveness in COPD, but generally recommended e. Oxygen therapy i. Indicated for resting PO2 < 55 (or < 59 with polycythemia or signs of cor pulmonale) or oxygen saturation < 88% ii. May improve end-organ function (e.g. cognitive) and life-expectancy f. Exercise training/pulmonary rehabilitation program i. Addresses the “vicious” cycle that occurs in COPD ii. Primarily involves lower extremity endurance training (e.g. treadmill) iii. Consider in all COPD patient with persistent dyspnea despite medical management g. Surgical management i. Lung volume reduction surgery 1. Involves removing ~30% of the volume of each lung surgically. The areas most involved with emphysema are targeted 2. Consider in moderate-severe emphysema, especially if the disease primarily involves the upper lobes ii. Lung transplantation

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1. For severe end-stage disease (FEV1 < 25% of predicted) VII. Prognosis a. FEV1 most commonly used prognostic indicator i. For example if FEV1 > 50% of predicted, little excess mortality (compared to smokers without COPD) ii. If FEV1 < 30% of predicted, 4 year mortality is ~40% b. Poor exercise capacity, increased dyspnea and low body weight are also associated with increased mortality i. “BODE” (body mass index, obstruction, dyspnea, exercise capacity) index recently shown to be highly predictive of survival

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Pathology of Pneumonia
Date: Time: Faculty: Phone: Email: September 18, 2008 8:30 – 9:20 am Charles L. Hitchcock, M.D., Ph.D., Department of Pathology 081 - Heart and Lung Research Institute Office 247-7469

Learning Objectives: 1. Describe the normal pulmonary defense mechanisms and the classification for pulmonary infections. 2. Compare and contrast the etiologic, pathologic, morphologic and clinical features of the following pulmonary infections of bacterial pneumonia, and viral/mycoplasma infections Learning Resources 1. Robbins Pathologic Basis of Disease, 7th Ed., pp. 747-757. 2. Harrison’s Principles of Internal Medicine, 16th Ed., ch 239. I. GENERAL CONSIDERATIONS A. Impact 1. The organs of the respiratory system are the most common organs involved by infection and are among the most common causes of morbidity and mortality. 2. Upper respiratory infections (URIs), primarily due to coronaviruses and rhinoviruses, are the most common type of respiratory infection. 3. Infections have an uncertain linkage to the development of chronic lung disease. This linkage involves both innate and adaptive immune responses. B. Routes of Infection 1. There are several routes whereby organisms can gain entry to the lungs. a. Aspiration of oral contents is the most common b. Inhalation of airborne droplets c. Bacteremia d. Direct extension of an inflammatory process from other organs. C. Host Defense Mechanisms 1. Pneumonia may develop whenever pulmonary defenses are compromised. The upper and lower respiratory systems have a variety of innate and adaptive immune response mechanisms to remove inhaled particles and organisms.
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2. Pulmonary infections are associated with inhibition of one or more host defenses. These include: a. Suppression of the cough reflex may lead to aspiration. b. Injury of the mucociliary apparatus predisposes patients to pulmonary infections. This is a common feature of chronic airway diseases such as asthma, cystic fibrosis, ciliary dyskinesia, and chronic bronchitis. c. Interference with phagocytic function of alveolar macrophages can lead to granulomatous inflammation. d. Immune deficiency, immunosuppression, and leukopenia place patients at a markedly increased risk for all types of infections. e. Chronic airway obstruction and accumulation of secretions impairs removal of infectious agents and promotes their growth. f. Pulmonary congestion and edema. g. Chronic debilitating diseases. 3. Virulence factors of the infecting organisms are associated with an ability to impair the innate and/or the adaptive immune response. This may include: a. Surface capsule and/or antigen make up b. Resistance of proteolysis c. Toxin production d. Increased motility e. Production of enzymes (e.g. catalase) f. Intracellular resistance (M. tuberculosis) g. Fe-acquiring systems that decrease the Fenton reaction and generation of oxygen free radicals h. Development of antibiotic resistance D. Classification of Pneumonia 1. Pneumonias can be classified as either interstitial or intraalveolar. Intraalveolar pneumonias are further classified as either bronchopneumonia with its patchy consolidation or as lobar pneumonia where the pneumonia involves all or a majority of a lobe. 2. Pneumonias may be classified as to their etiology (e.g. viral vs. bacterial), staphylococcal or pneumococcal pneumonia. a. Bacterial pneumonia has suppurative exudate rich in neutrophils, macrophages and fibrin within the alveoli. b. Viral pneumonia is characterized by an interstitial mononuclear (lymphocyte and macrophage) infiltrate with minimal intra-alveolar exudate.
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3. Classification by host response includes necrotizing pneumonia or granulomatous pneumonia. 4. Pneumonias can be classified on the basis of the clinical setting. This includes: a. Community acquired acute pneumonia b. Community acquired atypical pneumonia c. Hospital (nosocomial) pneumonia d. Severe acute respiratory syndrome (SARS) 5. Pneumonias are can also be classified as aspiration, abscess, or chronic. E. Diagnosis of Pneumonia 1. The initial diagnosis and treatment of pneumonia are often empiric. 2. Failure of antibiotic therapy should result in obtaining a sputum sample for Gram stain and culture. The quality of the sputum is important in order to exclude a false positive result due to oral contamination. An adequate sputum should have <10 squamous epithelial cells per low power field and >25 leukocytes per low power field. The presence of alveolar macrophages is also a good indicator of a deep sampling. 3. Blood cultures should be obtained upon admission to the hospital. F. Prevention 1. Pneumococcal vaccine – polyvalent, can give every 5 years. 2. Influenza vaccine – yearly in the autumn for both you and your patients. II. BACTERIAL PULMONARY INFECTIONS A. Bronchopneumonia 1. Clinical features include: a. Very common infections that tend to affect the very young and the elderly. b. The presenting symptoms may include fever with or without chills, cough, purulent sputum production, chest pain, dyspnea, and rapid shallow respirations. c. Imaging studies may be negative in early disease but later have a patchy distribution of consolidation. 2. Common etiologic agents include: Staphylococcus, Streptococcus, Pseudomonas, Haemophilus, Moraxella, the coliforms. 3. Gross pathologic features include: a. Patchy areas of consolidation - slightly elevated, dry, granular, gray to yellow, poorly-circumscribed areas - within one or more lobes.
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b. There may be a concurrent fibrinous pleuritis and/or small parenchymal abscesses. 4. The microscopic features are those of a suppurative exudate in small bronchi, bronchioles and adjacent alveoli that is rich in neutrophils and macrophages. Focal parenchyma necrosis may lead to abscess formation. 5. Bronchopneumonia may resolve without lung damage or lead to organization and scarring. B. Lobar Pneumonia 1. Clinical features include: a. Effects otherwise healthy adults, 30-50 years of age, and predominately men (M:F=3-4:1). b. The symptoms relate to a relatively sudden onset of fever, chills, and blood tinged sputum. c. Chest X-rays show lobar consolidation. d. The incidence of lobar pneumonia is infrequent due to the effectiveness with which antibiotics abort these infections and prevent full-blown development of lobar consolidation. 2. 95% of cases are caused by community acquired Streptococcus pneumoniae; most commonly associated with types 1, 2, 3 and 7. 3. The gross pathologic features include a widespread fibrinopurulent consolidation of large areas of lobe, and a fibrinous pleuritis. 4. The microscopic features can be divided into four classic stages: a. Congestion: this first phase occurs within the first 24 hours due to vascular congestion & alveolar edema. The lungs are heavy and hyperemic. b. Red hepatization: this phase occurs within 2 to 3 days and is due to extravasation of RBCs into the purulent exudate. c. Gray hepatization: results from lysis of the intra-alveolar RBCs while the fibrinopurulent exudate remains. d. Resolution: occurs with the clearing of the exudate. 5. Outcomes include: a. The most common outcome is that of resolution of the normal pulmonary architecture. Organizing pneumonia that results in pulmonary fibrosis is a less likely outcome.

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b. Adverse sequelae include the formation of an abscess and/or an empyema, as well as sepsis with resulting endocarditis, pericarditis, and/or meningitis. C. Pulmonary Abscess 1. An abscess represents a localized suppurative process characterized by tissue necrosis. 2. Clinical features include: a. Aspiration of oral contents gives rise to about 60% of cases, and results in an infection due to mixed organisms and anaerobes. Aspiration may be due to loss of consciousness, dementia, loss of the gag and/or cough reflexes. b. Other predisposing factors include an antecedent pulmonary infection, a sinobronchial infection, septic emboli, or an obstructing tumor. c. Radiologic studies demonstrate one or more lesions that may cavitate. 3. On gross examination, pulmonary abscesses appear well circumscribed nodules with central necrosis. 4. Microscopic examination reveals a focus of pulmonary parenchyma destruction by liquefactive necrosis. The lesion may have a fibrous limiting wall. 5. A pulmonary abscess may result in a chronic infection or septic emboli. These in turn can cause an empyema, suppurative pericarditis, and/or bacteriemia. III. MYCOPLASMAL AND VIRAL PULMONARY INFECTIONS A. General Features 1. Viral infections usually lead to an interstitial pneumonia. 2. Viral infections are commonly associated with URIs, but pulmonary extension may occur with debilitation, malnutrition, alcoholism, or a coexistent cardiopulmonary disease. 3. The etiologic agents include: a. Mycoplasma pneumoniae (primary atypical pneumonia) is the most common cause. b. Influenza A, B, RSV, Coxsackie, Adenovirus, ECHO virus are common viral causes c. Chlamydia pneumoniae and psittaci

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B. Atypical Pneumonia 1. Clinical features include: a. Sometimes referred to as a “chest cold” or severe upper respiratory infection. May also be called atypical pneumonia in contrast to “typical” pneumonia associated with a viral infection. b. Patients often present with an insidious onset of fever, malaise, headache, myalgia, and a non-productive cough. Rales and rhonchi are heard on physical examination. The course is usually mild but pandemics (esp. 1915, 1918) have occurred. c. These pneumonias can be classified as atypical pneumonia in an otherwise healthy patient or as a viral pneumonia in immunosuppressed or immunocompromised patients. d. Laboratory findings include elevated cold agglutinins (Anti-I) that are present in > 50% of mycoplasma infections. e. A pleural effusion may be present on chest X-rays. 2. The etiologic agents of atypical pneumonia include bacteria, viruses, and fungi. a. Mycoplasma pneumoniae is the most common cause of atypical pneumonia, second only to Strep. pneumoniae in causing pneumonia, and causes 20-25% of pneumonias in all age groups. b. Chlamydia pneumoniae, Influenza viruses and Legionella are other relatively common causes. 3. Gross examination of lungs from uncomplicated cases demonstrates red, firm lungs, patchy or extensive involvement, without consolidation. Complicated cases are associated with a secondary bacterial infection. 4. Microscopic examination may demonstrate: a. Interstitial mononuclear (lymphocytes, macrophages) inflammation and congestion. b. Hyperplasia of type II pneumocytes, edema of alveolar wall and/or hyaline membranes lining the alveolar surface of the septal wall. c. Bronchial/bronchiolar inflammation may be present. d. Cytopathic effects of viral infections are seen with CMV, HSV, and measles. e. Secondary bacterial infection may occur.

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C. Influenza 1. The influenza virus is a single-stranded RNA virus divided into five genera with types A, B, and C causing “the flu”. These three have a very similar structure. 2. The surface envelope is lipid bilayer with hemagglutinin (H) & neuraminidase (N). The N and H determine the serotype based on the antibody response. Antigenic diversity - year-to-year mutations - in the H and N genes is a means to avoid the host immune response. Vaccines are generated against them. 3. Influenza Type A infects humans, pigs, horses, birds. Avian subtype H5N1 circulating in SE Asia, Europe, Middle East & Africa is the etiology of bird flu. a. Humans lack immunity to the H5N1 virus. This leads to a potential of severe disease and a pandemic. Mortality rate ~ 60% b. Oseltamivir may be an effective drug, but resistance strains have already been identified in humans. c. Infection of an immunocompetent patient results in a cytokine storm associated with cytokines IFN-α and IFN-β and cytotoxic T cells. The result is severe interstitial pneumonia with diffuse alveolar damage. Clinically, this is ARDS. 4. Types B & C – mostly infect kids, do not show Ag drift/shift.

D. Severe Acute Respiratory Syndrome (SARS) 1. SARS is caused by a novel coronavirus which first appeared in China in November 2002. It is highly contagious at close contact. Those at risk include: travelers, health care workers, and laboratorians. 2. Patients appear 2-10 days after exposure with a dry cough, malaise, myalgias, fever, chills. 3. Approximately two-thirds resolve of the patients develop respiratory distress with a 5-10% mortality rate. 4. Severe interstitial pneumonia with diffuse alveolar damage, secondary to a cytokine storm, results from this infection.

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Lower Respiratory Tract Infections in Adults
Date: Time: Faculty: Email: September 18th 2008 9:30 AM Troy Schaffernocker, MD; Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine

Objectives: 1. Recognize the host defense mechanisms and pathophysiology involved in the development of pneumonia. 2. Identify the most common pathogens responsible for “Community Acquired” and “Health Care Associated” pneumonia. 3. Recognize the common organisms responsible for pneumonia in patients with specific defects in host defense including hypogammaglobulinemia, neutropenia, long term glucocorticoid therapy, and low CD4 lymphocyte counts i.e. HIV/AIDS. 4. List the most common infectious causes of pulmonary cavities. 5. Recognize the common diagnostic testing utilized in the evaluation of the hospitalized patient with pneumonia. 6. Select appropriate antibiotics for treatment in the setting of “Community Acquired” (Outpatient and Inpatient) and “Healthcare Associated” pneumonia. 7. Know the indications for administration of the pneumococcal vaccine. 8. Recognize the clinical presentation of bronchiectasis. 9. Identify the clinical presentation of pulmonary tuberculosis including primary and post-primary disease. 10. Recommend a diagnostic approach to a patient with suspected tuberculosis. 11. Recognize the importance of drug susceptibility testing and directly observed therapy in the treatment of pulmonary tuberculosis. 12. Recognize nontuberculous mycobacterial and fungal infections as unusual, but identifiable causes of pulmonary infections given their often unique clinical scenarios. 13. Identify the clinical presentation of influenza infection along with the appropriate diagnostic and treatment measures. 14. Be aware of the indications for influenza vaccination. Reading: Harrison’s 17th Ed. Chapter 251: Pneumonia Supplemental Reading: Chapter 252: Bronchiectasis and Lung Abscess, Chapter 200: Pneumocystis, Chapter 158: Tuberculosis, Chapter 160: Nontuberculous Mycobacteria, Chapter 192: Histoplasmosis, Chapter 193 Coccidiomycosis, Chapter 194: Blastomycosis, Chapter 195: Cryptococcus, Chapter 196 Candidiasis, Chapter 197: Aspergillosis, Chapter 180: Influenza.

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Pneumonia a. Definition-An infection of the pulmonary parenchyma. i. Various bacteria, viruses, and fungi may be responsible. ii. In 1/3 of cases etiologic organism is not identified b. Defense i. Upper Airway 1. Sneezing 2. Swallowing 3. Expectoration ii. 80% of cells in central airways Ciliated, pseudostratified, columnar epithelium iii. Alveoli 1. Alveolar Macrophages (phagocytes) 2. Lining fluid: surfactant, fibronectin, immunoglobulins which can opsonize or lyse microbial pathogens c. Pathophysiology i. Alveolar Macrophages 1. Process and present microbial antigens to lymphocytes 2. Secrete cytokines ii. Cytokines 1. Generate inflammatory response 2. Activate alveolar macrophages 3. Recruit more phagocytes and immunologic factors from plasma iii. Inflammatory Exudate 1. Pulmonary Consolidation 2. Systemic Manifestations a. Fever b. Chills c. Myalgias d. Malaise d. Transmission i. Aspiration 1. Level of consciousness (alcohol, drugs) 2. Neurologic Dysfunction (seizure, stroke) 3. Mechanical Impairments (endotracheal tube, nasogastric tube) ii. Inhalation 1. Particles >  m get deposited in nose and oropharynx 2. 5-10 m Central airways 3. <5 m can make it all the way to alveoli iii. Hematogenous 1. Extrapulmonary Sites a. Endocarditis b. Vascular Catheter infections c. Retropharyngeal infections iv. Direct Inoculation/Contiguous Spread 1. Tracheal intubation 2. Penetration of the chest wall e. Pathology i. Lobar pneumonia 1. Involvement of entire lobe

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ii. Bronchopneumonia 1. Restricted to alveoli and contiguous bronchi iii. Necrotizing pneumonia 1. mulltiple small cavities, < 2cm iv. Lung Abscess 1. 1 or more cavities, > 2cm f. Epidemiology i. Community-acquired pathogens 1. Streptococcus pneumoniae 2. Haemophilus influenzae 3. Chlamydia pneumoniae 4. Legionella pneumophila 5. Mycoplasma pneumoniae ii. Health care acquired pathogens 1. Enteric gram-negatives 2. Pseudomonas aeruginosa 3. Staphylococcus aureus g. Physical Exam i. Fever ii. Purulent Sputum iii. Signs of pulmonary consolidation 1. Dullness 2. Increased fremitis 3. Egophony 4. Bronchial breath sounds 5. Rales h. Specific Defects in Host Defense i. Hypogammaglobulinemia 1. Encapsulated Organisms: Streptococcus pneumoniae, Haemophilus influenzae ii. Neutropenia 1. Pseudomonas aeruginosa, Enterobacteriaceae, Staphylococcus aureus, Aspergillus iii. Long-term glucocorticoid therapy 1. Mycobacterium tuberculosis, Nocardia iv. Cell-mediated immunity 1. CD4 count <500/mL a. Mycobacterium tuberculosis 2. CD4 count <200 a. Pneumocystis jiroveci b. Histoplasma capsulatum c. Cryptococcus neoformans 3. CD4 count <50 a. Mycobacterium avium-intracellulare b. Cytomegalovirus i. Chest Radiography i. Confirm the presence and location of an infiltrate ii. Assess the extent of infection iii. Detect pleural involvement iv. Gauge hilar lymphadenopathy v. Monitor response to therapy

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Causes of Pulmonary Cavities i. Infectious 1. Bacteria: Oral Anaerobes, enteric aerobic gram-negative bacilli, Pseudomonas aeruginosa, Legionella, Staphylococcus aureus, Streptococcus pneumoniae serotype III, Mycobacterium tuberculosis, Nocardia 2. Fungi: Histoplasma capsulatum, Coccidioides immitis, Blastomyces ii. Noninfectious 1. Neoplasms: Lymphoma, Squamous cell carcinoma 2. Other: Wegener’s granulomatosis, infarction, infected bullae and cysts k. Sample Analysis i. Sputum 1. Gram’s staining 2. Acid-fast staining (mycobacteria) 3. Legionella direct flouresence antibody 4. Giemsa stain (Pneumocystis) ii. Fiberoptic Bronchoscopy 1. Bronchoalveolar lavage (BAL) 2. Protected Sheath Brush 3. Transbronchial Biopsy iii. Thoracentesis 1. Consider if significant pleural effusion iv. Open-Lung Biopsy l. Other Diagnostics Tests 1. Peripheral Blood Cultures (all patients) 2. If clinical suspicion a. Antibody titers: Mycoplasma pneumoniae, Chlamydia pneumoniae, Cytomegalovirus b. Urine antigens: Streptococcus pneumoniae, Legionella pneumophila, Histoplasma capsulatum m. Clinical Considerations i. Hospitalization 1. Mental status change 2. Tachypnea (>30/min) 3. Tachycardia (>140/min) 4. Hypotension (< 90mmHg systolic) 5. Advanced age (>65yrs) 6. Significant co-morbidity (kidney, heart, or lung disease, diabetes mellitus, cancer) 7. Inability to take oral medication 8. Failure of outpatient management n. Treatment i. Outpatient: 1. Macrolides 2. Flouroquinolones ii. Inpatient: Community Acquired1. General Wards: Flouroquinolone or Beta-lactamase resistant penicillin + macrolide 2. ICU: Beta-lactamase resistant penicillin + macrolide


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iii. Inpatient: Healthcare Associated 1. Anti-pseudomonal cephalosporin, carbapenem, or penicillin + Aminoglycoside or Flouroquinolone + Vancomycin or Linezolid o. Prevention i. Pneumococcal Vaccine 1. Age > 65 2. Chronic Lung, Heart, or Kidney disease 3. Immunosuppressed 4. Sickle Cell Anemia 5. Diabetes Mellitus 6. Cancer 7. HIV Bronchiectasis a. Abnormal and permanent dilation of the bronchi. i. Often associated with chronic or recurrent infections. ii. Can be focal or diffuse. b. Etiology i. Recurrent bacterial infections ii. Mycobacterial disease – Mycobacterium Avium Complex iii. Generalized impairment of pulmonary defense mechanisms 1. Immunoglobulin deficiency 2. Ciliary Disorders a. Primary ciliary diskinesia b. Kartagener’s syndrome 3. Cystic Fibrosis a. Tenacious secretions impair bacterial clearance c. Clinical Symptoms i. Recurrent Cough ii. Purulent Sputum production iii. Hemoptysis iv. Dyspnea v. Wheezing d. Diagnosis i. High Resolution Chest CT e. Treatment i. Treatment of any precipitating conditions ii. Antibiotics for acute exacerbations iii. Preventive antibiotics in patients with recurrent exacerbations iv. Chest physiotherapy v. Maintain adequate hydration vi. Inhaled corticosteroids and bronchodilators as needed vii. Consider lung transplantation in advanced disease Pulmonary Tuberculosis i. Most commonly transmitted by droplet nuclei which are aerosolized by coughing, sneezing, or speaking. ii. Probability of disease contraction is dependent upon intimacy, duration, and degree of infectiousness of contact. b. Primary Disease i. Initial infection with tubercle bacilli ii. In areas of high prevalence of TB iii. Affects Children

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iv. Mid to lower lung fields v. Hilar Lymphadenopathy vi. Often heals spontaneously into a calcified nodule (Ghon Lesion) c. Post-primary disease i. Occurs in adulthood ii. Affects apical and posterior upper lobes most frequently iii. Can vary from small infiltrates to extensive cavitary disease d. Signs and Symptoms i. Often insidious ii. Night sweats, fever, weight loss, anorexia, malaise, weakness iii. Cough iv. Hemoptysis v. Dyspnea e. Important opportunistic infection in HIV population f. Diagnosis i. Chest Radiography ii. AFB (Acid Fast Bacillus) Microscopy iii. Mycobacterial Culture iv. PPD Skin testing v. Drug Susceptibility Testing [MDR (Multidrug-Resistant) TB] g. Treatment i. Dependent upon Drug Susceptibility ii. Most often require 6 months of therapy 1. First two months: Four drug therapy with Isoniazid, Rifampin, Ethambutol and Pyrazinamide. 2. Next four months: Two drug therapy with Isoniazid and Rifampin. iii. DOT: Directly observed therapy h. Prevention i. BCG Vaccine – not recommended in USA Non-tuberculous Mycobacteria a. Most Common in Pulmonary Infections i. M. intracellulare ii. M. avium iii. M. Kansasii iv. M. Abscessus b. NTM are ubiquitous in the environment and rarely pathogenic c. Clinical Aspects i. Chronic Cough ii. Low grade fever iii. Malaise iv. Occaisionally hemoptysis v. AIDS patients may develop more fulminant symptoms d. Treatment i. Generally 3-4 drug combination therapy based on sensitivities ii. Duration often a year or more Fungal Infections a. Aspergillus i. Pulmonary Syndromes 1. ABPA (Allergic Bronchopulmonary Aspergillosis): Treatment Steroids

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2. Aspergilloma: Treatment - Surgery 3. Angioinvasive Aspergillus: Treatment - Antifungals 4. Chronic necrotizing pulmonary aspergillosis: Treatment Antifungals b. Histoplasma capsulatum i. Soil dwelling fungus – endemic to Ohio river valley ii. Frequent cause of pulmonary nodules, mild pneumonitis, mild lymphadenopathy - often do not require treatment, depends on symptoms iii. Progressive and disseminated disease requires treatment with antifungals – usually only occurs in immunocompromised – i.e. organ transplant, chronic glucocorticoid therapy, chemotherapy, and HIV. c. Coccidioidomycosis i. Endemic to Desert Southwest ii. Most patients with primary disease have no symptoms, or a mild flu-like illness that lasts 1-3 weeks. No treatment is required. iii. Immunocompromised individuals, diabetics, blacks, and pregnant women have a high risk of dissemination and should be treated with antifungal therapy Influenza a. Definition i. An acute respiratory illness caused by infection with the influenza virus. ii. Influenza A and B are members of the genus that cause most infections in humans. b. Epidemiology i. Often occurs in outbreaks ii. Global epidemics or pandemics occur every 10-15 years – usually Influenza A is responsible iii. Usually isolated to the Winter months i.e. “flu season” c. Clinical Presentation i. Abrupt Onset (first 24 hours) 1. Fever 2. Headache 3. Chills 4. Myalgias 5. Malaise ii. Later (Over 2-5 days) 1. Cough 2. Sore Throat 3. Coryza d. Complications i. Viral Pneumonia ii. Secondary Bacterial Pneumonia 1. Staphylococcus aureus 2. Streptococcus pneumoniae 3. Haemophilus influenzae iii. COPD or Asthma Exacerbation iv. Respiratory Failure e. Diagnosis i. Clinical History ii. Throat Swab

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1. Rapid – can have diagnosis within minutes 2. Sensitivity ~ 85% iii. Viral culture 1. Takes 2-3 days to get results f. Treatment i. Supportive ii. Antivirals – Effective in reducing duration of symptoms if started within 24 hours of symptom onset. 1. Influenza A a. Amantadine b. Rimantidine 2. Influenza A and B a. Oseltamivir b. Zanamivir g. Prevention i. Influenza Vaccine 1. Age 50 or older 2. Nursing Home residents 3. Chronic Pulmonary, Heart, Renal, or Liver disease 4. Diabetes 5. Immunosuppressed 6. Sickle Cell (asplenia) 7. HIV 8. Women that will be pregnant during flu season 9. Health Care Workers

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Lower Respiratory Infections in Children
Date: Time: Faculty: September 18, 2008 10:30 am Dwight Powell, MD Professor of Pediatrics Division of Pediatric Infectious Disease Nationwide Children’s Hospital

Objectives 1. Compare and contrast the clinical presentation, pathogens, and management of the four main syndromes of pediatric lower respiratory tract infection: croup, tracheobronchitis, bronchiolitis, and pneumonia. 2. Describe the seasonal epidemiology of common pediatric respiratory pathogens. 3. List the diagnostic tests available for identifying the main respiratory viruses causing pediatric lower respiratory infections. 4. Given a clinical vignette, recognize symptoms of, recommend diagnostic testing for and recommend treatment for pertussis. 5. List the common pathogens causing pediatric community-acquired pneumonia. 6. List the physical examination findings of pneumonia. 7. Chose correct diagnostic tests for different pathogens that cause pneumonia. 8. Given a clinical vignette, recommend appropriate antibiotics for pediatric community-acquired pneumonia.

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Pathology of Lung Cancer
Date: Time: Faculty: Phone: Email: September 19, 2008 8:30 – 9:20 Charles L. Hitchcock, M.D., Ph.D., Department of Pathology 081 - Heart and Lung Research Institute Office 247-7469

Learning Objectives: 1. List the etiology, pathogenesis and predisposing factors for lung cancer. 2. List the histologic classifications and morphologic features of the various subtypes of primary tumors of the lung. 3. Describe the pathogenesis of pulmonary metastasis (carcinoma metastatic to lung). Learning Resources 1. Robbins Pathologic Basis of Disease, 7th Ed., pp. 757-766. 2. Harrison’s Principles of Internal Medicine, 16th Ed., ch 75. I. PRIMARY PULMONARY CARCINOMA A. Epidemiology 1. Lung cancer is a major global public health problem. It is the number one cancer in the world relative to incidence and mortality. 2. In the U.S. this year there will be 215,000 new cases diagnosed and 162,000 deaths from lung cancer. It is the leading cause of cancer death in both men and women. 3. There has been a sharp increase in incidence among women smokers, to the extent that it has surpassed breast cancer as the leading cause of cancer deaths in women. 4. The incidence varies with location, age, sex, and over time. 5. The death rate is decreasing in men but increasing in women. Cancer Type All New Cancers All Cancer Death Men – Lung 13% 31% Men - Prostate 33% 19% Women – Lung Women - Breast 12% 31%
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26% 15%

B. Etiology 1. Cigarette smoking is the most important risk factor and increases the risk X10 compared with the general population. In men ~ 87% of lung cancers occur in smokers (women – 85%). a. Risk is dose dependent: exposure to 25 pack-years doubles the cancer risk over nonsmokers. b. The fact that lung cancer occurs in less than 15% of smokers indicates that the etiology is multifactorial. c. There are >1200 different carcinogens in tobacco smoke. These include both initiator and promoter chemical carcinogens, radioactive compounds, and various elements. d. Part of the difference may be related to genetic differences in how the cells metabolize the carcinogens. These include: 1) Phase I enzymes of the cytochrome p450 system that form reactive intermediates of the various carcinogens in tobacco smoke that damage DNA. 2) Glutathione S-transferase, a phase II enzyme that detoxifies reactive metabolites of polycyclic aromatic hydrocarbons, has also been proposed as a mechanism to explain the differences in susceptibility to lung cancer among smokers. e. Cessation of smoking reduces risk of carcinoma progressively, almost to that of "never-smokers" after 10 - 12 years of abstinence. 2. Other exogenous carcinogens are also implicated in the development of lung cancer include: radioactive gases and dusts (uranium workers, radon gas), chromate, nickel, arsenic, asbestos, polycyclic aromatic hydrocarbons, beryllium, coal, mustard gas, and iron. 3. Molecular genetic events have been identified in lung carcinogenesis indicating a multifactorial process. a. Changes in TP53 have been described. b. Germline mutations of KRAS and EGFR have been identified. These mutations within a tumor are being used to clinically segregate patients for treatment. c. A marker on chromosome 15 has also been identified. d. A recent study has demonstrated 16 genes that were related to increased or decreased survival.
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II. PATHOLOGY OF PRIMARY LUNG TUMORS A. Clinical Features 1. Symptoms tend to occur late in the disease process. These include: a. Cough (75%) b. Weight loss (40%) c. Dyspnea (20%) d. Hemoptysis e. Chest pain f. Pleural effusions g. Pneumonia 2. Signs and symptoms are closely related to tumor location. a. Common signs and symptoms include: 1) Post-obstructive pneumonia in central lesions 2) Pleural effusions are more common with peripheral lesions 3) Hoarseness is associated with invasion of the recurrent laryngeal nerve 4) Dysphagia is associated with invasion into the esophagus b. Superior vena cava syndrome arises from compression of the superior vena cava; which in 80% of the cases is caused by cancer of the right lung. The signs and symptoms include: 1) Dyspnea 2) Swelling of the trunk, upper extremities and the face 3) Orthopnea c. Pancoast syndrome arises from a tumor growing in the apex of the lung that compresses the structures within the thoracic inlet including the phrenic, recurrent laryngeal and vagus nerves; subclavian artery and brachiocephalic vein, and brachial plexus. The signs and symptoms may include: 1) Atrophy of muscles of the hand and arm on the involved side 2) Shoulder pain 3) Vascular compression leading to edema of the involved extremity 4) Horner syndrome – ptosis, miosis, hemianhidrosis, and enophthalmos due to compression of sympathetic ganglia d. Paraneoplastic syndromes occur in up to 10% of primary lung cancers. Tumor cell derived hormones include: 1) Cushing Syndrome due to ACTH secreted by small cell carcinomas. 2) Hyponatremia due to ADH secreted by small cell carcinomas. 3) Hypercalcemia due PTH-like substances (PTH, cytokines, PGE) secreted by squamous cell carcinomas. 4) Carcinoid syndrome due to serotonin and bradykinin secreted primarily by carcinoid tumors.
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B. General Pathologic Features 1. Respiratory epithelium gives rise to 99% of primary lung cancers. 2. Approximately 75% of lung tumors arise in the hilar area from the first to third order bronchi. More peripheral lesions arise from terminal bronchioles and alveoli. Patterns of growth include: a. Intraluminal to cause obstruction b. Penetration of the bronchial wall with invasion of the pulmonary parencyma 1) Grow along (near) peribronchial tissue 2) Produce an intra-parenchymal mass c. Mixed growth pattern may be seen. 3. Lung tumors tend to have a gray-white appearance with areas of hemorrhage and necrosis that can lead to cavitation. a. Peripheral tumors often pucker the pleural surface. b. Tumor may penetrate the pleura and extend into the chest wall or into the heart, trachea, esophagus, or aorta. c. Metastasis to the bronchial nodes is common. d. Distant metastases involve adrenal glands, liver, brain, and bone 4. Lung carcinomas are clinically classified as either a small cell (neuroendocrine) or non-small cell carcinomas (SCLC and NSCLC). As a group, they are often referred to as bronchogenic carcinomas. a. The TNM system is used for patient staging. b. Most common histologic types associated with smoking are squamous cell carcinoma and small cell carcinoma (highest association). 5. Non-small cell carcinomas are further divided into the following histologic types: a. Squamous cell carcinomas represent 25-30% of cases b. Adenocarcinoma represent 30-40% of cases 1) Bronchioalveolar carcinoma is a special subtype c. Large cell carcinoma represents 10-15% of cases d. Mixed tumors are also noted

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6. Neuroendocrine carcinomas are classified on the basis of their differentiation. These include: a. Carcinoids well differentiated neuroendocrine carcinoma b. Atypical carcinoid moderately differentiated neuroendocrine carcinoma c. Small cell carcinoma poorly differentiated neuroendocrine carcinoma d. Large cell neuroendocrine carcinoma C. Squamous Cell Carcinoma 1. Squamous cell carcinoma represents up to 30% of primary lung tumors. It is common in smokers and in males. 2. It most commonly occurs in the central (hilar) region due to its origin in major bronchi. Chest X-ray often shows hilar or mediastinal shadow. 3. Premalignant changes (squamous metaplasia, dysplasia, carcinoma in-situ) and invasive carcinoma are often seen in association with the tumor. This implies that they arise from the basal cells of the respiratory epithelium. Support for this comes from immunohistochemical stains. 4. Squamous cell carcinomas are grossly characterized by bulky, hard tumors that cause bronchial obstruction and secondary obstructive pneumonia. a. They are often exhibit extensive hemorrhage, necrosis and cavitation. 5. Classic squamous cell carcinoma is characterized by large polygonal cells with a tendency to stratify with large hyperchromatic nuclei showing evidence of squamous differentiation (keratinization of cytoplasm, intercellular bridges, and formation of squamous pearls). a. Poorly differentiated squamous cell carcinomas lack squamous pearls and only a few cells will exhibit cytoplasmic keratinization. We use immunohistochemical stains to help prove its differentiation. D. Adenocarcinoma 1. At 40%, adenocarcinoma represents the most common bronchogenic carcinoma in the United States. a. They are associated with smoking history, but to a lesser extent than squamous cell and small cell carcinoma. They are the most common type of lung cancer in women and non-smokers. 2. Adenocarcinomas commonly arise subpleurally, can arise in small bronchi and central airways. Atypical alveolar adenomatous hyperplasia serves as a premalignant precursor. 3. Most common symptoms include pleural effusion and chest pain. Often discovered incidentally on routine chest X-rays as an area of density in the periphery of the lung. 4. Grossly, they tend to be well-circumscribed, gray, firm masses, often associated with scarring of the pleura.
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5. Histologically characterized by the formation of acinar or glandular spaces lined by atypical epithelial cells that may be mucin-secreting. May also form papillary structures. 6. Five year survival is 27% overall, but is highly dependent on stage at the time of diagnosis. Prognosis is worse for the less differentiated variants. 7. Bronchioloalveolar Carcinoma (BAC) a. A special and distinctive variant of adenocarcinoma that accounts for up to 9% of all bronchogenic carcinomas. These tumors arise from small airways beyond the last cartilage-containing bronchus. Their appearance on imaging studies is very similar to pneumonia. b. They are histologically characterized by a monolayer proliferation of neoplastic cells that grow along the alveolar walls (lepidic growth pattern). 1) They resemble the normal lung but in which the airspaces are lined by very well-differentiated tumor cells. They do not invade and destroy the lung parenchyma nor do they distort the underlying architecture. There is no desmoplastic response. 2) There are two histologic types: 1) alveolar lining is made up of small cells with large nuclei reminiscent of type-II alveolar pneumocytes; and 2) lining is made up of tall, columnar mucin-secreting cells. c. Atypical alveolar adenomatous hyperplasia serves as a premalignant lesion that can give rise to a BAC. The tumors arise from a multipotent cell, the bronchioalveolar stem cells, that have been identified at the bronchioalveolar junction. d. BACs spread through the lung via air passages and can resemble grossly lobar pneumonia, or they can be solitary and well-circumscribed and amenable to resection. Bilateral and multifocal lesions are also frequently seen in these lesions. e. Prognosis depends on whether the tumor is well-circumscribed and solitary or multifocal and diffuse. The solitary lesions are associated with an excellent prognosis when completely resected; the diffuse or multifocal lesions are associated with a poor prognosis similar to conventional adenocarcinoma. 8. Histology is helping to individualize therapy. Women with no history of smoking who have an adenocarcinoma with specific mutations of their EGFR (epidermal growth factor receptor) are reported to respond to treatment with drugs that block the tyrosine kinase activity of the EGFR. A concurrent mutation of KRAS has been reported to result in resistance to this type of treatment.

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E. Large cell Carcinoma 1. Large cell carcinomas represent up to 15% of bronchogenic carcinomas, and is a diagnosis of exclusion. 2. They are undifferentiated non-small cell carcinomas that lack squamous or glandular differentiation. They contain sheets or nests of large malignant cells with vesicular nuclei and prominent nucleoli. 3. The tumors can occur anywhere in the lung and are often associated with early metastases and invasion of the pleura and chest wall. Their clinical behavior is very aggressive with early mortality. F. Small Cell Carcinoma (Poorly Differentiated Neuroendocrine Carcinoma) 1. Small cell carcinomas are neuroendocrine tumors that arise from the neuroendocrine cells (Kulchitsky cells) that are scattered throughout the respiratory epithelium. 2. These highly malignant tumors account for up to 25% of all bronchogenic carcinomas. Less than 1% occur in non-smokers. Commonly associated with ectopic hormone production. 3. They tend to arise in lobar or mainstem bronchi. On gross examination, they are soft, gray-white tumors with extensive necrosis and frequent early spread to regional lymph nodes. 4. Histologically, small cell carcinomas are characterized by proliferation of small, primitive-appearing cells with scant cytoplasm and dense chromatin; tumor cells are approximately 2-3 times the size of a small lymphocyte. Tumor cells may histologically resemble malignant lymphocytes. An older term for SCLC is “oat-cell” carcinoma due to small size of the cells compared with other forms of bronchogenic carcinoma. 5. Small cell carcinomas are associated with very poor prognosis. Very good initial response to radiation/chemotherapy, but in most cases the tumor is disseminated at the time of diagnosis. G. Carcinoid Tumors (Well Differentiated Neuroendocrine Carcinoma) 1. Carcinoids usually arise as a polypoid endobronchial mass. Patients are most often non-smokers and younger than 40 years of age. Patients may present clinically with hemoptysis. 2. Carcinoids are thought to arise from Kulchitsky cells and are closely related to small cell carcinoma (well-differentiated variant). 3. Histologically, these tumors are characterized by their striking “endocrine” growth pattern (nests, ribbons and festoons) composed of monotonous tumor cells with scattered chromatin and abundant cytoplasm. They are sub classified into “typical” & “atypical” on the basis of mitoses and necrosis.
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4. Their clinical behavior is much better than bronchogenic carcinoma. Only 1525% metastasize; the majority are cured by resection. H. Hamartoma 1. Relative uncommon benign tumors containing varying amounts of mesenchymal tissue in varying proportions, including hyaline cartilage, adipose tissue, smooth muscle, and connective tissue that entrap respiratory epithelium. 2. Usually found incidentally in asymptomatic patients. Radiologic studies may demonstrate an isolated lesion; up to 14% as a “coin lesion”. Their clinical significance is the differential diagnosis of a malignancy based on imaging studies.

III. METASTATIC PULMONARY CANCER A. General Features 1. The lung is the most common visceral site of metastases from other internal organ malignancies. Thus, metastases represent the most common lung tumors. a. Some malignancies, e.g. breast and hepatocarcinomas, may invade the lungs by direct extension. 2. Metastatic cancer is usually peripheral and multicentric. Most common form of presentation is to find multiple bilateral subpleural nodules. 3. Lymphangitis carcinomatosa is a distinctive pattern of infiltration in which the carcinoma follows the pulmonary lymphatics causing diffuse interstitial edema. It originates from a primary carcinoma at another site, especially those of breast and stomach. It also may arise from primary bronchogenic carcinoma.

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Lung Cancer: Diagnosis & Treatment
Date: Time: Faculty: Email: September 19, 2008 9:30 AM James Allen, MD; Division of Pulmonary & Critical Care Medicine

Objectives: by the end of this lecture and the associated small group case studies, you should be able to: 1. Accurately recognize the appropriate risk factors, including the epidemiology and demographics of cigarette smoking, for lung cancer when given a patient’s clinical history. 2. Given a clinical vignette, accurately recognize the common symptoms of lung cancer. 3. Given a clinical vignette, accurately recognize the common symptoms of associated with a paraneoplastic syndrome associated with lung cancer. 4. Given a clinical vignette, decide on the appropriate test(s) to order for diagnosing lung cancer. 5. Given the results of clinical and pathologic findings, accurately assess the stage of small cell and non-small cell lung cancer. 6. Contrast the staging system used in small cell lung cancer to the staging system used in non-small cell lung cancer. 7. Compare the treatment of limited and extensive stage small cell lung cancer. 8. Compare the treatment of non-small cell lung cancer stages I, II, IIIA, IIIB, and IV. 9. Determine patient eligibility for lung resection based on pulmonary function tests, quantitative ventilation perfusion tests, and pulmonary exercise tests. 10. List and define the common palliative techniques used in advanced lung cancer. 11. Recommend a diagnostic approach for solitary pulmonary nodules based on lung cancer risk factor analysis. Required Reading: Harrison’s Principles of Internal Medicine – 17th Ed (2008); Chapter 85: Neoplasms of the lung; John D. Minna and Joan H. Schiller
A. Epidemiology: 1. 215,000 new cases per year 2. 162,000 deaths per year 3. currently the #1 cause of cancer deaths in both men and women 4. racial differences in incidence exist 5. incidence increases with age B. Etiology: 1. tobacco smoke - 87% (90% of cases in men and 79% of cases in women) a) risk of cancer correlates with age of smoking onset, number of cigarettes smoked per day and duration of smoking (1) "pack-year" = (# packs smoked per day) x (# years smoked) b) currently 18.1% women and 23.9% of men smoke

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c) 80% of smokers start before age 18 d) for life-time heavy smokers, some studies indicate that as many as 30% of men and 15% of women will develop lung cancer if they live long enough 2. asbestos - 5% a) asbestos exposure without cigarette smoking = 6-fold risk b) cigarette smoking without asbestos exposure = 11-fold risk c) cigarette smoking with asbestos exposure = 59-fold risk 3. radon - 2% 4. environmental tobacco smoke - 1% 5. other minor risk factors: a) arsenic b) BCME & CMME (chloromethyl ethers) c) chromium d) mustard gas e) nickel f) vinyl chloride g) genetic (family history of lung cancer) C. Classification: 1. small cell 2. non-small cell a) adenocarcinoma b) squamous cell carcinoma c) large cell carcinoma d) bronchoalveolar carcinoma D. Clinical Manifestations: 1. Common signs & symptoms: a) anorexia b) cough c) chest pain d) dyspnea e) hemoptysis f) supraclavicular node enlargement g) bone pain h) neurologic manifestations i) hoarseness (left recurrent laryngeal nerve involvement) j) post-obstructive pneumonia k) ** 5-15% asymptomatic at the time of diagnosis** 2. Paraneoplastic syndromes (occur in 10% of patients): a) clubbing and hypertrophic pulmonary osteoarthropathy b) thrombophlebitis c) hypercalcemia d) hyponatremia e) peripheral neuropathy f) Lambert-Eaton syndrome (myasthenia gravis-like condition with neuromuscular weakness) E. Diagnostic Approach: 1. Radiography a) screening chest x-rays not cost-effective and do not affect overall mortality; however, new preliminary studies suggest that CT scans of the lungs MAY be useful for screening - routine use must await results of more clinical

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research; currently, screening is not recommended by major professional organizations b) chest x-ray is overall 70-88% accurate in overall detection of lung cancer when patients have symptoms (1) 61-71% accurate for hilar nodes (2) 47-60% accurate for mediastinal nodes c) chest CT permits identification of enlarged lymph nodes, adrenal masses, and liver metastases involving the superior portion of the liver (1) lymph nodes and adrenal masses can be benign and if the patient is otherwise and operative candidate, nodes and/or the adrenal glands should always be biopsied if they appear to be abnormal by CT 2. Sputum Cytology a) diagnostic in less than 20% of all patients with lung cancer (1) positive in less than 5% of patients with peripheral cancers (2) false positives do occur b) screening with sputum cytology detects cancer earlier but due to lead time bias, there is no survival benefit 3. Bronchoscopy a) solitary pulmonary nodules by x-ray but not visible within the airway (1) yield 10% if nodule is < 2 cm (2) yield 40-50% if nodule is >2-4 cm b) overall diagnostic accuracy for bronchoscopically visible lesions = 94% 4. Trans-Thoracic (CT-guided) Needle Aspirate a) diagnostic yield is 43-97% if radiographically visible 5. Mediastinoscopy - often useful in establishing a diagnosis of cancer if disease is limited to the mediastinum; also sometimes useful to provide staging of the mediastinal lymph nodes 6. Thoracoscopy (rigid scope inserted through small chest incision) a) can use as an initial procedure to be followed by formal thoracotomy if necessary b) average hospital stay for thorascopy only = 2.5 days 7. Thoracotomy (large incision permitting surgeon to get his/her hand into the chest) F. Staging System: 1. small cell lung cancer: it is controversial whether to use the TNM system or the limited/extensive system (most physicians use the limite/extensive system): a) limited stage: confined to the hemithorax, mediastinum, & ipsilateral supraclavicular lymph nodes b) extensive stage: any distant metastasis outside of above locations 2. non-small cell lung cancer: use the TNM system for classification a) definitions (Harrison’s, Table 75-3): (1) Tumor (T) - based on size and location (2) Lymph nodes (N) - based on presence and location (3) Distant metastasis (M) - either present or absent (b) overall 5-year survival = 14% (c) survival correlates with stage: the lower the stage, the higher the likelihood of cure and long term survival (d) unfortunately, most lung cancer is diagnosed at a surgically unresectable stage (e) general approach – must be tailored to each individual patient (1) history and physical examination

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(2) basic laboratory tests (CBC, chemistry profile, liver enzymes, calcium) (3) chest CT scan (4) PET (positron emission tomography) scan – at many centers has become a standard part of staging, after CT scan (5) biopsy of any suspicious abnormalities detected by any of the above G. Treatment: 1. small cell lung cancer a) limited stage - chemotherapy + radiation therapy b) extensive stage - chemotherapy 2. non-small cell lung cancer a) stage I & II - surgery ("never miss an opportunity to operate on a surgically curable lung cancer"). For patients with stage IB, IIA, and IIB, adjuvant chemotherapy following surgery will improve long-term survival rates. Adjuvant chemotherapy is not presently used in stage IA non-small cell lung cancer. (1) PFT assessment of lung function prior to surgery (a) FEV1 > 2 L or > 60% predicted - predicts successful pneumonectomy (removal of an entire left or right lung) (b) DLCO > 60% predicted - predicts successful pneumonectomy (c) PCO2 > 45 – associated with worse outcomes (2) V/Q assessment of lung function (a) FEV1 x % perfusion to the lung that will remain after pneumonectomy (b) > 40% predicted predicts successful pneumonectomy (3) exercise assessment of lung function (a) maximum oxygen consumption > 20 ml/kg/min - predicts low complication rate & low death rate (b) maximum oxygen consumption between 10-20 ml/kg/min predicts increased complication rate (c) maximum oxygen consumption < 10 ml/kg/min - predicts increased death rate b) stage IIIA – chemoradiotherapy with re-staging after treatment for evaluation for possible surgery; Some IIIA tumors can be treated with an initial attempt at surgery followed by adjuvant chemotherapy with or without radiation therapy. c) stage IIIB - chemoradiotherapy d) stage IV - chemotherapy (marginally effective [adds an average of 6-8 weeks of life] but not curative) 3. palliative treatment of lung cancer a) external beam radiation therapy b) endobronchial brachytherapy (high dose intrabronchial radiation therapy) c) endobronchial stents (metal sleeve-like devices that prop open obstructed airways) d) endobronchial laser therapy e) endobronchial cryotherapy (bronchoscopic destruction of tumor with a probe that freezes tissue to -40 degrees) f) endobronchial argon plasma coagulation (bronchoscopic destruction of tumor using high voltage electricity to burn tumor)

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g) endobronchial photodynamic therapy (bronchoscopic destruction of tumor using bright white light after injecting a patient with a photosynsitizing agent that is preferentially taken up by cancer cells) h) pleurodesis H. The Solitary Pulmonary Nodule: a) smallest lesion detectable with chest x-ray is 2-3 mm b) 2-13% of those found by plan chest x-ray are malignant c) 50-60% of those found by plain chest x-ray are benign (1) 40-50% granulomas (rate depends on patient's geographic location - there is a high incidence of histoplasmosis-induced benign granulomas in Ohio (2) 5-10% benign tumors (adenomas, carcinoid tumors, hamartomas) (3) chest CT is far more sensitive for nodules and often finds nodules not visible on plain chest x-ray; a much higher percentage of these small nodules are benign however, they still must be followed radiographically or biopsied to fully exclude early cancer d) benign calcium patterns (often better visualized with CT than plain chest x-rays): (1) laminated (2) diffuse (3) central (4) note: eccentric or speckled can be seen with malignant or benign (a) 13% of bronchogenic cancers have CT evidence of calcification (eccentric or speckled) e) malignant nodules have a doubling time of 21 - 400 days (1) a lesion which is unchanged in size for ≥ 2 years is usually benign (2) a commonly employed strategy is to follow small nodules with serial chest CT scans for 2 years to determine if they are likely to be benign. f) indicators of malignancy: (1) size (a) 0.2% malignant if < 3 mm (b) 0.9% malignant if 4-7 mm (c) 18% malignant if 8-20 mm (d) 50% malignant if > 20 mm (2) age (a) 3% malignant in 35-39 years old (b) 15% malignant in 40-49 years old (c) 43% malignant in 50-59 years old (d) 50% malignant in > 60 years old (3) smoking (4) history of cancer (5) PET scans (positron emission tomography) is a nuclear medicine test that can differentiate benign from malignant nodules in many patients (Standardized Uptake Value [SUV] of > 2.5 is highly suspicious for cancer). PET is only sensitive for tumors > 8 mm in diameter g) clinical approach to the solitary pulmonary nodule: (1) if available compare to old x-rays (preferably > 2 years old) (2) if old x-rays unavailable, obtain chest CT scan (a) if very low risk of cancer after CT - nodules < 4 mm – follow up imaging is optional - nodules 4-6 mm – follow up CT in 12 months - nodules 6-8 mm – follow up CT in 6-12 months (b) if moderate risk of cancer after CT – perform PET scan

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- if PET is positive – resect - if PET is negative – serial CT scans at least at: 3 months 6 months 12 months 24 months (c) if high risk of cancer after CT – biopsy the nodule - if biopsy positive – resect - if biopsy negative – serial CT scans at least at: 3 months 6 months 12 months 24 months

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Interstitial and Occupational Lung Disease
Date: Time: Faculty: Phone: Email: September 19, 2008 11:00 – 11:50 Charles L. Hitchcock, M.D., Ph.D., Department of Pathology 081 - Heart and Lung Research Institute Office 247-7469

Learning Objectives: 1. Describe the pathogenesis of diffuse interstitial pulmonary diseases relative to the cell types and their products. 2. Recognize the morphologic features that distinguish diffuse interstitial lung disease fibrosis from sarcoidosis and occupational lung diseases. 3. Recognize the major morphologic features of the following disorders and correlate them with their etiology, clinical signs and pathogenesis. a. Coal Workers’ pneumoconiosis b. Silicosis c. Asbestosis-related diseases Learning Resources 1. Robbins Pathologic Basis of Disease, 7th Ed., pp. 728-737. 2. Harrison’s Principles of Internal Medicine, 16th Ed., ch 238. I. DIFFUSE INTERSTITIAL LUNG DISEASES (ILD) A. General Features 1. There are many occupational respiratory diseases that involve every component of the upper and lower respiratory system. We will focus on but a few. 2. Patients present with dyspnea, tachypnea, and cyanosis. 3. Restrictive pulmonary function testing demonstrates decreased lung volumes, and decreased CO diffusing capacity and compliance. 4. Imaging studies show a number of findings ranging from diffuse small nodules, irregular lines or ground glass appearance to calcified nodules or consolidation. 5. Long term disease leads to secondary pulmonary hypertension, right-sided heart failure (cor pulmonale).

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6. Diffuse, chronic involvement of pulmonary connective tissue – predominantly the interstitium of the alveolar septal walls. 7. Most common examples of ILD include: a. Environmental/occupational exposures (25%): asbestos, silica, fumes, gases b. Sarcoidosis (20%) c. Idiopathic Pulmonary Fibrosis, IPF (15%) d. Collagen vascular diseases (10%): rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and others B. Pathogenesis 1. Accounts for about 15% of noninfectious pulmonary disorders. 2. Histologic features include scarring with destruction of normal lung parenchyma, which in the advanced stage is termed end-stage lung or honeycomb lung. a. Recall that the alveolar walls consist of basement membranes, collagen and elastic fibers, proteoglycans, fibroblasts and few lymphocytes, monocytes and mast cells. b. Alveolitis is a common early finding regardless of the etiology. This involves increased inflammatory cells (PMNs, lymphocytes, eosinophils) in the alveolar walls and spaces. The inflammation may resolve or result in parenchymal destruction and chronic interstitial fibrosis. c. Direct toxic insult, inhaled dusts, blood-borne toxins, and unknown antigens stimulate alveolar macrophages which in turn activate cells of both the innate and adaptive immune response. These cells synthesize and secrete IL-8 and LTB4 that are strong chemotactic agents for PMNs. The macrophages and the PMNs release proteases and reactive oxygen species that damage the normal pulmonary parenchyma. d. Destruction of the type I pneumocytes leads to proliferation of type II pneumocytes. e. Chronic stimulation of the alveolar macrophages is associated with release of FGF, PDGF, and TGF-β that stimulate fibrosis by attracting and activating fibroblasts. Alveoli are replaced by cystic spaces separated by thick bands of connective tissue. Vascular shunting occurs over time II. PNEUMOCONIOSES A. General Features 1. Occupational lung disorders affecting the pulmonary interstitium are mainly pneumoconiosis (dust diseases) and hypersensitivity pneumonitis. 2. Pneumonoconioses are non-neoplastic lung reactions to organic/inorganic particulates, chemical fumes and vapors. Although the diseases are
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declining, even in developed countries they remain common. Examples include: a. Coal – Anthracosis e. Tin - Stannosis b. Silica – Silicosis f. Barium - Baritosis c. Asbestos – Asbestosis g. Beryllium – Berylliosis d. Iron – Siderosis 3. Air pollution (particulates) in urban centers cause increased morbidity (asthma incidence) and mortality. 4. Occupational ILD’s result from inhaling and retaining dusts that induce inflammation & fibrosis. 5. Only a subset of exposed persons develops disease suggesting a genetic susceptibility component to the disease. B. Particles and the Pathogenesis of Pneumoconiosis 1. The pathogenesis of pneumoconiosis is dependent upon the amount of dust retained in the lung and airways. 2. The size and shape (buoyancy) of the particles is an important factor. a. Particles of 1-5 μm are the most dangerous because they can reach the terminal small air spaces. b. Particles 5 -10 μm are too large to reach the distal airways. c. Particles <0.5 μm are small enough to freely move in and out of the airways without causing damage. 3. Particles may interact directly with interstitial cells (macrophages or fibroblasts). If they have Fe on their surface they may stimulate oxygen free radical formation via the Fenton reaction and thus cell injury that will result in an inflammatory response. They may reach the lymphatics (directly or indirectly if carried there by macrophages) and initiate an immune response. Particles may enter the blood and there may be a systemic response. 4. Smoking may have an additive effect. C. Coal Workers’ Pneumoconiosis (CWP) 1. CWP is a parenchymal lung disease caused by inhalation of coal mine dust, and has been referred to black lung. a. Risk for CWP increases with the dust level, cumulative exposure, hardness of the coal. b. Silica present in coal dust also contributes to the damage.

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2. Simple CWP a. Small macules (coal nodules), < 1 cm, containing carbon-laden macrophages in a fine network of collagen fibers. b. They are located near respiratory bronchioles of the upper lobes or upper zones of the lower lobes. The macule may extend to the alveoli, may show fibrosis, and the distortion of the alveoli may lead to centrilobular emphysema. c. Simple CWP lacks specific clinical manifestations and is often asymptomatic. 3. Complicated CWP (Progressive Massive Fibrosis or PMF) is characterized by many nodules that are at least 1 cm in diameter by radiographs, or are at least 2 cm on gross examination. a. The coal nodules are composed of dense collagen, pigment, and the center is usually necrotic. These lesions also disrupt lung architecture. b. PMF clinically presents with progressive dyspnea, pulmonary hypertension, and respiratory failure. Both obstructive and restrictive physiology may be present (many patients also smoke). c. Caplan’s Syndrome - is inflammation and scarring of the lungs in people with rheumatoid arthritis who have been exposed to coal dust. It is uncommon in the US. There may be multiple nodules that can be quite large. 4. Anthracosis – inhaled carbon pigment in the lungs and hilar lymph nodes. It is a very common autopsy finding in miners, urban city residents, tobacco users. Not a disease per se, patients are asymptomatic. D. Silicosis 1. Silica is a major component of rock and sand. It exists in both crystalline and amorphous forms. a. The crystalline forms include quartz, crystobalite and tridymite. Of these, quartz is the most important form. b. Amorphous silica includes talc, vermiculite and mica. Although these forms of silica are much less biologically active, heavy exposure can cause lesions in the lungs. c. Exposure to silica occurs in miners, sandblasters, stone carvers, workers in foundries, tunnels, quarries, and silica flour production occupations. It is considered the most prevalent chronic occupational lung disease in the world. 2. After inhalation, silica particles interact with alveolar epithelial cells and macrophages to cause injury, release mediators and cause fibrosis.
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a. In the early stages, lesions are discrete nodules, often in the upper lobes. b. In chronic silicosis, multiple nodules form both in the lungs and in the hilar lymph nodes. c. The nodules may form hard, collagenous scars; calcium may be deposited, often in layers, giving an “eggshell” appearance. Some nodules may undergo central softening and cavitation. d. Progressive massive fibrosis (PMF) results from coalescence of the lesions. At this point there is extensive fibrosis and lung function is compromised. 3. There are 3 clinical forms recognized, acute, accelerated and chronic silicosis. The differences in these forms are usually related to the intensity (dose) of the exposure. a. With progressive disease patients, will have increasing dyspnea; at first the symptoms occur with exertion, but later on the symptoms will occur even while at rest. b. Persons with silicosis are at increased risk for fungal infections (cryptococcosis, blastomycosis and coccidioidomycosis). c. Silicosis is associated with an increased susceptibility to TB or other mycobacterial infections. d. There is no treatment for silicosis. Prevention is the best way to address this disorder. The prognosis for patients with silicosis is not good (5-8 years) and depends on the amount of fibrosis present. E. Asbestosis 1. Asbestos is a family of crystalline hydrated silicates that form fibers. a. There are 2 geometric forms of asbestos: serpentine (curly and flexible fibers) and amphibole (straight, stiff and brittle fibers). b. Although the serpentine chrysotile fiber is the most common fiber found in the environment, the amphiboles (crocidolite, amosite, tremolite, anthopyhllite and actinolyte) are more pathogenic in terms of association with mesotheliomas. c. Again the key factors for pneumoconiosis are fiber size, shape, concentration and solubility in the pathogenesis of disease. d. Asbestos is found in mining and milling operations, in insulation for ships or buildings, in the manufacturing of brake linings and clutch facings, in cement, textiles and some fireproofing products.

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2. The inhaled fibers are deposited in the small airways and alveoli where they are incompletely ingested by the alveolar macrophages. a. Macrophages will coat the fiber with iron and this causes the fibers to be visible under the microscope (ferruginous bodies). b. The activation of the macrophages leads to the release of a number of inflammatory mediators that, over time, will cause scarring (fibrosis). 3. Diffuse interstitial fibrosis is a hallmark feature of asbestosis. The fibrosis begins around the respiratory bronchioles and alveolar ducts, usually in the subpleural areas of the lower lobes (contrast this to silicosis!). a. Eventually all lobes can be involved though. Asbestos bodies may be found in the parenchymal lesions. b. In addition, there is a thickening of the pleural surfaces and this can bind the lung to the chest wall. Pleural plaques are the most common manifestation of asbestos exposure. c. The scarring can also involve the pulmonary vessels leading to pulmonary hypertension. They consist of well-circumscribed areas of dense collagen that often contain calcium. They do not usually contain asbestos bodies. d. There is a considerable latency period, of at least 10 years, between the exposure and the development of clinical disease. (20 years is most common). Pleural plaques are usually asymptomatic but may be detected on chest x-rays. 4. The clinical symptoms of asbestosis are similar to other diffuse interstitial lung diseases. a. Dyspnea is usually the first symptom, at first it occurs with exertion, but later it occurs at rest. b. The disease may remain stable or it can progress to congestive heart failure, right-sided heart failure and death. Similar to silicosis there is no treatment for asbestosis. c. Workers diagnosed with asbestosis should be removed from further asbestos exposure and should be counseled to eliminate any other factor that can cause lung disease (e.g. quit smoking). 5. Occupational exposure to asbestos is linked to bronchogenic carcinoma, mesotheliomas, and cancers of other sites (larynx, colon, retroperitoneum). a. Asbestos is both a tumor initiator and tumor promoter. b. The risk of bronchogenic cancer in asbestos workers is increased about 5 times over persons not exposed to asbestos. If an asbestos worker also smokes, then the risk of bronchogenic cancer is even greater (estimated
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55-fold increased risk). c. The relative risk of mesotheliomas, in asbestos workers is about 1000 fold higher than the risk in persons not exposed to asbestos (baseline risk for mesotheliomas is 2-17 cases per 1 million persons). III. DIFFUSE INTERSTITIAL FIBROSES A. Idiopathic Pulmonary Fibrosis (IPF) 1. IPF, old term is Usual Interstitial Pneumonia (UIP), tends to occur more often in men than women and in patients over 50 years of age. Patients complain of a slowly progressive, non-productive cough and dyspnea. Clubbing may be seen. a. Radiologic studies (HRT) show a patchy, subpleural reticular pattern with subpleural cysts seen in latter stages. 2. Because the disease process involves the periphery of the lung, a surgical biopsy – VATS – is needed a. The disease process is patchy with abrupt transitions between normal alveolar parenchyma to dense remodeled lung. Fibroblastic foci are seen in the walls, not in the airspaces, at the transition between these two areas. b. Microscopic cysts, containing mucus and/or inflammatory cells, are noted beneath the pleura. The interstitial mononuclear cell infiltrate is mild. B. Nonspecific Interstitial Pneumonia (NSIP) 1. NSIP refers to a diffuse patchy interstitial pneumonia of unknown etiology. Patients present with a complaint of a progressive cough and dyspnea. a. The disease process involves all of the lobes to varying degrees, usually <40%. Radiologic studies are variable and nonspecific. 2. The histologic pattern is that of a patchy, mild to moderate, uniform interstitial lymphoplasmacytic infiltrate. When fibrosis occurs late in the disease process it is generally mild with little or no architectural destruction or honeycombing. C. Organizing Pneumonia 1. Lung injury often leads to airspace organization. Patients often present with a nonproductive cough and dyspnea, and radiologic studies show patchy airspace consolidation. a. The etiology is highly variable or unknown (cryptogenic). 2. The histologic pattern is that of aggregates of loose fibroblasts in an immature collagen matrix (myxoid-like) within the alveoli and bronchioles, and a mononuclear cell infiltrate in the interstitium. The normal architecture of the lung is maintained.

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IV. GRANULOMATOUS DISEASES A. Sarcoidosis 1. Sarcoidosis is a systemic disease, which in the lungs has a clinical picture of restrictive lung disease and hilar lymphadenopathy seen in up to 90% of cases. 2. Highest incidence is among Scandinavians and African-Americans, 40 yearsof age or younger, and without a history of smoking. 3. The pathogenesis involves a type IV hypersensitivity reaction to one or more antigens that remain unknown. 4. The microscopic examination reveals prominent, non-necrotizing granulomas with immune type giant cells that may contain asteroid bodies and Schaumann bodies. a. The granulomas within the pulmonary interstitium are often fused and associated within the pleura and around venules and bronchioles. Interstitial fibrosis is seen in up to 15% of cases. b. Increased CD4 (+) TH1 cells are seen in BAL samples. B. Hypersensitivity Pneumonitis (Allergic Alveolitis) 1. Involves both Type III and Type IV hypersensitivity reactions to inhaled extrinsic antigen, most commonly job related exposure. a. The immune response occurs at the level of the alveoli. 2. The clinical picture is one of a restrictive process. 3. The microscopic features include a patchy, mononuclear cell infiltrate in the interstitium, primarily around the bronchioles. Non-necrotizing, poorly formed, granulomas are seen in up to 2/3 of cases. a. Chronic exposure can lead to interstitial fibrosis.

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Immunologic and Rheumatologic Lung Disease
Date: Time: Faculty: September 22th, 2008 8:30AM Jeffrey Weiland, MD

Optional Reading: Harrison’s Principles of Internal Medicine 17th Edition (2008), Chapters 313, 314, 316, 317, 319

Objectives: 1. List the 6 pulmonary manifestations of Rheumatoid Arthritis. Be able to differentiate Bronchiolitis Obliterans from BOOP, clinically and radiographically. 2. List the 6 pulmonary manifestations of Systemic Lupus Erythematosus. Know which are more common and how they are treated. 3. Describe the clinical features of Goodpasture’s syndrome and Wegener’s granulomatosis. How do these syndromes differ in pathophysiology, clinical presentation and treatment.

Outline: I. Overview a. These diseases encompass a broad spectrum of conditions where the immune mediated injury is directed at either the interstitium( space between alveolar epithelium and vascular endothelium) or the vascular endothelium itself. b. With certain exceptions that will be noted, the link between the immunologic derangement and the tissue injury is poorly understood. c. Symptoms are non-specific (cough, dyspnea). d. Chest X-rays and pulmonary function tests, while very useful in assessing response to therapy, are not particularly helpful in diagnosis. Therefore e. The astute young physician must be adept at gleaning important historical clues and physical findings that suggest environmental exposures or the presence of other systemic diseases.

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Diseases Associated with Systemic Rheumatic Disorders a. Rheumatoid Arthritis i. Interstitial Pulmonary Fibrosis 1. Male predominant 2. Associated with HLA B8 and HLA Dw3 3. Histology similar to UIP but usually indolent course 4. Cough dyspnea, restricted PFT’s , low diffusion 5. ? Prevalence 6. With progressive disease, always think about drug toxicity ii. Pleuritis with or without effusion 1. Seen in 50% at autopsy 2. Effusions in only 5% (mainly males) 3. Usually asymptomatic but can present acutely with pleuritic pain and fever/leukocytosis 4. Pleural fluid is lymphocytic with low glucose iii. Bronchiectasis 1. Common but usually not symptomatic 2. Distinguished from interstitial fibrosis by volume of sputum 3. Treated like other airway diseases (bronchdilators,steroids) iv. Rheumatoid Nodules 1. Rare (<1%) 2. Usually asymptomatic, hemoptysis if cavitate 3. Single or multiple 4. Always have extensor surface nodules elsewhere 5. Caplan’s Syndrome

Bronchiolitis Obliterans Organizing Pneumonia Prevalence Rare More Common Pathology Bronchiole wall effaced by Lymphocytic infiltration of well Granulation tissue preserved bronchiolar walls and interstitium PFT’s Obstruction Restriction, low DCO CT Bronchiolitis Multifocal, patchy consolidation Prognosis Poor Good with corticosteroids b. Systemic Lupus Erythematosus i. Acute Lupus Pneumonitis 1. Rare (2%) 2. May be initial manifestation of SLE 3. Acute cough, dyspnea and pleuritic pain 4. Bilateral infiltrates, cardiomegaly and effusions 5. Treatment with high dose steroids but must exclude infection first

Bronchiolitis Obliterans

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ii. Diffuse Alveolar hemorrhage 1. Similar to acute lupus pneumonitis except bronchoalveolar lavage fluid is bloody 2. Treatment with steroids but must exclude infection first iii. Chronic Interstitial Lung Disease 1. Develops in <5% 2. Closely resembles Idiopathic Pulmonary Fibrosis except more frequent pleuritic pain 3. Treatment with steroids iv. Pulmonary Hypertension(PHT) 1. Once considered rare, is being reported with increasing frequency 2. Subclinical PHT found in 10% of SLE patients 3. Frequently associated with Raynaud’s phenomenon so potential mechanism is vasoconstriction 4. Alternative mechanism might be chronic thromboembolism a. Antiphospholipid antibodies 5. Vasodilators, anticoagulation and immunosuppressives have all been advocated for treatment v. Pleural Disease 1. Most common pulmonary manifestation a. 20% of patients at onset of disease b. 50% at some point in their course 2. Asymptomatic or pleuritic pain which may be intractable 3. Fluid is exudates and either neutrophilic(acute) or lymphocytic(chronic) 4. SLE cell( described here at OSU ) or antinuclear antibody level in the fluid may be helpful in diagnosis vi. “Shrinking Lung Syndrome” 1. Exertional dyspnea and orthopnea 2. PFT’s restricted and CXR shows high diaphragms and tiny lungs 3. Thought to be a myopathy of the diaphragms 4. ? treatment, usually self-limited but can be severe c. Scleroderma i. Interstitial Pulmonary fibrosis 1. Found in up to 90% of patients at autopsy 2. Strongly associated with Scl-70 antibody 3. Genetic predisposition (HLA-DR3 and DR52a) 4. May antedate the diagnosis of Systemic Sclerosis 5. Cough, dyspnea and rales 6. Chest pain and clubbing are uncommon 7. PFT’s are restricted with low diffusion 8. Association with Bronchogenic carcinoma 9. ? Treatment

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ii. Pulmonary Hypertension 1. Concentric fibrosis of small vessels, plexiform lesions are absent 2. Associated with CREST syndrome 3. Main symptom is dyspnea 4. CXR, CT and Bronchoalveolar lavage are normal 5. PFT’s reveal isolated reduction in diffusion 6. 2D echo can reveal pulmonary hypertension iii. Aspiration Pneumonia 1. Due to esophageal dysmotility d. Polymyositis/Dermatomyositis i. Pulmonary complications in 40% 1. Non-specific interstitial pneumonitis 2. Bronchiolitis Obliterans Organizing Pneumonia (BOOP) 3. Symptoms are cough and dyspnea 4. PFT’s are restricted with low diffusion 5. CT reveals peripheral reticular densities with patchy ground glass infiltrates 6. Usually steroid responsive e. Sjogren’s Syndrome i. Diffuse lung disease 1. May be present in up to 10% of patients with Sjogren’s 2. Usually clinically silent 3. Pathology most frequently is a lymphocytic interstitial pneumonia but may be a pseudo lymphoma or frank lymphoma ii. Tracheobronchial Disease 1. Xerotrachea in up to 25% 2. Relentless dry cough 3. Inflamed mucosa in trachea and bronchi 4. May respond to steroids Diseases Associated with Pulmonary Vasculitis or Diffuse Alveolar Filling a. Goodpasture’s Syndrome i. Typically young men ii. Present with cough, dyspnea and hemoptysis 1. CXR reveals diffuse alveolar filling 2. Microcytic anemia, hematuria, azotemia 3. May have elevated diffusion capacity on PFT’s 4. Anti-GBM antibodies 5. Close link to smoking 6. Corticosteroids, cytotoxic drugs and plasmapheresis b. Wegener’s Granulomatosis i. A systemic vasculitis commonly involving ears or sinuses, lungs, kidneys and skin (ELKS) ii. Etiology unknown

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iii. Frequency of 1 in 30,000, typically middle age , equal in men and women iv. Classic pathology is a “necrotizing granulomatous vasculitis” although renal biopsies show focal segmental glomerulonephritis with crescent formation v. Clinical Manifestations 1. Very broad- average delay in diagnosis is 6-12 months a. May be fulminant with diffuse alveolar hemorrhage, renal failure and death in a matter of days b. More typical is sub acute to chronic complaints of upper airway problems(sinusitis, otitis) c. Lung involvement may manifest as cough, pleuritic pain and hemoptysis or may be an asymptomatic lung nodule (cavitation is frequent) d. Skin involvement is typically palpable purpura on the lower extremities vi. Diagnosis 1. Gold standard is biopsy of an involved organ…but 2. In the appropriate clinical setting, positive serologist for Anti-Neutrophil Cytoplasmic Antibodies (c-ANCA) or PR3 are acceptable vii. Treatment 1. Corticosteroids 2. Cytotoxic Drugs (Cyclophosphamide)

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Occupational and Inhalational Lung Disease
Date: Time: Faculty: Email: September 22, 2008 9:30 am Roy Essig, M.D.

Objectives: 1. Describe the common etiologic agents of occupational asthma 2. Given a clinical vignette, accurately recognize the symptoms and describe means of diagnosis of occupational asthma 3. Describe the pathophysiologic mechanism of carbon monoxide poisoning at level of the red blood cell 4. Recognize the common environmental settings in which carbon monoxide poisoning may occur 5. Given a clinical vignette, accurately recognize the symptoms and appropriate treatment of carbon monoxide poisoning 6. Recognize that drug-induced lung disease has protean and often non-specific signs, symptoms, radgiographic and pathologic findings 7. Given a clinical vignette, accurately recognize some of the clinical pulmonary effects of cocaine use I. Occupational Asthma a. Most common occupational lung disease b. Asthma and the workplace i. Work-aggravated asthma 1. Exacerbated by work: exertion, dusts/fumes/odors, temperatures ii. Work-related asthma 1. Variant syndromes such as organic dust exposures, cotton exposure 2. Eosinophilic bronchitis a. Chronic cough, sputum eosinophilia, lack of airway obstruction or bronchial hyperresponsiveness iii. Occupational asthma 1. 2-15% cases of new adult asthma, over attributable 300 agents identified 2. Without latency a. Asthma without an “immunologic mechanism” i. Irritant-induced asthma ii. Reactive airways dysfunction syndrome (RADS) b. 10-15% cases of occupational asthma 3. With latency

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a. Asthma with underlying “immunologic mechanism” i. Occupational asthma b. 85-90% cases c. Definition of occupational asthma i. Variable airflow limitation and airway hyperresponsiveness ii. Due to causes/conditions attributable to a particular occupational environment (dust, gas, chemical, protein) and not to stimuli encountered outside the workplace iii. Without preexisting history of asthma c. Pathophysiology i. Non-immunologic (or occupational asthma without latency or RADS) 1. Irritant effects of agent 2. Symptoms after a single, high level of exposure such as accidental spill, explosion, exposure in a confined space 3. Mechanism unclear a. Bronchial mucosa injury, neurogenic and nonspecific inflammation b. Regeneration with airway remodeling and chronic inflammation c. Non-specific airway hyperresponsiveness 4. Effected occupations and causative agents a. Chemicals, painting/spraying/fumigating b. Agents include chlorine, sulfur dioxide, combustion products, ammonia ii. Immunologic (or occupational asthma with latency) 1. Agents/occupations a. Farming, painting, plastics/chemicals b. Agents i. Isocyanates most common ii. Western red cedar (plicatic acid), resins, colophony, metal salts (platinum), latex, flour, animal dander iii. Often exposure to multiple agents 2. Agent acts as an antigen based on molecular weight a. Most High-molecular weight agent acts as complete antigen i. Flour, lab/animal protein, latex b. Low molecular weight agents i. Some act as haptens 1. Platinum, trimellitic anhydride c. Produce IgE antibodies that react with mast cells, macrophages, eosinophils to produce inflammatory cascade

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d. Others (isocyanates, plicatic acid) do not consistently induce IgE antibodies and mechanism unclear d. Predisposing factors i. Host factors (genetic) (HLA class II molecules, acetyl transferase, glutathione s-transferase) ii. Atopy iii. Smoking history iv. Type of agent, level of exposure, duration of exposure e. Clinical Presentation i. Latency period where exposed (sensitized) but asymptomatic ii. Inflammation iii. Upper airway symptoms (rhinoconjunctivitis) iv. Dyspnea, wheezing, cough, rhinitis, conjunctivitis symptoms after exposure 1. Initially, symptoms occur early (within hours) or late (4-6 hours) after exposure 2. Over time, progressive and prolonged symptoms to exposure 3. Can ultimately develop persistent symptoms after nonspecific stimuli f. Diagnosis i. RADS 1. Appropriate exposure history-massive, high level irritant exposure 2. Lack of pre-existing asthma 3. Rapid onset of asthma symptoms (usually within 24 hours) 4. Persistence of symptoms and non-specific airway hyperresponsiveness for at least 3 months after exposure ii. Occupational asthma 1. Appropriate exposure history, lack of pre-existing asthma 2. Demonstration of airway hyper-responsiveness (asthma) a. Pulmonary function tests with bronchodilators b. Methacholine challenge testing 3. Demonstration of relation to work environment/exposure a. Peak flow monitoring at work/away from work (2025% drop at work) b. Serial methacholine challenge testing (changes in PC20 over time) c. Controlled environment challenge testing 4. Immunologic testing a. Specific IgE antibodies documented by skin prick reactions, RAST testing. Can also measure IgG antibodies b. Indicates prior exposure

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g. Prognosis/Treatment i. Confirm diagnosis and removal from offending agent/environment ii. Minimize exposure to nonspecific irritants (dusts, smoke, tobacco) iii. Treatment similar to conventional asthma therapy iv. Appropriate return to work and work environment v. Most with occupational asthma do not recover completely, persistent symptoms inn 50-90%. RADS may have better prognosis vi. Pulmonary function testing plateaus at 1-2 yrs after exposure removed Carbon monoxide poisoning a. Chemistry i. Colorless, odorless gas created by incomplete combustion of fossil fuels b. Epidemiology i. Most common cause of poisoning death in the U.S. (5000-6000 deaths/year) ii. Majority associated with exposure to automobile exhaust (intentional and unintentional) iii. Poorly functioning furnaces/heaters/stoves, smoke inhalation due to fires, and exposure to methylene chloride (which is metabolized to CO in the liver) are other important sources 1. Spike in accidental exposures during the winter months 2. Ethnic groups accustomed to cooking/heating fires indoors in less airtight homes in their native countries c. Pathophysiology i. Non-irritating to upper airways ii. Readily absorbed through the lungs iii. Competes with oxygen for hemoglobin binding 1. Hgb has affinity for CO > 200 times as great as its affinity for oxygen 2. Decreased blood oxygen content 3. Shift to left of oxyhemoglobin dissociation curve and decreased oxygen unloading at tissue level a. Particularly pronounced in developing fetus, due to intrinsic left shift of fetal hemoglobin 4. Consequent cellular hypoxia 5. Normal COHb levels 1-3 % in non-smokers, may reach 1015% in smokers iv. CO also appears to have direct cellular toxicity 1. impairs cytochrome oxidase function 2. induces nitric oxide activity and free-radical production

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d. Clinical presentation i. Signs and symptoms nonspecific, and can mimic viral infection ii. Initial symptoms include headache, dizziness, blurred vision, nausea/vomiting, myalgias, difficulty concentrating, dyspnea, and chest pain iii. As exposure worsens, may display tachycardia, hypotension, seizures, dysrhythmias, coma, and death iv. “Classic” sign of cherry-red lips seen only rarely v. Survivors may develop chronic/persistent neuropsychiatric symptoms e. Diagnosis i. Requires high index of suspicion 1. Particular attention to presence of housemates with similar symptoms 2. Presence of gas stove/furnace/water heater ii. Carboxyhemoglobin level 1. Requires co-oximetry a. Multiple (as many as 8) wavelengths of light b. Standard 2-wavelength pulse oximeter cannot distinguish between oxyhemoglobin and carboxyhemoglobin 2. May decrease or normalize by time of presentation iii. Environmental testing of area of exposure 1. Readily performed by all fire departments f. Treatment i. Removal from source of exposure ii. Supplemental oxygen 1. Competes with CO for binding sites on hemoglobin 2. Shortens half-life of CoHb a. 4-6 hours when breathing room air b. 40-80 minutes when breathing 100% oxygen c. 15-30 minutes when breathing hyperbaric oxygen iii. Hyperbaric oxygen 1. 100% O2 given in hyperbaric chamber at 2-3 atm 2. Indications subject of ongoing debate 3. Should be considered patients with: a. COHb > 40% b. COHb > 15% and pregnant c. Significant neurologic signs (focal deficits, seizures, altered mental status, history of loss of consciousness) d. History of ischemic heart disease, particularly if symptomatic e. Persistent symptoms despite normobaric oxygen

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iv. Neuropsychiatric testing 1. Helpful in tracking long-term progression of neurologic symptoms 2. Some have advocated use acutely to help decision-making regarding hyperbaric therapy 3. Should be considered in all CO poisoning, even if no overt neurologic symptoms g. Prevention i. Frequent inspection & maintenance of fuel-burning heating devices ii. Appropriate maintenance of vehicle exhaust systems and education about the dangers of running motor vehicles in enclosed spaces iii. Public education regarding the danger of indoor fires iv. Use of home CO detectors Drug-induced lung disease a. Scope i. Many hundreds of drugs known to have potential adverse effects on the lungs b. Mechanisms i. Induction of oxidant injury ii. Direct cytotoxic effects iii. Intracellular phospholipid deposition iv. Immune-mediated c. Diagnosis i. Requires high index of suspicion ii. Physical exam, laboratory, radiographic, and pathologic findings often non-specific iii. Often a diagnosis of exclusion 1. biopsy may be helpful to rule out other causes d. A few specific drugs of importance i. Bleomycin 1. History a. Antibiotic with antitumor activity discovered in 1966 b. Used to treat germ-cell tumors, lymphomas, Kaposi’s sarcoma, cervical cancer, and head/neck squamous cell cancers 2. Epidemiology a. Pulmonary toxicity occurs in as many as 20 % of those treated b. Risk factors include high cumulative dose (> 400 mg), age > 70, renal dysfunction (impaired clearance of bleomycin), concomitant oxygen therapy, concomitant radiation, and possibly smoking 3. Pathophysiology

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a. Still debated, but appears to caused by cytokine induction with concomitant inflammatory response and free-radical formation b. Acute/sub-acute pneumonitis initially, may develop progressive fibrosis 4. Clinical presentation a. Dyspnea and non-productive cough typical symptoms b. Often gradual in onset, may occur up to 6 months after bleomycin cessation c. Inspiratory rales on exam, but may be normal d. Pulmonary function tests may demonstrate decreased diffusing capacity and decreased lung volumes 5. Radiography a. Non-specific, typically have bilateral alveolar or interstitial infiltrates 6. Treatment a. Cessation of bleomycin b. Corticosteroids often used i. No good randomized data exists c. Majority recover if recognized/treated before fibrosis develops ii. Amiodarone 1. History a. Iodine-based Class III antiarrhythmic b. Used to treat a variety of atrial and ventricular arrhythmias c. Use has increased dramatically in last 10 years i. Very prominent role current ACLS guidelines 2. Epidemiology a. Pulmonary toxicity in 4-6% b. More common in men, age > 40, dose ≥ 400 mg/day, concomitant oxygen therapy 3. Pathophysiology a. Exact mechanism of toxicity unclear b. Typical pathologic finding is alveolar macrophages and type II pneumocytes with “foamy” appearance, due to multiple phospholipid-laden inclusions i. Also seen in those on amiodarone without pulmonary toxicity 4. Clinical presentation a. Non-specific: dyspnea, cough, fevers b. May occur within days to years of initiating therapy, but most commonly within several months

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c. Pulmonary function tests demonstrate decreased diffusing capacity 5. Radiography a. Very wide variety of presentations i. Interstitial infiltrates ii. Pulmonary mass iii. Cavitating lesion iv. Alveolar infiltrates v. Pleural effusions vi. Radiopaque (iodine) infiltrates 6. Treatment a. Cessation of amiodarone b. Uncontrolled data supporting corticosteroids c. Most recover iii. Cocaine 1. General a. Stimulant alkaloid derived from leaves of the coca plant b. Used regularly (≥ once/month) by approximately 1.5 million in the U.S. 2. Route of administration a. Nasal insufflation (“snorting”) i. Majority of a dose taken in this manner does not reach the lungs, but is absorbed via the mucous membranes of the nose/sinuses b. Smoking i. “Freebasing” 1. Cocaine base extracted from the salt (cocaine HCL, typical powder form) by precipitating it with ammonia, then recovering the pure base from solution with ether 2. Base then smoked via pipe ii. “Crack” cocaine 1. Cocaine base extracted from salt by precipitating with sodium bicarbonate, decanting supernatant, and allowing precipitate to dry 2. Avoids dangers (primarily fire) of handling ether c. Injection i. Cocaine HCL dissolved in water and injected ii. Often administered with heroin (“speedball”)

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3. Pulmonary effects a. Smoked i. “Crack lung” 1. Cough, carbonaceous sputum, chest pain, dyspnea, hemoptysis, fever within minutes-hours of use ii. Acute bronchospasm iii. Thermal airway injury iv. Non-cardiogenic pulmonary edema v. Alveolar hemorrhage vi. COP (aka, BOOP) vii. Pulmonary hypertension viii. Pulmonary barotrauma (i.e., pneumothorax, pneumomediastinum) 1. User technique may increase risk a. Valsalva against closed glottis after inhaling (to increase absorption) b. Exhaling smoke under pressure directly into 2nd user’s mouth (“shotgunning”) b. Injected i. Alveolar hemorrhage ii. Talc granulomatosis and obstructive lung disease due to impaction of insoluble impurities in pulmonary microvasculature iii. Pulmonary hypertension iv. Pulmonary barotraumas 1. May stem from attempt to inject directly into internal jugular or subclavian vein (“pocket shot”) 4. Radiography a. Non-specific, varies with type of complication 5. Treatment a. Cessation of use b. Supportive care as appropriate Additional resource (if interested—not required): Murray & Nadel’s Textbook of Respiratory Medicine, 4th ed. Chapters 60 & 67. --available on MD Consult via Health Sciences Library website

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Interstitial Lung Disease
Date: Time: Faculty: Email: September 22, 2008 10:30 AM James Allen, MD; Division of Pulmonary & Critical Care Medicine

Objectives: by the end of this lecture and the associated small group case studies, you should be able to:
1. Recognize common chest x-ray and high resolution chest CT scan findings of interstitial lung disease including ground glass infiltrates and honeycomb infiltrates. 2. Recognize pulmonary function test patterns in interstitial lung disease. 3. Given a clinical vignette, identify common causes of interstitial lung disease from the patient history. 4. Differentiate sarcoidosis and idiopathic pulmonary fibrosis based on clinical, radiographic, and pathologic findings. 5. Given a clinical vignette, distinguish between usual interstitial pneumonitis, non-specific interstitial pneumonitis, acute interstitial pneumonitis, and desquamative interstitial pneumonitis based on demographic, clinical, radiographic, and pathologic findings. 6. Identify sarcoidosis and idiopathic pulmonary fibrosis by microscopic examination of lung biopsy images. 7. Apply bronchoalveolar lavage findings to the differentiation of common forms of interstitial lung disease including sarcoidosis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, allergic drug reaction, and chronic eosinophilic pneumonia. 8. Contrast the advantages and disadvantages of lung biopsy using bronchoscopy and videoassisted thorascopic surgery. 9. Given a clinical vignette, recommend appropriate pharmacologic and non-pharmacologic treatment for sarcoidosis, usual interstitial pneumonitis, and non-specific interstitial pneumonitis.

Optional Reading:
Harrison’s Principles of Internal Medicine – 17th Ed (2008); Chapter 255: Interstitial Lung Disease, Talmadge E. King 2. Harrison’s Principles of Internal Medicine – 17th Ed (2008); Chapter 322: Sarcoidosis, Robert P. Baughman and Elyse E. Lower

I. Pathogenesis: A. Anatomic considerations within the lung: 1. interstitial components 2. alveolar components 3. small airway components 4. blood vessel components B. Pathogenesis: 1. general principles: a) inhaled injury agent – alveolar injury - interstitial fibrosis b) circulating injury agent - endothelial injury - interstitial fibrosis 2. common causes (refer to text for a more extensive differential):

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a) collagen vascular diseases (systemic lupus erythematosus, rheumatoid arthritis, scleroderma) b) occupational causes (asbestos & silicosis) c) drug reactions (methotrexate & amiodarone) d) radiation pneumonitis e) hypersensitivity pneumonitis f) diseases of unknown cause; most common include sarcoidosis & idiopathic pulmonary fibrosis II. Clinical Presentation: A. History: 1. symptoms: cough, dyspnea 2. duration of symptoms 3. what makes symptoms worse? 4. what makes symptoms better? 5. occupational & drug exposures? B. Physical examination: 1. vital signs: respiratory rate, temperature 2. pulmonary exam: crackles (rales) present? 3. cardiac exam: cor pulmonale (pulmonary hypertension) present? 4. extremities: nail clubbing present? arthritis? skin rash? III. Diagnostic Testing: A. blood tests: occasionally useful, mainly to look for evidence of rheumatologic diseases that can cause interstitial lung disease (such as rheumatoid arthritis, systemic lupus erythematosus, etc.) B. Chest x-ray: nodules? interstitial markings? alveolar markings? pleural disease? hilar/mediastinal lymph node enlargement? C. High resolution chest CT: 1. used for diagnosis: a) some patterns relatively specific for certain diseases; eg.: bronchiectasis, emphysema, Langerhan's cell granulomatosus b) location of abnormalities can guide site of lung biopsy 2. used for disease management: a) ground glass infiltrates: correlate with inflammation and are potentially reversible b) "honeycombing": correlate with fibrosis and are irreversible C. Pulmonary function tests: 1. lung volumes - generally reduced 2. diffusing capacity - generally reduced 3. spirometry - generally normal 4. pulmonary exercise testing - typical findings include: a) reduced maximum oxygen uptake b) resting or exercise-induced hypoxemia c) reduced ventilatory reserve D. Bronchoalveolar lavage: 1. normal findings: a) >90% alveolar macrophages b) <10% lymphocytes most are T-cells with a usual T-helper:suppressor ratio is between 1:1 and 2:1 c) <2% neutrophils d) <2% eosinophils 2. important abnormal findings:

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a) increased lymphocyte percentage (1) increased T-helper:suppressor ratio: sarcoidosis (2) decreased T-helper:suppressor ratio: hypersensitivity pneumonitis (3) current immunologic theory recognizes 2 forms of T-helper cells: Th1 & Th2 cells. (a) Th1 cells make interleukin-2 and gamma-interferon (b) Th2 cells make interleukin-4, interleukin-5, & interleukin-10. b) increased neutrophils: most cases of IPF, most other interstitial lung diseases (1) diagnostically, the least specific when present in increased percentages (2) contain a number of oxidants and enzymes with potential for lung tissue damage c) increased eosinophils: chronic eosinophilic pneumonia, some cases of drug-induced lung disease (1) eosinophils are largely controlled by interleukin-5 and other mediators produced by Th2 lymphocytes (2) make a variety of high pH granule contents which are extremely toxic to parasites and normal lung tissue E. Lung Biopsy 1. transbronchial biopsy (via a flexible bronchoscope) a) advantages (1) minimally invasive (2) outpatient procedure b) disadvantages (1) very small tissue samples (2) pulmonary vessels usually not present in specimens (3) usually too small to make a pathologic diagnosis except for sarcoidosis, some cancers, and some infections 2. video-assisted thorascopic biopsy a) advantages (1) larger tissue pieces than transbronchial biopsy (2) shorter hospital stay and less post-operative discomfort than open lung biopsy b) disadvantages (1) inpatient procedure requiring general anesthesia (2) inability to palpate lung during procedure may lead to sampling error (3) difficult to obtain deep samples 3. open lung biopsy a) advantages (1) provides large samples (2) surgeon can better identify involved portions of lung b) disadvantages (1) inpatient procedure requiring general anesthesia (2) longest recovery time IV. Diagnosis & Treatment Of Two Common Interstitial Lung Diseases: A. Sarcoidosis: 1. diagnosis

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a) organs typically involved: lungs, skin, eyes, CNS, heart, kidney, musculoskeletal system b) clinical presentation: (1) high prevalence in African Americans & Scandinavians (2) may be asymptomatic (3) dyspnea; dull, non-exertional chest pain (4) occasional erythema nodosum on skin exam (5) absence of crackles on chest auscultation (6) lymphopenia; occasional hypercalcemia (7) serum angiotensin converting enzyme level often elevated (not very specific) c) chest x-ray - many possible presentations: (1) hilar or mediastinal lymph node enlargement (2) interstitial infiltrates (3) large "fluffy" nodules (4) fibro-cavitary infiltrates (5) chest x-ray may be normal d) pulmonary function tests (1) occasionally normal (2) restriction (early) (3) low diffusing capacity (late) (4) occasionally mild obstruction if sarcoid granulomas involve large/medium sized airways e) BAL (1) increased lymphocytes (2) increased T-helper:suppressor ratio f) lung biopsy (1) transbronchial biopsy usually sufficient for diagnosis (a) if chest x-ray interstitial markings present = 90% yield (b) if chest x-ray interstitial infiltrates absent = 60% yield (2) pathology: (a) non-caseating granulomas (b) multi-nucleated giant cells (c) lymphocytic infiltrates 2. treatment a) indications for treatment: (1) ocular involvement (2) pulmonary or other organ symptoms due to sarcoidosis (3) abnormal pulmonary function tests (4) note: an abnormal chest x-ray per se is not an indication for treatment b) many patients improve spontaneously without treatment c) if symptomatic: prednisone (1) 30-40 mg/day x 3-4 weeks (2) taper to 10-20 mg every day or every other day x 4-6 months (3) in prednisone-intolerant patients, methotrexate is an alternative d) prognosis is excellent in the majority of patients if recognized and treated promptly and appropriately

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B. Idiopathic pulmonary fibrosis: 1. diagnosis a) organs typically involved: (1) lung b) clinical presentation: (1) usual age = 50-70 (2) subacute onset dyspnea on exertion (3) non-productive cough (4) dry inspiratory crackles (90%) (5) nail clubbing in about 50% (6) genetic (autosomal dominant) in 10-20% of cases c) chest x-ray: (1) basilar or diffuse interstitial changes (2) no hilar lymph node enlargement (3) no pleural disease (4) high resolution chest CT is moderately specific (a) peripheral/subpleural interstitial densities (b) patchy "ground-glass" infiltrates (c) small (2-4) cystic areas d) pulmonary function tests (1) reduced lung volumes (2) reduced diffusing capacity (3) low pO2 (4) low MVO2 during exercise testing e) BAL (1) increased lymphocytes (a) usually an early finding (b) when present, often predicts favorable response to treatment (2) increased neutrophils (a) the more frequent finding (b) when present, usually indicates a less favorable response to treatment f) biopsy (1) thorascopic or open lung biopsy usually required (2) histologic subtypes: (a) usual interstitial pneumonitis (UIP): typically an isolated lung disease occurring in older adults (1) interstitial fibrosis (2) absence of granulomas & vasculitis (3) decreased type 1 pneumocytes (4) collagen deposition (5) temporal heterogeneity (as if the lung was repeatedly injured over time) – some areas of end-stage fibrosis, some areas of interstitial thickening, and some areas of relatively normal lung (b) non-specific interstitial pneumonitis (NSIP): typically a disease occurring in patients with underlying collagen vascular disease such as rheumatoid arthritis, systemic lupus

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erythematosus, systemic sclerosis (scleroderma), polymyositis, etc. (1) temporal homogeneity (as if the lung injury occurred at one time) – all areas of the lung in the same stage of damage (2) relatively less collagen deposition (3) relative absence of fibroblast foci (c) desquamative intersitial pneumonitis (DIP): typically a disease of young smokers (1) large increase in alveolar macrophages in the alveoli with abundant hemosiderin granules (2) relatively little fibrosis and collagen deposition (d) acute interstitial pneumonitis (AIP): rare and very rapidly progressing disease resulting in respiratory failure within days to weeks. (1) diffuse alveolar damage with hyaline membranes and resembling acute respiratory distress syndrome (ARDS) 2. treatment a) UIP treatment (1) there is no known cure (2) daily steroids (prednisone), cyclophosphamide, azathioprine – minimally effective (3) single lung transplantation (a) last resort in patients failing other treatment (b) must be < 60 or 65 at most transplant centers (c) lung transplant is not easy – 25% mortality rate in the first 2 years after transplant (4) generally fatal with or without pharmacologic treatment with mean survival = 5 years b) NSIP treatment (1) daily prednisone (2) daily cyclophosphamide, daily azathioprine, or daily mycophenolate (3) prognosis: most patients will improve and have good prospects for long term survival c) DIP treatment (1) smoking cessation (2) steroids with or without cyclophosphamide or azathioprine (3) prognosis: excellent with smoking cessation d) AIP treatment (1) mechanical ventilation and supportive care (2) steroids are often used but are of questionable value (3) prognosis: 60% mortality rate; if patients survive the initial bout of respiratory failure, long term survival is possible and substantial lung recovery can occur

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Traumatic Chest Emergencies
Date: Time: Faculty: Email: I. September 23, 2008 8:30 Roy Essig, M.D. Objectives a. Accurately describe the underlying pulmonary mechanics leading to tension pneumothorax b. Given a clinical vignette, recognize the signs and symptoms of tension pneumothorax, and accurately describe emergency treatment c. Accurately describe the underlying pulmonary mechanics of an open pneumothorax d. Given a clinical vignette, recognize the signs and symptoms of open pneumothorax, and accurately describe emergency treatment e. Accurately describe the pulmonary physiology that occurs in flail chest f. Recognize the type of injury required to cause flail chest g. Given a clinical vignette, recognize the signs and symptoms of flail chest, and describe emergency treatment h. Describe the anatomic basis and pulmonary physiologic basis of diaphragmatic rupture i. Given a clinical vignette, recognize the signs and symptoms of diaphragmatic rupture, and describe treatment Tension pneumothorax a. Terminology i. Pneumothorax 1. Air in pleural space ii. Simple pneumothorax 1. Air in pleural space, associated with some degree of lung collapse, but no compression of mediastinal structures and no significant communication of pleural space with ouside environment iii. Tension pneumothorax 1. Air in pleural space of sufficient volume/pressure to cause compression and shift of mediastinal structures, and hemodynamic compromise iv. Open pneumothorax 1. Air in pleural space due to communication with external environment through open chest wall defect b. Physiology i. Tension pneumothorax occurs when air accumulates in the pleural space progressively, due to ongoing air leak into pleural space without means for air to escape ii. Results in collapse of ipsilateral lung


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iii. Ultimately causes compression of mediastinal structures, including SVT, heart (especially RA and RV), trachea and lower airways, followed by contralateral shift of mediastinum iv. Hypotension and cardiovascular collapse ultimately occur due to compression of the low-pressure RA and RV, with consequent inability of heart to fill with venous blood adequately c. Etiology i. Introduction of air into pleural space due to lung injury 1. Mechanical ventilation a. Especially in patients with pneumonia, severe lung injury, or those being ventilated at high pressures 2. Blast/blunt trauma to lung 3. Rib fractures that lacerate lung 4. Airway disruption/tear 5. Attempted CVC (central venous catheter) placement with puncture of lung ii. Introduction of air into pleural space from outside environment 1. Penetrating/avulsive injury to chest wall d. Diagnosis i. Symptoms 1. Shortness of breath, respiratory distress (usually severe) 2. Chest pain ii. Signs 1. Decreased/absent breath sounds on side of pneumothorax 2. Hyperresonance to percussion 3. Palpable tracheal shift to opposite side (often subtle/absent) 4. Palpable crepitus (crackling) in chest wall due to subcutaneous air 5. Tachycardia/hypotension 6. Hypoxemia 7. Cardiopulmonary arrest (especially PEA) iii. Radiography 1. Air in pleural space with shift of mediastinal structures to opposite side 2. Diagnosis is primarily a clinical one—DO NOT wait for chest x-ray prior to initiating treatment!!! Patient may die while you are waiting. . . e. Treatment i. Immediate goal is decompression of affected side and restoration of hemodynamic stability 1. Needle decompression a. Large bore needle (14 gauge) inserted into chest at second intercostal space, mid-clavicular line b. Usually results in large “whoosh” as compressed air escapes

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c. Converts tension pneumothorax into simple pneumothorax d. Stopgap measure—buys you time ii. Secondary goal is ongoing evacuation of air leaking into pleural space 1. After decompression, still need to evacuate remaining air and address ongoing air leak 2. Tube thoracostomy (aka, chest tube) a. Large-bore tube inserted through chest wall into pleural space to allow continued drainage (often under suction) of air and fluids from pleural space Open pneumothorax a. Physiology i. Introduction of air into pleural space due to traumatic chest wall defect ii. Results in lung collapse iii. If chest wall defect is ≥ 2/3 diameter of trachea, air will preferentially be sucked through defect into chest (rather than drawn through trachea) during attempts at inspiration 1. Hence the moniker, “sucking chest wound” iv. Results in inadequate ventilation of unaffected lung through trachea b. Etiology i. Can occur due to any penetrating injury to chest ii. May convert to tension pneumothorax if chest wall tissue causes “one-way valve” effect 1. That is, air can enter pleural space on inspiration, but cannot escape on expiration because “valve” closes and blocks chest wall defect c. Diagnosis i. Symptoms 1. Shortness of breath 2. Chest pain ii. Signs 1. Evident chest wall defect 2. May see/hear air bubbling (through blood) in wound 3. Breath sounds may or may not be decreased a. May hear air rushing in and out of pleural space though defect, or gurgling through blood/secretions 4. Hypoxemia 5. Hemodynamic compromise if tension physiology develops iii. Radiography 1. Demonstrates air in pleural space 2. Usually not necessary d. Treatment i. Two primary goals

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1. Seal chest wall defect to prevent further introduction of air and allow ventilation through trachea to occur normally a. In theory, should place “3-sided” dressing that allows air to escape pleural space but not enter b. In reality, often difficult to achieve, and may need to completely occlude defect 2. Evacuate air from pleural space a. Tube thoracostomy ii. Once patient stabilized, will need surgical closure of chest wall defect Flail chest a. Physiology i. Occurs when 2 or more ribs are broken in 2 or more places, causing a section of chest wall to “detach” from the thoracic cage ii. Flail segment moves “paradoxically” during respiration, and can lead to inadequate ventilation of lung 1. Flail segment moves inward on inspiration, outward on expiration (unlike rest of chest wall) iii. Also usually associated with: 1. Pulmonary contusion (bleeding into the lung) 2. “Splinting” and poor ventilation due to chest pain b. Etiology i. Usually blunt force or crush injury to chest c. Diagnosis i. Symptoms 1. Chest pain a. Often severe, worse with cough and deep breathing 2. Shortness of breath 3. Hemoptysis due to concomitant lung contusion ii. Signs 1. Palpable rib fractures 2. Paradoxical chest wall movement 3. Hypoxemia iii. Radiography 1. 2 or more rib fractures in 2 or more places 2. Alveolar infiltrates due to pulmonary contusion iv. Treatment 1. Primarily supportive a. Aggressive pain control b. Supplemental oxygen c. Non-invasive ventilation or invasive mechanical ventilation if needed until segment heals/stabilizes 2. Surgical repair/stabilization of flail segment only rarely necessary Diaphragmatic rupture a. Etiology

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i. Can occur after penetrating or blunt trauma (usually the latter) ii. Stabbings and MVA’s most common causes, respectively 1. Also reported after bouts of severe vomiting iii. Occurs in as many as 5% of hospitalized MVA victims iv. Approximately 10-15% escape initial diagnosis and are found weeks-years later (greatest reported delay = 45 years) b. Anatomy i. Rupture typically occurs at weakest part of diaphragm, posterior insertion of muscular portion (pars lumbalis) into central tendon 1. Site of embryologic fusion of pleuroperitoneal membrane with septum transversum and body wall mesoderm ii. Majority are L-sided 1. Liver protects R hemidiaphragm, and may also “seal” a Rsided defect and prevent visceral herniation 2. R-sided rupture harder to diagnose 3. R hemidiaphragm inherently stronger c. Physiology i. Blunt trauma usually results in tears d/t increased intra-abdominal pressure 1. Normal abdominal-thoracic pressure gradient = 5-15 mm Hg 2. Rapid increase of intra-abdominal pressure of ≥ 100 mm Hg said to be required for rupture ii. Pressure gradient between peritoneum and chest cavity results in herniation of abdominal contents into chest 1. Commonly herniated viscera include stomach, colon, small bowel, and spleen iii. Patients with emphysema or other causes of increased intrathoracic pressure may experience herniation of lung into peritoneum d. Signs/symptoms i. Acute 1. Chest pain, dyspnea, cyanosis, decreased breath sounds 2. Hemodynamic compromise due to tension physiology or due to strangulation/infarction of viscera 3. Cardiac tamponade due to viscera in pericardial sac has been described ii. Chronic 1. Dyspnea, abdominal pain, GERD (may be subtle) 2. Symptoms due to compromised viscera in hernia sac 3. Several reports of tension fecopneumothorax (i.e., stoll and air in pleural space) due to perforation of colon iii. Radiography 1. Plain x-ray may show apparent elevation of hemidiphragm, or air-filled viscera in pleural space 2. CT scan useful in the acute setting

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a. Indentation of herniated viscera (“collar sign” d/t impingement on torn diaphragmatic margin) highly suggestive 3. MRI extremely accurate; probably best modality for stable/chronic hernias iv. Low threshold for diagnosis via surgery in trauma patients in whom rupture is suspected e. Treatment i. Surgical repair 1. Either primary closure or patch over defect 2. Indicated in all cases, including “stable” chronic injury— risk of strangulation is perpetual, and mortality increases with delayed treatment ii. Literature mixed regarding approach (transthoracic vs. transabdominal) 1. Transabdominal more commonly used in acute rupture d/t blunt trauma a. May be done laparoscopically 2. Thoracotomy (approach through chest) often preferred for chronic hernia (due to likelihood of adhesions in chest cavity), large hernias (> 10 cm), or those involving the esophageal hiatus Additional resource (if interested, not necessary): Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed, Ch. 42. (available through MDConsult through Health Sciences Library website)

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Pediatric Pulmonary – Neonatal & Congenital Disorders
Date: Time: Faculty: Phone: Email: September 23, 2008 9:30 am Elizabeth D. Allen, M.D. Department of Pediatrics, Division of Pulmonary Medicine Nationwide Children’s Hospital Office 722-4766

Resources: Nelson Textbook of Pediatrics, 17th ed., 2004 Part 11, Section 1, Chapter 90 Part 18 Pediatric Pulmonology – Neonatal & Congenital Disorders Objectives 1. 2. 3. Describe characteristics of children which place them at increased risk for respiratory compromise List signs and symptoms of respiratory distress in the newborn Describe key features of common newborn respiratory illnesses, including hyaline membrane disease, meconium aspiration, neonatal pneumonia, and persistent pulmonary hypertension of the newborn 4. 5. 6. 7. 8. 9. Identify the most common problem of ventilatory control in premature infants, commonly associated health problems, and treatment options Distinguish between these illnesses, based on history, exam, and radiographic findings Describe bronchopulmonary dysplasia Recognize that there are a multitude of congenital malformations of the respiratory system Describe key features of laryngomalacia Describe key features of diaphragmatic hernia

10. Describe key features of tracheoesophageal fistula

Introduction A. B. Respiratory disease is the major source of morbidity and mortality in the pediatric age group Factors involved in children's susceptibility to pulmonary mortality: 1. Congenital abnormalities 2. Perinatal transition in oxygen supply 3. Tiny upper airway 4. Increased virulence of infections 1. Risky behaviors 2. Hardiness of cardiovascular system

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Categories of Childhood Respiratory Illness A. B. C. D. E. F. G. A. Neonatal Respiratory Disorders Congenital Abnormalities Infectious Lung Diseases Accidental Lung Injury Asthma Cystic Fibrosis Misc. Clinical Features of Respiratory Distress in Newborns 1. 2. 3. 4. 5. 6. 7. B. 1. 2. 3. 4. 5. 6. C. Tachypnea/Apnea Expiratory grunting Chest wall retraction Loss of muscle tone Decreasing response to external stimuli Bradycardia Cyanosis Most common cause of newborn respiratory distress Incidence correlates with prematurity Surfactant deficiency causes alveolar collapse Deterioration over 24-48 hours, then gradual recovery Treatment: surfactant replacement, supportive care Prevention: betamethasone administered to mother prior to delivery better – reduce rates of prematurity Meconium Aspiration 1. 2. 3. 4. 5. D. 1. 2. 3. 4. Typically term or post-term infant Prenatal stress (+/- asphyxia) often involved Meconium (stool) released into amniotic fluid, then inhaled Airway plugging/hyperinflation/pneumonitis Treatment: acute suctioning, supportive care Any gestational age May present identically to hyaline membrane disease, with sepsis, or after a delay Common organisms: Gram (-) bacteria, Grp B Treatment: Antibiotics, supportive care -Streptococcus

Neonatal Respiratory Disorders

Hyaline Membrane Disease (AKA Respiratory Distress of Newborn)

Neonatal Pneumonia

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Persistent Pulmonary Hypertension of the Newborn (PPHN) 1. 2. Elevated pulmonary vascular resistance with shunting of pulmonary blood flow to the systemic circulation (persistent fetal circulation) Associated with: a. b. c. d. 3. 4. Severe neonatal stress (sepsis, asphyxia, etc.) Pulmonary parenchymal disease Lung hypoplasia No obvious pulmonary defect

Most common in term or post-term infants Treatment difficult Major form of chronic lung disease in infants Especially frequent in very low birthweight infants Combined effects of lung injury & arrested lung development Oxygen requirement beyond 36 weeks post menstrual age (PMA), or 56 days postnatally CXR findings: perihilar thickening and hyperinflation Prognosis: Improvement with time – vast majority Deaths often related to cor pulmonale (right heart failure secondary to chronic lung disease/hypoxia), or RSV infection


Bronchopulmonary dysplasia 1. 2. 3. 3. 4. 5.


Apnea 1. 2. Definition: cessation of inspiratory gas flow for 20 seconds, or for a shorter period if accompanied by bradycardia (HR <100), cyanosis or pallor. Types: a. b. c. 3. a. b. c. d. 4. a. b. c. d. e. Central Obstructive Mixed Common cause of apnea in newborns Incidence inversely proportional to age (50% of infants < 1500 gms need intervention) Peaks between postnatal days 5 and 7 Normally resolves between 34-36 weeks postconceptual age RDS Pulmonary mechanical problems – e.g. atelectasis Infection Hypotension Seizures

Apnea of Prematurity

Problems associated with apnea (partial list)

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f. g. 5. a. b.

Metabolic disturbances – hypoglycemia, acidosis, hyponatremia Gastroesophageal reflux Treat underlying health problem Avoid triggering reflexes i. “Back to Sleep” ii. Cautious suctioning iii. Tube feedings

Therapies for newborn apnea

c. d. e. A.

Cutaneous stimulation Nasal prong oxygen > nasal cpap > mechanical ventilation Methylxanthine therapy

Examples of Common Congenital malformations Laryngomalacia 1. Floppy and elongated epiglottis and arytenoids 2. Most common cause of stridor (inspiratory high pitched noise) from birth 3. Resolves spontaneously over 1-2 years 4. Differential: Congenital or acquired upper airway lesions B. Diaphragmatic hernia 1. 2. 3. 4. Defect in diaphragm allows abdominal contents to migrate into chest Most common form = posterolateral defect on left side, develops at roughly 6 weeks of fetal age Pulmonary hypoplasia, PPHN, and surfactant system dysfunction contribute to high mortality 25% also have congenital heart disease; 40% total with some other congenital defect Intubation, oral-gastric suctioning, mechanical ventilation ECMO (total circulatory bypass) may be needed Surgical repair of defect Survey for associated anomalies C. Tracheoesophageal fistula 1. 2. 3. Defective separation of the trachea and esophagus during fetal development Several forms – typically abnormal connection between esophagus and trachea, with Clinical clues (a) Excessive secretions (b) Severe choking on feeding attempts (c) Inability to pass nasogastric tube 4. Treatment: Surgical 5. Management:

interruption of normal esophagus (“blind pouch”)

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Complications: gastroesophageal reflux, persistent fistulas. Recurrent esophageal

strictures Congenital Pulmonary Malformations A. B. C. D. Pulmonary function is not needed for fetal development Multiple abnormalities may occur – and unless discovered by prenatal testing – not be evident until post birth Abnormalities range from mild and temporary, to life-threatening Some malformations may not cause symptoms until adulthood choanal atresia laryngomalacia laryngeal webs, cysts tracheomalacia tracheal stenosis Neonatal and Congenital Lung Disease A. B. C. The respiratory tract is a major source of vulnerability for children Infants, particularly, are susceptible to life-threatening pulmonary disease Congenital disorders are quite variable, usually (but not always) present in infancy, and range from benign to lethal pulmonary hypoplasia pulmonary sequestration pulmonary cysts esophageal atresia diaphragmatic hernia

Congenital pulmonary malformations typically presenting in childhood

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Pediatric Pulmonary – Beyond the Newborn Period
Date: Time: Faculty: September 23, 2008 10:30 am Elizabeth D. Allen, M.D. Department of Pediatrics, Division of Pulmonary Medicine Nationwide Children’s Hospital 722-4766

Phone: Email:

Resources: Nelson Textbook of Pediatrics, 17th ed., 2004 Part 18, Section 3 Chapter 61 Chapter 134 I. Pediatric Pulmonology – Childhood Objectives 1. 2. 3. 4. List major sources of respiratory difficulty beyond the neonatal period List ways the pediatric respiratory tract can be “accidentally” injured Identify some unique features of asthma in childhood Distinguish between pediatric illnesses that are likely to present with stridor, versus those likely to present with wheezing 5. 6. Identify at least 3 respiratory infections that can be prevented by immunization Describe symptoms which can be caused by chronic aspiration, and populations at risk for this process 7. 8. List common sites of drowning injury in children, based on age range Identify the most common reasons for hemoptysis in children, and describe methods used to diagnose them 9. Identify common causes of chronic cough in childhood

10. List the “usual” reasons otherwise healthy children experience difficulty with shortness of breath during exercise

Categories of Childhood Respiratory Illness A. Neonatal Respiratory Disorders B. Congenital Abnormalities C. Infectious Lung Diseases D. Accidental Lung Injury E. Asthma F. Cystic Fibrosis G. Miscellaneous

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Respiratory Infections Example: Croup (Laryngotracheobronchitis) Major cause of acute stridor in infants & toddlers Viral mediated Treatment – nebulized epinephrine & steroids Diff – epiglottitis, bacterial tracheitis, retropharyngeal abscess, foreign body, anaphylaxis A. Viral mediated disease most common reason for acute febrile respiratory illness 1) RSV bronchoilitis major problem in infants 2) Influenza, para-influenza, adenovirus also virulent B. Bacterial pneumonia similar to adults 1) Mycoplasma/atypicals less common < 7 yo C. Pertussis can be life-threatening to infants, severe in young children D. Immunizations have had significant (+) impact 1) In Use: Pertussis, H. influenza, S. pneumococcus 2) In development: RSV E. Drug resistance increasing problem “Accidental” Injuries A. Foreign body aspiration B. Food/Gastric content aspiration C. Near drowning/drowning Foreign Body Aspiration A. Toddlers at increased risk B. Peanuts, hotdogs, hard candies, small toys C. Can result in: 1. 2. 3. 4. Complete airway obstruction Stridor Wheeze Persistent pneumonia

Chronic Aspiration A. Food or gastric juice “down the wrong pipe” B. Sources: abnormal swallow, gastroesophageal reflux, or both C. Diagnostic testing; video-swallow study, pH probe, others . . . Chronic Aspiration Symptoms A. Recurrent pneumonia B. Chronic cough C. Recurrent stridor D. “Noisy breathing” in infancy E. Difficult to control asthma

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Populations at Risk for Aspiration A. Infants B. Neurologically impaired C. History of congenital GI abnormalities D. Pre-existing pulmonary disease E. (Also normals!) Near Drowning A. Drowning: Second most common cause of injury & death in 1 mo to 14 yo children B. Most common sites of drowning < 1yo Preschool Teens Bathtubs Residential pools Ponds, lakes, ocean (EtOH)

C. In those who survive, neurologic impairment common Pediatric Asthma : Highlights in Kids A. Most common cause of hospitalizations, school absences, outpatient ill visits B. 10-15% of children affected: 1/3 "outgrow" C. Symptoms and treatment similar to adults, except for: 1. 2. special concerns regarding inhaled steroids & growth special challenges regarding administering inhaled meds

Differential Diagnosis of Wheezing in Children A. Asthma B. Chronic aspiration (GERD or dysphagia) C. Large airway obstruction 1. 2. Hemoptysis A. Top 3 Causes of pediatric hemoptysis 1. 2. 3. Respiratory infections (TB, Histoplasmosis) Foreign bodies Bronchiectasis (Cystic fibrosis, dysmotile cilia syndrome, etc.) Intrinsic anatomic problems: Tracheal stenosis, tracheomalacia Acquired intra-airway obstruction: Tumors, foreign bodies

B. Other causes . . . 1. 2. 3. 4. 5. 6. Lung malformations Vascular abnormalities Neoplasms Immune-mediated syndromes Left heart failure/congenital heart defects Idiopathic

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Work-up 1. 2. 3. 4. Radiographic imaging: CXR, CT scans Bronchoscopy Arteriography Laboratory evaluations aimed at identifying underlying disorders

D. Interventions to Stop Bleeding 1. Bronchoscopic Iced saline, topical epinephrine, fibrin & thromin mix, selective occlusion 2. 3. Embolization Lung resection

Chronic Cough A. Top causes of chronic (> 3 weeks) cough in otherwise healthy patients 1. 2. 3. 4. Asthma Postnasal drip – allergy or sinusitis Gastroesophageal reflux (“Habit cough”)

B. Other causes Infection, retained foreign body, cystic fibrosis, tracheoesophageal fistula, Immunodeficiency Shortness of Breath with Exercise Most common causes in otherwise healthy kids: • • • Exercise induced bronchospasm Vocal cord dysfunction Deconditioning

Primary pulmonary tumors Malignant and benign forms Very rare Conclusion A. B. The respiratory tract is a major source of vulnerability for children Beyond the neonatal period, pulmonary illness due to infection, asthma, “injury,” and cystic fibrosis are common C. “Adult” pulmonary problems – such as interstitial lung diseases, pulmonary hypertension, embolic disease, and cancer are seen in children – but much less commonly

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Clinical Approach to Cough
Date: Time: Faculty: Email: September 24, 2008 8:30 AM Karen Wood, MD; Division of Pulmonary & Critical Care Medicine

Objectives: by the end of this lecture, you should be able to: 1. Distinguish between acute, subacute, and chronic cough. 2. Recognize the common complications of cough. 3. Given a clinical vignette, decide on the appropriate test(s) to order for diagnosing chronic cough. 4. Recommend a diagnostic approach to Upper Airway Cough Syndrome as a cause of chronic cough 5. Recommend a diagnostic approach to cough variant asthma. 6. Recommend a diagnostic approach to GERD as a cause of chronic cough. Required Reading: Harrison’s Principles of Internal Medicine – 17th Ed (2008); Chapter 34: Cough and Hemoptysis; Steven E. Weinberger, David A. Lipson. 1) Epidemiology: a) 3.6% of all office based physician visits are for cough. b) 29.5 million visits per year. 2) Definition: a) Acute cough (< 3 weeks duration) b) Subacute cough (3 – 8 weeks duration) c) Chronic cough (> 8 weeks duration) 3) Mechanism: a) Afferent Limb – i) vagal afferent nerves receptors (1) c-fibers (2) RAR – Rapidly Adapting Receptors (3) SARs – Slowly Adapting Stretch Receptors ii) Sites of stimulation (1) Pulmonary (2) Esophagus (3) Pharynx (4) Ear (5) Consciousness b) Efferent Limb – i) Deep Inspiration ii) glottic closure iii) expiratory effort against closed glottis with high intrathoracic volume causes elevated intrathoracic pressures. iv) narrowing of trachea v) glottis opens - rapid flow rates 4) History a) Duration of symptoms? b) Infectious symptoms at onset?

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c) Associated symptoms of fever, dyspnea, chest pain, orthopnea, weight loss, night sweats? d) sputum production? e) any evidence of asthma or allergy symptoms (wheezing, seasonal symptoms, exercise symptoms)? f) cigarette smoker? g) ACE Inhibitor treatment? h) Symptoms of GERD such as heartburn or cough after eating i) Symptoms of post nasal drip (nasal drainage, throat clearing, nasal congestion) j) Is the patient immunocompromised? 5) Initial Testing: a) CXR b) Spirometry 6) Differential: a) Acute i) Severe or life threatening disease (1) Pneumonia (2) PE (3) Heart Failure (4) Severe exacerbation of asthma or COPD ii) Other Infectious iii) Exacerbation of pre-existing condition (1) Asthma (2) Bronchiectasis (3) Upper Airway Cough Syndrome (UACS) (4) COPD b) Subacute i) Post infectious ii) Exacerbation of pre-existing condition (1) Asthma (2) Bronchiectasis (3) Upper Airway Cough Syndrome (UACS) c) Chronic i) ACE Inhibitor ii) Smoking iii) UACS (upper airway cough syndrome) iv) Asthma v) NAEB (nonasthmatic eosinophilic bronchitis) vi) GERD (gastroesophageal reflux disease) vii) COPD viii) Cancer ix) ILD x) Bronchiectasis xi) Aspiration xii) Post-infectious xiii) Tuberculosis or other infection xiv) Habit cough xv) Other lung disease 7) Complications of Cough a) Embarrassment / self consciousness b) Urinary incontinence

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c) Disturbed sleep / fatigue d) Dizziness / Syncope e) Chest and abdominal wall soreness f) Rib fractures g) Arrythmias h) Herniations i) Fear of serious disease 8) Approach and Treatment a) History, PE, CXR, Spiro i) If disease suggested – treat it! b) If smoker – quit smoking c) If on ACE Inhibitor – stop the treatment d) If everything normal or still coughing evaluate and treat most common causes: i) UACS – Upper Airway Cough Syndrome (1) Diagnosis – empiric (2) Treatment: (a) Antihistamine and Decongestant (b) nasal steroids (c) Oral leukotriene inhibitors (d) nasal ipratroprium ii) Asthma (1) Diagnosis (a) Spirometry with bronchodilators (b) Methacholine challenge (bronchial provocation testing) (2) Treatment (a) Inhaled corticosteroids (b) Bronchodilators (c) Leukotriene receptor antagonists iii) NAEB (1) Diagnosis (a) Sputum for eosinophils (2) Treatment (a) Inhaled corticosteroids iv) GERD (1) Diagnosis (a) Empiric Treatment (2) Treatment (a) Proton Pump Inhibitor (b) Diet and Lifestyle modifications 9) Further testing that can be considered: a) 24 hour esophageal pH monitoring b) Swallow evaluation c) Barium esophagram d) Sinus CT e) High resolution chest CT f) Bronchoscopy g) Echocardiogram h) Videolaryngostroboscopy (VLS)

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Clinical Approach to Dyspnea
Date: Time: Faculty: Email: September 24, 2008 9:30 AM James Allen, MD; Division of Pulmonary & Critical Care Medicine

Objectives 1. List the neural sensors that contribute to the sensation of dyspnea. 2. List the pathophysiologic conditions that contribute to the perception of dyspnea. 3. List the psychologic conditions that contribute to the perception of dyspnea. 4. Identify common causes of chronic dyspnea and list the 4 most common causes of chronic dyspnea. 5. Identify common causes of acute dyspnea and list the 4 most common causes of acute dyspnea. 6. List the tests that are recommended in the initial evaluation of dyspnea 7. Distinguish between the different measurements of oxygenation and given a clinical scenario, be able to choose the correct test. 8. Interpret the brain natiuretic peptide level (BNP). 9. Distinguish between cardiac and pulmonary causes of dyspnea using the cardiopulmonary exercise test. 10. Associate the following tests with the conditions that they test for: methacholine challenge test, eucapneic voluntary hyperventilation test, videolaryngostroboscopy test. 11. List specific strategies to reduce dyspnea by: reduce metabolic load, alter afferent information, improve efficiency of carbon dioxide elimination, reduce ventilatory impedance, and alter central perception. 12. Identify the main components of a pulmonary rehabilitation program.

Optional Reading Harrison’s Principles of Internal Medicine, 17th edition 2008. Chapter 33: Dyspnea and Pulmonary Edema; Richard M. Schwartzstein.

1. Contributions to dyspnea: a. Origins of the sensation of dyspnea: a. Upper airway receptors – trigeminal nerve b. Chest wall mechanoreceptors c. Pulmonary vagal receptors 1. Slowly adapting receptors – respond to tension in the walls of the airways 2. Rapidly adapting receptors – stimulated by rapid changes in lung volumes and inhaled irritants 3. C-fibers in small airways – stimulated by mechanical and chemical factors

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d. Chemoreceptors

- hypercarbia is a more powerful

contribution to the sensation of dyspnea than hypoxemia 1. Central – medulla a. pH and PCO2 2. Peripheral – carotid bodies and aortic arch a. PO2, pH, and PCO2 b. Contributions to the perception of dyspnea: a. Increased ventilatory demand: b. Anemia c. Hypoxemia d. Hypercapnia e. Deconditioning f. Respiratory muscle weakness g. Lung hyperinflation - excessive length of inspiratory muscles h. Airflow obstruction c. Qualities of dyspnea: a. Progression (from studies of methacholine challenge test subjects): chest tightness - sensation of effort - air hunger b. Psychologic effects: 1. Anxiety 2. Pain 3. Anger 4. Depression 2. Causes of chronic dyspnea (most common have an “*”): a. Cardiac: a. *Congestive heart failure b. Coronary disease c. Cardiac arrhythmias d. Pericardial disease e. Valvular disease

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b. Pulmonary: a. *COPD b. *Asthma c. *Interstitial lung disease d. Pleural effusion e. Malignancy f. Bronchiectasis c. Non-cardiac/non-pulmonary: a. Thromboembolic disease b. Psychologic c. Deconditioning d. Pulmonary hypertension e. Obesity f. Anemia g. Gastroesophageal reflux disease h. Metabolic conditions (acidosis, uremia, etc.) i. Cirrhosis j. Thyroid disease k. Neuromuscular disorders l. Chest wall deformity m. Tracheostenosis n. Paradoxical vocal cord dysfunction 3. Assessment of chronic dyspnea: a. Initial studies: a. History and physical exam b. CBC c. Metabolic profile d. Chest x-ray e. EKG f. Spirometry g. Pulse oximetry

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b. History and physical exam - your most important tool to initially categorize patients as most likely due to cardiac, pulmonary, and neuromuscular etiologies a. Orthopnea (shortness of breath when laying flat) – suggests heart failure b. Paroxysmal nocturnal dyspnea (shortness of breath that awakens the patient from sleep) – suggests heart failure or asthma c. Intermittent episodes of dyspnea – suggests myocardial ischemia or bronchospasm c. Oxygenation a. Resting pulse oximetry b. Exercise pulse oximetry: 1. 6 minute walk test 2. oxygen titration study c. Overnight oximetry d. Arterial blood gas e. High altitude hypoxia simulation test d. Pulmonary function tests a. Spirometry: answers the question “is there obstruction?” 1. Asthma 2. COPD 3. Bronchiectasis 4. Bronchiolitis obliterans b. Lung volumes : answers the question: “is there restriction?” 1. Interstitial lung disease 2. Respiratory muscle weakness 3. Chest wall deformity 4. Diaphragm paralysis c. Diffusing capacity: answers the question: “is there gas diffusion impairment?” 1. Emphysema

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2. Interstitial lung disease 3. Pulmonary vascular disease e. Specialized tests (directed by initial evaluation) a. Brain Natiuretic Peptide (BNP) 1. A negative study is very helpful to rule out heart failure 2. False positives (particularly in low level elevations) are common b. Cardiac echo 1. LV systolic function 2. LV diastolic function 3. Estimated PA pressure 4. Valvular heart disease 5. Pericardial effusion c. Cardiac radionuclide study (ischemic heart disease) d. Holter monitor (24 recording cardiac rhythm monitor to test for intermittent cardiac arrhythmias) e. Inducible asthma tests: 1. Methacholine challenge test: answers the question: “is there occult pharmacologically-inducible asthma?” 2. Eucapneic voluntary hyperventilation test: answers the question: “is there exercise-induced asthma?” f. Cardiopulmonary exercise test: answers the question: “is the dyspnea due to heart disease, lung disease, or deconditioning?” 1. Low maximum oxygen uptake = impairment 2. Achieves maximum predicted heart rate = cardiac limited 3. Achieves maximum predicted minute ventilation = pulmonary limited 4. Four basic questions from the cardiopulmonary exercise test: a. Is the patient impaired? b. Is the impairment cardiac in origin?

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c. Is the impairment pulmonary in origin? d. Did the patient develop oxygen desaturation? g. Videolaryngoscopy: answers the question: “is there paradoxical vocal cord dysfunction?” h. High resolution chest CT: answers the question: “is there bronchiectasis or interstitial lung disease?” i. CT pulmonary angiogram (or V/Q scan): answers the question: is there thromboembolic disease?” j. Cardiac catheterization 1. Left – evaluates the coronary arteries 2. Right – evaluates the pulmonary artery pressures k. Bronchoscopy: mainly to search for tracheostenosis, to search for occult airway tumor, or to investigate abnormal findings on radiographs l. Esophageal pH probe – evaluates for gastroesophageal reflux 4. Treatment of chronic dyspnea: a. Treat the underlying disease! b. Reduce metabolic load: a. Exercise training b. Supplemental oxygen during exercise - To qualify for home

oxygen, the PO2 must be less than 55 or the SaO2 must be less than 88%. Importantly, most insurers are now requiring that you document that the oxygen level returns to normal with supplemental oxygen (therefore, order an oxygen titration study!!) c. Altering afferent information: a. Vibration b. Ventilator settings c. Inhaled pharmacologic therapy d. Fans d. Improve efficiency of CO2 elimination:

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a. Altered breathing pattern (pursed lip breathing, etc.) b. Improve respiratory quotient (reduce carbohydrates and increase fat): R = number of carbon dioxide molecules generated per every molecule of oxygen consumed 1. R for carbohydrates = 1.0 2. R for fat = 0.7 e. Reduce ventilatory demand: a. Reduce airway resistance: 1. Bronchodilators 2. Corticosteroids b. Reduce hyperinflation: 1. Lung reduction surgery f. Improve inspiratory muscle strength and endurance a. Nutrition b. Exercise c. Patient positioning d. Ventilatory support (BiPAP, etc.) e. Minimize oral corticosteroids g. Altered Central Perception: 1. Education 2. Cognitive-behavioral approaches: relaxation, distraction 3. Desensitization 4. Pharmacologic therapy: anti-depressants, opiates, anxiolytics 5. Causes of acute dyspnea: a. Cardiac: a. Acute myocardial ischemia b. Congestive heart failure c. Pericardial tamponade b. Pulmonary: a. Bronchospasm b. Pulmonary embolism

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c. Pneumothorax d. Pulmonary infection e. Upper airway obstruction 6. Assessment of acute dyspnea: a. Pulse oximetry and/or arterial blood gas b. Plasma BNP level a. > 400 pg/ml – heart failure b. 100-400 pg/ml – left ventricular dysfunction without exacerbation, pulmonary embolism, cor pulmonale c. Chest x-ray d. CBC e. EKG

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Bronchiectasis & Cystic Fibrosis
Date: Time: Faculty: September 24, 2008 10:30 am Elizabeth D. Allen, M.D. Department of Pediatrics, Division of Pulmonary Medicine Nationwide Children’s Hospital 722-4766

Phone: Email:

Nelson Textbook of Pediatrics, 17th ed., (2004) Part 18, Section 33, Chapter 393 Harrison's Principles of Internal Medicine, 16th Ed. (2005) Part 8, Section 2, Chapter 236

CF and Bronchiectasis Objectives 1. Describe the airway abnormalities seen in bronchiectasis, and their functional consequences 2. 3. List common causes, and treatments, for bronchiectasis Identify common presenting symptoms and physical exam findings of a patient with bronchiectasis 4. List studies used to evaluate patients suspected of having bronchiectasis, and predict test results expected in a patient with the disease process 5. Describe the genetic abnormality, protein dysfunction, and resultant physiologic defects associated with Cystic Fibrosis (CF) 6. 7. 8. 9. Describe typical symptoms CF List the organ systems commonly affected by CF Identify criteria used to diagnose CF Describe therapies commonly utilized to treat CF

10. List common complications of CF

BRONCHIECTASIS Pathology A. Permanently scarred, misshapen medium sized airways B. May be localized, or diffuse C. Pool secretions; once infected, ongoing inflammation D. Often, overgrowth of vascular supply, with pulmonary-bronchial connections Causes – Infection A. Routine organisms a. Viral (Adenovirus, influenza, measles)

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Bacterial (Staphylococcus aureus, Klebsiella, Anaerobes, TB and non-TB) (More likely if treatment late, or partial)

B. Impaired Host Defense a. b. Endobronchial obstruction (tumor, foreign body, congenital stenosis) Generalized host defense problem i. Cystic fibrosis ii. Primary ciliary dyskinesia iii. Immunoglobulin deficiency Causes – “Other” A. Toxins (Inhaled irritants – e.g. ammonia; Aspirated material – e.g. gastric contents) B. Hyperactive immune response (allergic bronchopulmonary aspergillosis) C. Alpha-1-antitrypsin deficiency D. Yellow nail syndrome Symptoms A. Chronic/recurrent productive cough B. Purulent sputum C. Hemoptysis (coughed up blood) D. Shortness of breath, wheeze, if widespread or caused by underlying disease Findings A. Physical Exam – Crackles, rhonchi, wheeze; clubbing B. Radiographic a. “tram tracks” “ring shadows” on CXR

b. Thickened bronchial walls, with airway bigger than adjacent vessel, on CT Work-up A. Sputum Culture B. Radiographs and Lung function studies C. Search for specific causes a. b. c. d. e. f. Treatment A. Eliminate cause, if possible B. Improve clearance (chest therapy, mucolytics) C. Control infection (“As needed” or chronic rotating antibiotics) Bronchoscopy PPD Testing for ABPA Sweat test Cilia biopsy Immunoglobulin testing

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D. Treat bronchospasticity/airway inflammation E. If localize and severe, resection F. If diffuse and severe, transplantation Complications A. Hemoptysis B. Cor pulmonale (right heart failure due to lung disease related pulmonary hypertension) Last Ditch Treatment A. Local resection – especially if remaining lung healthy B. Lung transplantation – if widespread disease CYSTIC FIBROSIS Overview A. Most common lethal hereditary disease in Caucasians B. Multisystem disease with pulmonary mortality in early adulthood C. Autosomal recessive gene: carriers are asymptomatic CF Pathophysiology A. Cystic fibrosis transmembrane regulator (CFTR) gene is large 1. 2. 3. Over 5,000 aberrant forms DeltaF508 most common abnormality Genotype does not determine phenotype

B. CFTR Protein 1. 2. 3. 4. Transmembrane transport protein Primary function – Regulated chloride channel Also affects other chloride and sodium channels at cell surface Different classes of dysfunction have been identified – each with different levels of impact, and potentially different treatments C. Resultant pathology 1. Physical & chemical airway secretion abnormalities - Decreased chloride secretion - Increased sodium absorption - Excessive water absorption - Impaired ability to kill bacteria 2. Chronic infection

CF Typical Symptoms/Problems A. Pulmonary Chronic cough, recurrent pneumonia, wheezing, repeated “bronchitis” B. GI Meconium ileus, bulky greasy malodorous stool, poor weight gain

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C. Misc Salty taste, rectal prolapse, severe pansinusitis, nasal polyps, pancreatitis, clubbing D. Other complications Intestinal obstruction syndromes Cirrhosis, gallstones Diabetes CF Diagnosis A. Typical Symptoms and/or (+) family history B. Positive sweat chloride C. 2 Indentifiable CFTR abnormalities confirms diagnosis; LACK does not exclude it, however D. Newborn screening – Ohio Immunoreactive trypsinogen (IRT) & common alleles can be measured on newborn screen If IRT is high, then alleles are checked. If allele(s) are identified, sweat test is performed. If sweat test (+) then diagnosis is made CF Pulmonary Manifestations A. All patients, with variable onset and rate of progression B. Airway plugging with thick mucous C. Secondary infection with Staph. aureus, Pseudomonas sp., D. Asthma-like airway disease in roughly 50% E. Chronic bronchitis, with exacerbations marked by increased cough, sputum production, dyspnea, weight loss F. Progressive bronchiectasis (distortion and scarring of airways) G. Death due to respiratory insufficiency CF Pulmonary Treatment A. Secretion Removal Bronchodilators & chest drainage, Mucolytics, aerobic exercise B. Infection Control Oral, IV and nebulized antibiotics Isolation from other CF patients to avoid multi-resistant infection C. Anti-inflammatory therapy (steroid, ibuprofen, azithromycin) D. Control secondary causes of lung damage – GERD, viral infection, ABPA E. Good Nutrition F. Under development (anti-elastase, gene therapy, mechanistic therapies) CF Exocrine Pancreatic Dysfunction A. Present in 80-85% of CF patients B. Malabsorption of fats and proteins due to enzyme deficiency Male infertility Cor pulmonale Osteoporosis

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C. Meconium ileus – obstruction in newborn period D. Steatorrhea (oily, foul-smelling diarrhea) E. Malnutrition/poor growth

F. Treatment: Enzyme replacement (± acid suppression), high calorie diet, vitamin supplements
Outpatient Treatment A. Visits every 2-3 months

B. Regularly scheduled: a. Throat or sputum cultures b. Pulmonary function tests c. CXR d. Nutritional evaluation C. Social work availability D. “Team” review afterwards
“Simple” Home Regimen A. Enzymes with meals and snacks, daily vitamin B. “EAT!” C. Twice daily chest therapy D. Inhaled therapies – albuterol, dornase-alpha (mucolytic), inhaled tobramycin Outpatient Exacerbation Care A. Indications: Increase symptoms - cough, sputum production, dyspnea Decreasing PFT’s Poor growth or weight loss B. Therapy 10-21 days of atbs aimed at previous cultures Continue standard therapy - do chest therapy! CF: The “Clean-Out” A. Indications Failure to respond to outpatient therapy for milder exacerbation Initial presentation with severe problems Major drop in lung function New infiltrates on CXR Major weight loss Responding to outpatient therapy - but repeatedly re-flares B. Treatment IV antibiotics - dbl coverage TID chest therapy

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“PIC” line If nutritional issues: Nutrition consult, diabetes screen Often discharge on home IV’s CF Common Complications A. “ Little h” Hemoptysis Description: Streaks of blood in sputum Often with general increase in pulmonary sxs Non-emergent Treatment: Treat the exacerbation Make certain taking Vit K supplement (if pancreatic insufficient) ? Hold chest therapy & Pulmozyme briefly B. “Big H” Hemoptysis Description: > 1 cup/day bleeding Source: overgrown bronchial arteries Sudden onset - older patient Risk of death 2° suffocation Emergency! Treatment: Embolization C. Pneumothorax Presentation Acute unilateral chest pain Shortness of breath ranging from mild to severe Treatment Chest tube, video-assisted thoracoscopic surgery (VATS) D. CF Related Diabetes Description Combined poor production and poor response to insulin >20% of CF patient over 25 years old Symptoms: Increased thirst/urination Unexplained weight loss, fatigue Unexpected declining lung function Screening: Random, fasting, 2° post prandial glucoses Treatment: Insulin replacement (for most) E. Distal Intestinal Obstruction Syndrome (DIOS)

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Description: Viscous mucus and stool obstruct terminal ileum and large intestine Progressive colicky abdominal pain, nausea, anorexia If severe: frank small intestine obstruction Treatment: Acutely: Go-lytely or similar electrolyte solution Gastrografin enemas Surgery Chronically: More aggressive/consistent enzyme use Routine use of cathartics G. End Stage Care Lung Transplantation Nearly 1,600 CF patients have undergone lung transplantation 90% alive at one year; 50% at 5 years Many do not survive to transplantation Lung distribution determined by clinical score For those who do not receive transplants; care focused on patient comfort Reasons for Optimism Steady improvement in CF survival curves as new therapies become available Adults now make up >40% of living CF population – and are leading productive lives

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