Human Health & Disease

Mondays, Tuesdays, Thursdays and Fridays 9:00 - 11:50 AM Lectures: Room M-112, Labs: Fleischmann

IINNDDEE 222211 SSpprriinngg 22001100 Syllabus SSyyllllaabbuuss

(2010)

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Table of Contents

SYLLABUS SCHEDULE ______4 SYLLABUS PREFACE______7 HISTOLOGY______19 INTRODUCTION TO ANTIBACTERIAL DRUGS______27 STRUCTURE AND FUNCTION OF THE LUNG______29 DIFFUSION OF GASES ______35 ANTIBACTERIAL DRUGS 1 ______41 PULMONARY VENTILATION/ ABG ANALYSIS ______43 PFT TEST ANALYSIS ______55 ANTIBACTERIAL DRUGS 2 ______63 PULMONARY BLOOD FLOW ______65Syllabus CHEST IMAGING 2 ______75 ANTIBACTERIAL DRUGS 3 ______77 VENTILATION - PERFUSION RELATIONS______79 GAS TRANSPORT AND EXCHANGE ______89 ANTIBACTERIAL DRUGS 4 ______97 ( & COPD)______99 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/ ASHTMA______117 ALLERGIC DISEASES/ SARCOIDOSIS______131(2010) PULMONARY MECHANICS ______139 MECHANICAL VENTILATION ______155 ANTIFUNGAL AGENTS ______159 LUNG PHARMACOLOGY ______161 LUNG LAB 1______165 CONTROL OF VENTILATION ______171 ARDS ______183 RESPIRATORYYear's DISTRESS SYNDROME PATHOLOGY ______195 SURFACTANT/ INTERSTITIAL LUNG DISEASE ______201 IN UNUSUAL ENVIRONMENTS ______211 CHRONIC INTERSTITIAL LUNG DISEASES ______225 PULMONARY VASCULAR DISEASE/ HMD ______237 OCCUPATIONAL LUNG DISEASE ______243 LastLUNG CANCER ______251 LUNG LAB 2______267

CLINICOPATHOLOGIC FEATURES OF TUMORS______273 HUMAN CANCER BIOLOGY ______289 MOLECULAR BASIS OF CANCER PART 1 ______307 MOLECULAR BASIS OF CANCER PART 2 ______323 TUMORS OF THE LUNG ______341 CHEST IMAGING 3 ______353 ANTICANCER DRUGS 1 ______355 NEOPLASIA LAB______357 ANTICANCER DRUGS 2 ______365 MAMMALIAN LUNG DEVELOPMENT ______367

Syllabus

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Human Health & Disease

Inde 221 Spring 2010 Syllabus Schedule

Weekday Date Time Room Topic Instructor

Mon 3/29 9 – 10:50 FLRC Respiratory System Histology Lab A. Connolly 11 - 11:50 M104 Introduction to Antibacterial Drugs J. Whitlock Tues 3/30 9 - 9:50 M112 Structure and Function of the Lung P. Kao

10 – 10:50 M112 Diffusion of Gases P. Kao 11 - 11:50 M112 Antibacterial Drugs 1 J. Whitlock Thurs 4/1 9 – 9:50 M112 Ventilation/ABG Analysis A. Weinacker 10 - 10:50 M112 PFT Test Analysis N. Khazeni 11 - 11:50 M112 Antibacterial Drugs 2 J. Whitlock Fri 4/2 9 – 9:50 M112 Pulmonary Blood Flow SyllabusP. Kao 10 - 10:50 M112 Chest Imaging #2 A. Leung Wk 1 ends 11 - 11:50 M112 Antibacterial Drugs 3 J. Whitlock Mon 4/5 9 - 9:50 M112 Ventilation-Perfusion Relations P. Kao 10 - 10:50 M112 Gas Transport & Exchange P. Kao 11 - 11:50 M112 Antibacterial Drugs 4 J. Whitlock Tues 4/6 9 - 9:50 M112 Airway Obstruction (Asthma & COPD) T. Desai 10 - 10:50 M112 COPD / Asthma Pathology C. Lombard 11 - 11:50 M112 Allergic / C. Lombard Thurs 4/08 9 – 9:50 M112 Pulmonary(2010) Mechanics N. Rizk 10 - 10:50 M112 Mechanical Ventilation N. Rizk 11 - 11:50 M112 Anti-Fungal Agents R. Roth Fri 9 - 9:50 M112 Lung Pharmacology J. Whitlock

Wk 2 ends 10 - 11:50 FLRC Lung Lab 1 Faculty

Mon 4/12 9 – 9:50 M112 Control of Ventilation F. Kagawa 10 – 10:50 M112 ARDS A. Weinacker 11 - 11:50 M112 Adult & Neonatal Respiratory Distress Syndrome A. Connolly Tues Year's 4/13 9 - 10:50 M112 Interstitial Lung Disease P. Mohabir 10 - 10:50 M112 Breathing in Unusual Environments S. Ruoss 11 - 11:50 M112 Chronic Interstitial Lung Disease / Pneumoconioses A. Connolly Thurs 4/15 9 - 9:50 M112 Pulmonary Vascular Disease / HMD P. Kao 10 - 10:50 M112 Occupational Lung Disease W. Kuschner Fri 4/16 9 – 9:50 M112 Intro to Lung Cancer H. Wakelee LastWk 3 ends 10-11:50 FLRC Lung Lab 2 Faculty

Weekday Date Time Room Topic Instructor

Mon 4/19 9 - 9:50 M112 Clinical Features of Tumors R. West 10 – 10:50 M112 Human Cancer Biology J. Lipsick 11 - 11:50 M112 Molecular Basis of Cancer 1 M. Cleary Tues 4/20 9 - 9:50 M112 Molecular Basis of Cancer 2 R. West 10 – 10:50 M112 Tumors of the Lung C. Lombard 11 – 11:50 M112 Chest Imaging #3 A. Leung Thurs 4/22 9 - 11:50 M112 Anticancer Drugs 1 J. Whitlock 10 – 11:50 FLRC Neoplasia Lab Faculty

Fri 4/23 9 – 9:50 M112 Anticancer Drugs 2 J. Whitlock

Wk 4 ends 10 – 11:50 M112 Mammalian Lung Development M. Krasnow

Mon 4/26 9am-12pm FLRC BLOCK EXAM (Lung/ / Neoplasia) ------CV BLOCK BEGINS ------Tues 4/27 9 - 9:50 M112 Cardiac Muscle and FHC SyllabusR. Tsien 10 - 10:50 M112 Excitation-Contraction Coupling R. Tsien 11 - 11:50 M112 Nernst Potential & Osmosis D. Madison Thurs 4/29 9 - 9:50 M112 Excitability & Conduction R. Tsien 10 – 11:50 FLRC Circulatory Vessel Histology Lab A. Connolly Fri 4/30 9 – 9:50 M112 Cardiac Action Potential R. Tsien 10 – 10:50 M112 Control of Heart Rhythm R. Tsien

Wk 5 ends 11 – 11:50 M112 Autonomic Pharmacology Overview 1 J. Whitlock Mon 5/3 9 - 9:50 M112 ECG R. Tsien 10 – 10:50 M112 Lesions(2010) of Blood Vessels A. Connolly 11 – 11:50 M112 Thromboembolic Disease A. Connolly Tues 5/5 9 - 10:50 M112 Cardiac Reflexes B. Kobilka 11 - 11:50 M112 Autonomic Pharmacology Overview 2 J. Whitlock Thurs 5/6 9 – 10:50 FLRC ECG Small Groups Faculty 11 - 11:50 M112 Autonomic Drugs (Cholinergics) J. Whitlock Fri 5/7 9 - 10:50 M112 Muscle Mechanics R. Turcott Wk 6 ends 11 - 11:50 M112 Autonomic Drugs (Anticholinergics) J. Whitlock Mon 5/10 9 – 10:50 M112 Arrhythmias P. Wang Year's 11 – 11:50 M112 Autonomic Drugs (Sympathomimetics 1) J. Whitlock Tues 5/11 9 – 10:50 M112 Ventricular Physiology R. Turcott 11 - 11:50 M112 Autonomic Drugs (Sympathomimetics 2) J. Whitlock Thurs 5/13 9 – 9:50 M112 Starling Curve and Venous Return J. Wong 10 – 10:50 M112 Cardiac Output and Catheterization M. McConnell Last 11 - 11:50 M112 Autonomic Drugs (Adrenoceptor Blockers) J. Whitlock

Weekday Date Time Room Topic Instructor

Fri 5/14 9 - 10:50 M112 Physics of Circulation M. McConnell

Wk 7 Ends 11 – 11:50 M112 Case Discussions (Autonomic Drugs) J. Whitlock

Mon 5/17 9am-12pm FLRC BLOCK EXAM (Basic CV / Autonomics) Tues 5/18 9 – 9:50 M112 Smooth Muscle R. Tsien 10 – 11:50 M112 Ischemic and Valvular Heart Disease A. Connolly Thurs 5/20 9 – 9:50 M112 Renal Circulation S. Rockson 10 - 10:50 M112 Hypertension S. Rockson

11 – 11:50 M112 Cardiomyopathy, myocarditis and atrial myxoma G. Berry

Fri 5/21 9 – 9:50 M112 Endothelium & Coronary Circulation J. Topper 10 - 10:50 M112 Angina Pectoris J. Topper

Wk 8 Ends 11 - 11:50 M112 Drugs Used in Hypertension J. Whitlock Mon 5/24 9 – 9:50 M112 Shock SyllabusM. Rosenthal 10 – 11:50 FLRC Adult Cardiac Lab Faculty

Tues 5/25 9 – 9:50 M112 Cardiac Anesthesia & Bypass M. Kanevsky

10 – 10:50 M112 Exercise Physiology R. Fishman

11 - 11:50 M112 Ischemic Heart Disease J. Whitlock

Thurs 5/27 9 – 10:50 M112 Congestive Heart Failure D. Patterson 11 - 11:50 M112 Drugs Used in Angina Pectoris J. Whitlock Into to Cardiac & Tomographic Anatomy of the Fri 5/28 9 - 9:50 M112 N. Silverman Heart 10 – 10:50 M112 Positive(2010) Inotropic Agents J. Whitlock Wk 9 Ends 11 – 11:50 M112 Congestive Heart Failure Pharmacology J. Whitlock Mon 5/31 Holiday

Tues 6/1 9 – 9:50 M112 Fetal Circulation & Congenital Heart Disease D. Bernstein 10 – 10:50 M112 Congenital Heart Disease G. Berry 11 – 11:50 M112 Antiarrhythmic Drugs J. Whitlock Thurs 6/3 9 – 9:50 M112 Cardiovascular Pharm Case Discussions J. Whitlock

10 – 11:50 FLRC Pediatric Cardiac Lab Faculty

Fri Year's6/4 9am-12pm FLRC BLOCK EXAM (End-CV) Mon - Tues 6/7 - 6/8 HHD STUDY TIME

Wed 6/9 9am-12pm FLRC INTEGRATED FINAL EXAM

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HUMAN HEALTH & DISEASE

Inde221 Spring 2010 Academic Year 2009 - 2010

Course Directors: Peter Kao, MD, PhD Brian Kobilka, MD Donald Regula, MD James Whitlock, MD

Teaching Assistants: Cardiovascular Physiology: Greg Charville Pulmonary Physiology: Yul Yang Pathology: Roberto Riccardo, Michael Nguyen Pharmacology: Jonathan Leong Syllabus

Course Manager: Dianna Jouan Office: MSOB, X3C27 Phone: 723-1337 E-mail: [email protected]

Course Assistant: Vuong Vu Office:(2010) Lane, L-226 Phone: 723-5258 E-mail: [email protected]

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COURSE INFORMATION HUMAN HEALTH & DISEASE 221

HUMAN HEALTH & DISEASE II (Inde221) is the second quarter in a four-quarter sequence of courses that integrate histology, pathology, physiology and pharmacology in the study of the pulmonary and cardiovascular organ systems.

CONTACT INFORMATION

Course Directors Peter Kao – [email protected] Brian Kobilka – [email protected] Don Regula – [email protected] Jim Whitlock – [email protected]

Syllabus Teaching Assistants Greg Charville – [email protected] Jonathan Leong – [email protected] Michael Nguyen – [email protected] Roberto Riccardo – [email protected] Yul Yang – [email protected]

Course Staff Dianna Jouan — [email protected] Vuong Vu — [email protected](2010)

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Course Feedback Students are strongly encouraged to submit formative evaluation of individual faculty in order to improve and refine the curriculum. A link is available in CourseWork for your online feedback of each individual session in the HHD course, which can be completed at any time during the course. In addition, students will be asked to complete an online E*Value evaluation form at the end of the course.

Additional materials and syllabus revisions This syllabus will be distributed on the very first day of class and is available online on CourseWork. Every effort will be made to distribute an up to date copy of each lecturer’s notes before each block. No other handouts will be provided at lecture; rather we will continuously revise the on-line version of the syllabus on the course website. The course directors hope that you enjoy the course and are inspired to read further and ask questions. The syllabus and textbooks should supplement the lectures and provide you with the tools necessary to prepare for the final exam and for the upcoming boards. The syllabus does not supplant the need to consult with textbooks and journal articles for detailed information on specific diseases. Please do not expect lecturersSyllabus to follow these notes in a step-by-step manner, as the format of notes and tables may not be conducive to effective lecture presentation. Please feel free to contact the faculty and/or the TAs should you have any questions or suggestions to facilitate your learning or improve the course in the future. We are very interested in your feedback in making this the best class possible. Students are strongly encouraged to attend class and take an active role in the course. Please ask appropriate questions as this is very helpful to the lecturers and preceptors. It helps them to appropriately gauge the students' levels of interest and understanding.

Grading You will receive a Pass or Fail assessment(2010) after each quarter. Your grade will be based on your individual scores in the three scheduled end-block examinations and the integrated final exam. You must achieve an overall equally-weighted-average passing score of at least 70% on all exams (three block exams plus the integrated final exam). In addition, you must achieve a passing score of at least 65% on the integrated final exam in order to pass the course.

A STUDENT WITH AN AVERAGE BLOCK & FINAL EXAM COMBINED SCORE LESS THAN 70% OR AN INTEGRATED FINAL EXAM SCORE LESS THAN 65% MUST TAKE THE HHD 221 COURSE REMEDIAL EXAMINATION. A FAILING SCORE ON THIS REMEDIAL EXAMINATION WILL EARN A GRADE OF "FAIL" FOR THE COURSE. Year's

A student that Fails a quarter of HHD will be required to re-take that quarter the following year, including all required exercises and examinations. Depending on the specific circumstances, such a student may be allowed to continue in the HHD sequence (please see various five-year "split" schedules from the Office of Medical Education). Last

Policy for missed exams Every student is expected to sit for each examination in the Human Health and Disease course. A formal Dean's excuse, from their medical school advisor, is required to make-up any missed course examination (the 2009-10 Advising Deans are Neil Gesundheit, Susan Knox, Oscar Salvatierra, and Terry Blaschke). A Dean's excuse might be issued before a regularly scheduled exam to accommodate some essential extracurricular event or after an examination for illness. A score of zero will be credited towards a student’s final score if an examination is missed without their advising Dean's excuse. If a Dean's excuse is issued before a regularly scheduled block exam to accommodate some essential extracurricular event, the student will be expected to take the scheduled make-up exam at Stanford offered once (ie- Wednesday, April 28, 2010 for the scheduled April 26 exam, Wednesday, May 19 2010 for the scheduled May 17 exam, and Tuesday, June 8, 2010 for the scheduled June 4 exam). If the Dean's excuse extends beyond the second scheduled makeup date because of some essential activity away from Stanford, then the exam will be faxedSyllabus to the student and must be completed and returned within 24 hours. No other exam will be arranged for students with excuses granted before a scheduled exam. Failure to make such an arrangement will result in a score of zero on that exam. A student that misses an exam with a Dean's excuse for illness should contact the HHD course assistant, Vuong Vu. Every student is expected to sit for the integrated end-quarter examination (Wednesday, June 9, 2010 this quarter). Any student that misses the final examination and has a Dean's excuse must take a special final examination two days later (Friday, June 11, 2010 this quarter). A score of zero will be credited towards a student’s final score if the integrated final examination is missed without their advising Dean's excuse. (2010)

Policy for remediation of a Fail grade in an HHD course A student that receives a Fail in any quarter of HHD (Inde220, Inde221, Inde222 or Inde223) will be required to take a special remedial examination after the inter-quarter break, on the day before classes start in the next academic quarter. This examination will be offered ONCE. Vacation plans do not dictate when the exam will be taken. The course directors agree that a non-passing grade in HHD indicates a need for in-depth review of the entire quarter and have scheduled the remedial exam to allow such additional study. Year's A SINGLE REMEDIAL EXAMINATION, COVERING THE CONTENT IN THE ENTIRE INDE221 COURSE, WILL BE ADMINISTERED ON Wednesday, August 25, 2010.

Correction of a Fail grade in HHD requires a full passing score (≥70%).

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HHD221 2010 Exam Dates MONDAY, APRIL 26, 9:00AM - 12:00PM – LUNG/ ANTIBIOTICS/NEOPLASIA BLOCK EXAM MONDAY, MAY 17, 9:00AM - 12:00PM – BASIC CV/ AUTONOMICS EXAM FRIDAY, JUNE 4, 9:00AM - 12:00PM – END-CV EXAM WEDNESDAY, JUNE 9, 9:00AM - 12:00PM – INTEGRATED FINAL EXAM

Textbooks The following book is required for our Pharmacology sessions: Basic & Clinical Pharmacology, by Bertram G. Katzung (10th edition). Available online through ebooks. Katzung & Trevor's Pharmacology (Examination & Board Review, 8th edition).

You should already have the following books for our Histology sessions: Functional Histology, by Wheater et. al. (5th edition) Syllabus The following book is recommended for the pathology sessions: Robbins and Cotran: Pathologic Basis of Disease, by Kumar, Fausto and Abbas (8th edition, Elsevier 2009).

The following book is recommended for the physiology sessions: Medical Physiology, by Arthur Guyton and John Hall (2005).

The following books are recommended for the lung physiology sessions: Respiratory Physiology, by John B. West (8th edition). Pulmonary Physiology and Pathophysiology, by John B. West.

The following book is recommended for (2010)the cardiovascular physiology sessions: Cardiovascular Physiology, by Berne and Levy.

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Introduction to HHD Small Group Sessions (for all quarters of HHD) The small group sessions of HHD are essential to your understanding of factual material and concepts, and they contribute to the development of your clinical reasoning skills. These sessions consist of problem-based learning with unknown cases, prepared in advance by your assigned student lab group. Each laboratory session includes three cases with necessary written materials published in your syllabus, accompanied by unknown glass slides from your Study Set and digital photographs found in the Lab Materials section of the HHD web pages on CourseWork. The instructions that follow will be used throughout the course. Each student has been randomly assigned to one small group in one room and will remain in this group through the full year of HHD. Unless otherwise specified, cases are assigned to the respective groups (Case 1 by Group 1, etc.). Each student is required to attend all scheduled small-group sessions. A formal Dean’s excuse, from your medical school advisor, is required to miss any scheduled laboratory session. FAILURE TO ATTEND ALL SESSIONS IS CONSIDERED A BREACH OF PROFESSIONALISM AND WILL PREVENT YOU FROM PASSING THE COURSE. Your assigned small group will present their findings to the other students in the lab room. Complete preparation and active participation in your assignedSyllabus case is essential to the education of your colleagues. Working effectively in a team is an important professional skill expected of you now and through the rest of your career. Active learning in the laboratories requires that each student or study group examine the slides and cases as unknowns. Use of materials such as unpublished images, X-rays or TA review sessions, other student notes, Powerpoint presentations, or slide-keys from previous classes is forbidden. If you have a question about a resource, ask your facilitator, a TA or a course director. You have a two-box set of microscopic glass slides in your assigned locker with slide numbers that match the syllabus. If your box is missing any slides, you should plan to view the missing slide with a classmate who has a copy of it. Slide diagnoses will not be published, and you may not write notes (2010)on the slides or in the slide box. You will have access to formalin-fixed pathology specimens during the TA sessions and also for self- study in room M226 or the Student Closet in the hallway between the Fleischmann Labs and the Lane Building. Written instructions for care of the gross specimens are posted in M226. Each Fleischmann Lab room includes a video microscope and monitor. It is important that each small group uses the video microscope to demonstrate the pathology and normal histology on the tissue sections. Any gross photograph or radiograph provided for the case should be shown from the computer. Because all of the small group sessions are case-based, this is your only opportunity to cover the histopathology in this course in class.Year's

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Students with Documented Disabilities: Students who may need an academic accommodation based on the impact of a disability must initiate the request with the Student Disability Resource Center (SDRC) located within the Office of Accessible Education (OAE). SDRC staff will evaluate the request with required documentation, recommend reasonable accommodations, and prepare an Accommodation Letter for faculty dated in the current quarter in which the request is being made. Students should contact the SDRC as soon as possible since timely notice is needed to coordinate accommodations. The OAE is located at 563 Salvatierra Walk (phone: 723-1066).

Teaching Assistants Your teaching assistants are your primary resource for questions not answered in the syllabus, the lecture videos or your textbooks. This includes comments about questions in the self-test bank. The Human Health and Disease course offers teaching assistantships during Autumn, Winter and Spring quarters for the infectious disease, physiology and pharmacology disciplines. Advertising for an applicant pool is done in conjunction with the centralized TA application process through the Office of Medical Education (OME). All TA positions will be posted in March and selected in April. Syllabus Interested applicants should complete the online TA application form and submit their CV to the Pre-clinical Curriculum Manager, Dianna Jouan ([email protected]). Applicants will be invited to interview with at least one HHD course director based on their application and performance on the relevant course exams.

Printing Pay to Print is an automated system used in libraries across campus that enables users to pay for printing electronically. Pay to Print revenue is used to cover the cost of paper and toner, equipment purchasing, and maintenance. Stanford CashCards & Stanford ID cards can be used to pay for printing. Black and white printing costs 15 cents per printed page. For more information about the Pay to Print(2010) system, please visit the following website: http://lane.stanford.edu/howto/index.html?category=Printing%20%26%20Photocopying

Honor Code: In addition to the standard of academic conduct as described in the Honor Code, the following specific honor code standards apply to Human Health and Disease Inde 221: No questions are permitted of the monitor, TA, and/or director during any examination. You may note any questions or concerns on the inside cover of your test booklet and turn these in as you exit the examination. All examinations will begin in the Fleischmann Laboratories or in a room designated by the course director. Any notice posted during the exam will be posted only in those rooms. NoYear's allowance will be made for a student that elects to take his exam at another location. No answers are posted for remedial examinations and all remedial test materials must be returned to the exam monitor. Use or possession of any remedial exam question outside the exam room, at any time, will be considered a violation of the honor code The answer key to the microscopic glass slide sets shall not be made available and marking any written notations [diagnoses] in your slide set box or on the microscopic Lastslide label violates the honor code.

Answers to laboratory cases are not printed and not available. Obtaining previous years' information with respect to laboratory cases is a violation of the honor code.

Course Content Access and Appropriate Use Policy Stanford University School of Medicine course materials are intended for curriculum and course-related purposes and are copyrighted by the University. Appropriate access to this content is given for personal academic study and review purposes only. Unless otherwise stated in writing, this content may not be shared, distributed, modified, transmitted, reused, sold or otherwise disseminated. These materials may also be protected by additional copyright; any further use of this material may be in violation of federal copyright law. Violators of this policy will be referred to the Committee on Professionalism, Performance, and Promotion for disciplinary purposes.

What does this mean for students? Personal Use: Since I’m an enrolled student, can I keep the course materials I get from class or on CourseWork? Can I archive them on my hard drive? Yes, you may keep copies of these materials for your own personal use and reference only. All print and electronic content prepared for a School of MedicineSyllabus course, including TA and CourseWork materials, are owned and copyrighted by Stanford University. All materials are provided exclusively for use by students enrolled in Stanford’s School of Medicine. These materials may include but are not limited to TA handouts, course syllabi, video and audio, and lecture slides. Getting Permission: I would like to use an image from a faculty member’s lecture slides in a poster I’m creating. How can I repurpose course content? No, the law states that you must request permission to use copyrighted materials. An aspiring professional should always request permission from the copyright holder before repurposing content in any fashion, as it is unethical to display materials without giving explicit credit to the copyright holder. Lecture material contains content owned by the faculty, but also often materials copyrighted by other sources. Faculty can give you permission to use content they have created,(2010) but for other materials see the links below for more information on what is acceptable. Sharing With Classmates: I downloaded Genetics TA review slides from the CourseWork. Can I email or in any other way share this content with other students? Yes, if content is clearly labeled “Open to School of Medicine,” then you may share current content with other student enrolled in the medical school. Yes, if the content is labeled “Open to Current Quarter’s Students,” then you may share only with other students who are currently enrolled in that course. No, if there is no designation, then materials are by default restricted and intended for your own personal review and you may not share them. You can alwaysYear's share your own personal course notes with each other. Sharing With Classmates: One of my classmates was absent for a session and a handout was given out that isn’t on the CourseWork. The handout does not have a sharing statement or icon. Can I give my classmate a copy? No, by default unlabelled content should not be shared. In this case it possible that the faculty member intended for this handout only to be given out in the context of the particular session. If you believe a resource should be placed on the CourseWork for students to download, please contact the course director. LastHanding Down Prior Course Materials: Can I give a current 1st-year student some TA handouts and lecture videos I got last year in the same course?

No, faculty update course content regularly to reflect changes in medical practice and may have removed outdated or incorrect materials. Further, faculty often have educational reasons behind the timing for distribution of course materials, which could be undermined by this action. Content that is no longer available should not be shared nor used. If you believe that materials you have from a prior course might be useful for currently enrolled students, please contact the course director to suggest that it can be made available. Using Prior Course Materials: A 3rd-year student offered me a collection of her lecture videos and TA notes from her year. Should I use them to prepare better for my exams? No, you should not use course materials that were intended for students in an earlier year. The 3rd-year student is violating this policy by offering you these materials. Faculty review content often to ensure you are receiving the most relevant and useful content and any outdated or incorrect materials are removed. Also, your use of this material might undermine the educational goals or give you unfair advantage over your classmates, which could be a violation of the honor code. If you believe an archival resource might be useful for your classmates, please contact the course director. Access to CourseWork Course: If I’m a 1st-year student, can I log into Syllabusa 2nd year CourseWork course so I’ll know what to prepare for? Yes, if the course director determines that it would be helpful for students to gain access to course materials in advance. Course directors carefully plan out how to introduce course materials and they determine who may access individual CourseWork courses. EdTech staff help enroll students and auditors into the CourseWork as determined by course directors. If you believe you should have access to a course and cannot add that course by the CourseWork “Audit a Course” feature, email [email protected]. Sharing Outside of School: Can I share course materials with my friends at UCSF School of Medicine? No, all course content is private and restricted by default. You should not share course materials (lecture slides, videos, TA materials)(2010) with anyone outside the school in order to honor the copyright and intellectual property holders of these materials.

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Syllabus

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HUMAN HEALTH & DISEASE

Spring Quarter 2009-10

LLuunngg && NNeeooppllaassiiaa SSyyllllaabbuuss Syllabus

(2010)

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Syllabus

(2010)

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Last Respiratory System Histology – Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 19 RESPIRATORY SYSTEM HISTOLOGY Respiratory System

Respiration Conducting Portion: Vocalization  Transport of air to and from area of gas

exchange

 Clean, warm and humidify air Olfaction Respiratory Portion:  Facilitate the exchange of oxygen and carbon dioxide between air and blood

Goals: to identify theSyllabus key passageways and cell types associated with gas exchange, olfaction and vocalization and know their function as it is relates to both light and electron microscope structure.

Recommended: Readings: (1) Wheater: chapter 12 or Junqueira and Carneiro: chapter 17 (2010)(2) Cross and Mercer: chapter 13, in particular pgs 304, 312, 314, 316 and 398 Interactive slides on CWP

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Macrophage "walking" on a Type I alveolar cell (12,000X) Last

Respiratory System Histology – Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 20

CONDUCTING PORTION RESPIRATORY MUCOSA (epithelium and underlying connective tissue lamina propria) and SUBMUCOSA NASAL NASO- BRONCHI BRONCHIOLES CAVITY Large Small Regular Terminal Respiratory Transitional Ciliated Ciliated Ciliated EPITHELIUM Ciliated pseudostratified pseudo- simple simple stratified columnar cuboidal columnarSyllabus GOBLET Abundant Present Few Scattered None CELLS GLANDS Abundant Present Few None Complex C-shaped Irregular Plates CARTILAGE (hyaline rings rings and None and islands elastic) Spanning SMOOTH None open Crisscrossing spiral bundles MUSCLE ends of C- shaped(2010) rings ELASTIC Some More Abundant FIBERS

modified from Junqueira and Carneio Cartilage, smooth muscle and FUNCTIONS elastic fibers maintain and adjust Specific arrangement of superficial patency of airways. blood vessels carries blood opposite to incoming air providing countercurrent Mucous secretion and cilia work heat exchange system to warm the air. together to transfer particulateYear's and foreign material to pharynx for Serous gland watery Venus sinuses swell removal; Goblet cells and underlying protein-rich secretions periodically, closing off air glands provide the secretion provide humidity and flow to prevent drying ("mucociliary elevator"). defense (e.g. lysozyme). ("swell bodies"). Last Respiratory System Histology – Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 21

Terminal bronchioles are the final conducting portion of the respiratory tree. Goblet cells are replaced by Clara cells, which secrete a serous secretion important in defense and removing mucous from the smaller airways. Cilia continue to move the secretion toward the pharynx.

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ACINUS = TERMINAL RESPIRATORY UNIT

(2010)

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from Paulsen

All parts of an acinus contain alveoli, which are the regions where gas exchange occurs. The respiratory bronchiole has a few outpocketings of alveoli, the alveolar duct has many and the alveolar sac is completely composed of alveoli. Some smooth muscle and ciliated cells remain to Lastdefine the respiratory bronchiole and alveolar ducts.

Respiratory System Histology – Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 22

ALVEOLUS

Borysenko and Beringer

Gas exchange occurs in regions (as thin as 0.15 μm) where the attenuated cytoplasm of the Type I alveolar cell and capillary endothelial cellSyllabus are closely apposed and share basal lamina.

CELL LOCATION MAJOR FUNCTION(S) Alveolar Type I a few cells line facilitate gas exchange and at the same squamous over 90% of time prevents most water and molecules epithelium alveolar space from crossing Alveolar Type II many cells -secrete surfactant; phospholipid cuboidal interspersed as component prevents from collapse epithelium part of alveolar on exhalation and saves energy during space lining inhalation. (2010)-replaces Type I cells routinely and if damaged Alveolar defense cells in -phagocytose and remove inhaled Macrophage alveolar space, particles that have escaped the both under the mucociliary elevator in the conducting surfactant layer airways and free in - facilitate surfactant turnover by removal lumen Year's

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Respiratory System Histology – Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 23 RESPIRATORY SYSTEM - SLIDES

I. NASAL PASSAGES Slide 85 Nasal cavity, cat (H and E) (C&M 398 for ultrastructure of olfactory epithelium) This slide is a section through the bony extensions, conchae, that project into the nasal cavity. You will find both respiratory and olfactory epithelia covering the projections. Respiratory epithelium is pseudostratified ciliated epithelium containing goblet cells. Olfactory epithelium is also pseudostratified but lacks goblet cells and is much thicker than respiratory. In the olfactory epithelium the basal cell nuclei are small and lie adjacent to the basement membrane. The next layer of nuclei are round, lightly stained, and belong to the olfactory receptor cells, while more superficial oblong nuclei belong to support cells.Syllabus At the surface of the olfactory epithelium you will see the layer of olfactory "hairs" (actually specialized dendrites of the bipolar neurons) that are the initial receptors for odorous molecules. In the underlying connective tissue lamina propria of the mucosa, in addition to serous glands and venous sinuses (swell bodies), note the large bundles of nerves that carry axons from the receptor cells through the cribriform plate to the olfactory bulbs of the brain. II. LARYNX Slide 86 Larynx (H and E) (2010) This is a frontal section through the larynx. Many of the features described can be observed grossly, before you insert the specimen into the microscope. The "V"-shaped cartilage nearest the label of the slide is the . The two longest sections of cartilage are through the two sides of the thyroid cartilage. Next are sections through two sides of the cricoid cartilage, and cartilage sections below this belong to the rings of the trachea. The epithelium lining of the larynx is mostly typical respiratory mucosa, i.e., pseudostratified ciliated with Goblet cells and Year'sassociated seromucous glands. Surfaces subject to abrasion (glottis), however are lined by stratified squamous epithelium. The glottis region is recognized as the passageway between the true vocal folds, which are large projections inside of the thyroid cartilages. The bulk of these folds is skeletal muscle (pink), the thyro-arytenoid (or vocalis) muscle, seen here in cross section. The vocal cord, an elastic ligament, is seen in cross-section Last between the vocalis muscle and the stratified epithelium lining the glottis.

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This is a good slide to review muscles, fat, seromucous glands, blood vessels and nerves. Also there is an extensive area of thyroid gland included in some sections outside of the extrinsic muscles of the larynx. III. TRACHEA Slide 87 Trachea (MAz) (C&M 304 for ultrastructure of epithelium) This slide shows both the (wall is primarily muscle) and the trachea (wall is primarily cartilage). "C"-shaped trachea cartilage rings open posteriorly where the trachealis muscle lies. Note the prominent basement membrane of the tracheal epithelium. This section shows well the ciliated pseudostratified epithelium (with numerous bluish goblet cells). Look for seromucous glands in the lamina propria and submucosa (most visible in areas where the section runs between the rings of cartilage). Try to distinguish vessels and the numerous aggregations of lymphocytes in the lamina propria. Syllabus The two large nerves lying adjacent to the trachea are the recurrent laryngeal nerves which innervate muscles of the larynx. IV. LUNG A. Slide 88 Lung (MAz) Use this thick section to study the organization of the wall of an intrapulmonary . Note the irregular blue-stained cartilage plates which support the bronchial wall and the prominent layer of red-stained smooth muscle.(2010) The respiratory epithelium of the bronchus is red and Goblet cells and ciliated cells may be hard to distinguish. Glands, which are usually present, are not readily visualized in this preparation. B. Slide 89 Lung (H and E) (C&M 312- 316 for ultrastructure) This is a section of rat lung which was expanded by perfusing the fixative into the trachea. When you look at this section under low power, you see thin partitions dividing the lung into small rounded compartments, or alveoli. Here and there you will see blood vessels of various sizes containing red blood cells. Somewhat less Year'scommon are bronchioles, with a fairly prominent columnar or cuboidal epithelium, and thin bands of smooth muscle in the walls. Try to define a terminal bronchiole and the subsequent airways it supplies (i.e. terminal bronchiole to respiratory bronchioles to alveolar ducts to alveolar sacs to alveoli. If these cannot be found Last in sequence, try to find them separately.

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Alveolar ducts still contain smooth muscle (difficult to see) in the tips of the partitions between alveoli, whereas this is lacking in alveolar sacs. Examine the alveolar walls and determine where gas exchange takes place. Capillaries fill the alveolar septa and appear as empty spaces (red blood cells have mostly been removed). Nuclei associated with the septum belong to either alveolar cells Type I (squamous), Type II (cuboidal) or capillary endothelial cells. Cells with large more euchromatic nuclei which lie more within the alveolar space and contain occasional clusters of black or brown specks in their cytoplasm are alveolar macrophages, sometimes referred to as or "dust cells." C. Slide 90 Lung (elastic) Elastic fibers in this preparation are stained dark purple. Note their extensive distribution in the walls of the alveoli and bronchioles. RESPIRATORY WORD LIST acinus mucosa Syllabus alveolar cell (pneumocyte) type I olfactory neuron alveolar cell (pneumocyte) type II respiratory bronchiole alveolar sac respiratory mucosa alveolar duct seromucous glands alveolar macrophage submucosa alveoli surfactant blood-air barrier (2010) swell bodies bronchi terminal bronchiole bronchioles trachealis muscle Clara cells true vocal fold mucociliary elevator vocal ligament vocalis muscle

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Last Introduction To Antibacterial Drugs - James Whitlock, M.D. HHD221 Spring 2010 Page 27 Introduction to Antibacterial Drugs

Assigned Reading: Katzung, Ch. 51

LEARNING OBJECTIVES: 1. Understand the concept of selective toxicity and why it is important 2. Understand the difference between bacteriostatic and bactericidal drug action and why it is important 3. Understand the mechanisms of drug resistance, the transfer of drug resistance, 4. the selection of drug-resistant bacteria, and the importance of drug resistance to clinical medicine. 5. Understand the concept of empirical therapy and the clinical circumstances in which it is used Syllabus 6. Understand the relationships between host, pathogen, and drug in the treatment of bacterial infections

TOPICS: A. Selective toxicity B. Bactericidal vs. bacteriostatic action C. Drug resistance (2010) D. Host-bug-drug relationships E. Empirical therapy

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Last Structure And Function Of The Lung - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 29 Structure and Function of the Lung

Assigned Reading: West, Respiratory Physiology, Chapter 1.

I. FUNCTION OF THE LUNG A. Gas Exchange: 1. Absorbs oxygen, eliminating carbon dioxide B. Host defense: 1. Exists at the interface with the environment, 2. Must confer protection against pathogens, particulates, inhaled toxins C. Metabolism: 1. The entire cardiac output flows through the Syllabuslung – this is true only for the heart and lung 2. Metabolism of circulating factors occurs in the lung: a. Angiotensin I converted to Angiotensin II by angiotensin converting enzyme D. Reservoir for blood II. BLOOD-GAS INTERFACE A. Oxygen and carbon dioxide move between air and blood by diffusion: (2010) 1. Diffusion represents the flow of gas from area of high to low partial pressure. 2. Fick’s Law of Diffusion: Amount of gas that moves across a membrane is directly proportional to the surface area and inversely proportional to its thickness. B. Lung surface area for gas exchange is 50 – 100 square meters C. Huge surface area for gas diffusion is possible because of the Year'ssurface area of 300 million alveoli. D. Alveoli are air sacs, 1/3 mm in diameter: 1. Are polyhedral, not spherical 2. Surface area of all alveolar spheres would be 85 square meters, with volume of 4 liters 3. (Surface area of a single sphere of 4 L volume would be Last 0.01 square meters)

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III. AIRWAYS AND AIRFLOW A. Airways consist of a set of branching tubes. B. Trachea bifurcates at main carina into the left and right mainstem bronchus: 1. These divide into the lobar bronchi: Left upper lobe, left lower lobe, right upper lobe, right middle lobe and right lower lobe 2. Next divide into segmental bronchi C. Branching continues to 16 generations of conducting airways down to the terminal bronchioles: 1. Conducting airways perform no gas exchange and represent anatomic dead space. D. Respiratory bronchioles contain alveoli, branching continues to 23 generations to alveolar sacs Syllabus E. Acinus represents the anatomic unit distal to the terminal bronchiole F. Respiratory zone represents the lung parenchyma for gas exchange (acini): 2.5 – 3 Liters

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Structure And Function Of The Lung - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 31

G. Inspiration involves increase in the volume of the thoracic cavity, due to: 1. Contraction of the diaphragm (descent), and intercostal muscles raising the ribs to increase the cross section of the thorax. 2. Air moves by bulk flow within the conducting airways, then by diffusion in the respiratory zone. 3. Lung is elastic, and expiration is normally by passive relaxation. 4. Normal tidal breath of 500 cc requires a distending pressure of < 3 cm water.

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IV. VENTILATIONYear's ABNORMALITIES/AIRWAY DISEASES A. Asthma – inflammation of the airways, causing reversible airflow obstruction B. COPD – permanent destruction of lung by proteases triggered by cigarette smoking Last

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V. BLOOD VESSELS AND FLOW A. A set of branching tubes from the pulmonary artery to the capillaries back to the pulmonary veins. B. Capillaries form a dense network in the walls of the alveoli: 1. Diameter 10 microns, just large enough for a red blood cell 2. A continuous sheet of blood surrounding the alveolar air sacs 3. Easily damaged – can lead plasma or even red cells into the alveolar spaces C. Pulmonary circulation receives the entire cardiac output (5 - 6 Liters per minute): 1. Very low pulmonary vascular resistance 2. Low pulmonary artery pressures normally D. Each RBC spends about 3/4 second traversing 2 –Syllabus 3 alveoli, enough for full oxygenation E. Ventilation-Perfusion matching: 1. Key concept to understanding lung physiology 2. V/Q mismatching contributes to F. Perfusion Abnormalities: 1. – venous thromboembolism 2. – small vessel obliteration Injury to endothelial(2010) cells triggers smooth muscle proliferation, hypertrophy and neointimal formation

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Structure And Function Of The Lung - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 33

VI. STABILITY OF ALVEOLI A. Alveoli represent 300 million air bubbles, each 0.3 mm in diameter. B. Unstable structure, due to the surface tension of the liquid lining the inside of the alveoli, promoting collapse. C. Surfactant: Phospholipid protein mixture that lowers surface tension and prevents alveolar collapse ()

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VII. REMOVAL OF INHALED PARTICLES / HOST DEFENSE A. Surface area of 50 – 100 square meters, lung presents the greatest surface of the body to a hostile external environment B. Nose filters out large particles C. Year's Conducting airways are lined by ciliated epithelial cells D. Small particles are trapped in mucus and removed from the lung by mucociliary ladder, and swallowed in the epiglottis. E. Alveoli have no cilia, particles that deposit in alveoli are engulfed by macrophages: Last Alveolar macrophages are removed through lymphatics.

Structure And Function Of The Lung - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 34

REVIEW QUESTIONS 1) As air flows through the lungs it traverses the following segments in order: A Trachea, bronchiole, bronchi, terminal bronchiole, respiratory bronchiole, alveolar duct, alveolar sac B Trachea, bronchi, bronchiole, terminal bronchiole, respiratory bronchiole, alveolar duct, alveolar sac C Trachea, bronchi, bronchiole, respiratory bronchiole, terminal bronchiole, alveolar duct, alveolar sac D Trachea, bronchi, bronchiole, terminal bronchiole, respiratory bronchiole, alveolar sac, alveolar duct E Trachea, bronchi, bronchiole, respiratory bronchiole, terminal bronchiole, alveolar sac, alveolar duct 2) All of the following are important functions of the lung, EXCEPTSyllabus A Metabolism of hormones B Reservoir for blood C Gas exchange D Metabolism of epinephrine E Immune host defense

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)B 2) D 1) B Answers:

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Diffusion Of Gases – Peter Kao, M.D., Ph.D. (Stephen Ruoss, M.D.) HHD221 Spring 2010 Page 35 DIFFUSION OF GASES

Assigned Reading: West, Respiratory Physiology, Chapter 3.

OBJECTIVES 1. Understand Fick’s Law for diffusion of gases. 2. Understand why certain gases are limited by diffusion and others perfusion. 3. Understand the importance of hemoglobin and its avidity for oxygen and carbon monoxide in rates of diffusion. 4. Develop some appreciation for the clinical applications of measurements of diffusion capacity. I. DEFINITION Syllabus A. The passive movement of gas molecules across the alveolar membrane from areas of higher to lower partial pressures. II. LAWS OF DIFFUSION A. Diffusion through tissues is described by Fick’s Law (Figure 1). Thus, the rate of movement of a gas through a sheet of tissue is directly proportional to the tissue surface area (A), the diffusion constant for the gas (D), and the difference in the partial pressure of the gas on either side of the tissue (P1-P2). Diffusion is inversely proportional to(2010) the thickness (T) of the tissue. B. The diffusion constant (D) of a gas is proportional to its solubility and inversely proportional to the square root of the molecular weight. Thus, CO2 diffuses 20 times faster than O2 because of its much greater solubility despite similarities in molecular weight. III. LIMITATIONS OF GAS TRANSFER A. Diffusion Limitation – (e.g. Carbon Monoxide) 1. As indicated in Figure 2, it takes about 0.75 sec for blood to Year'straverse the pulmonary capillary bed at resting cardiac outputs. Note that there is virtually no change in the partial pressure of Carbon Monoxide dissolved in plasma from the beginning to the completion of blood flow through the pulmonary capillary system. Any CO diffusing from alveolus to capillary is immediately tightly bound to intracellular hemoglobin such that the partial pressure of CO dissolved in Last capillary plasma is miniscule compared to alveolar-capillary barrier is maintained for CO the entire time blood spends in

Diffusion Of Gases – Peter Kao, M.D., Ph.D. (Stephen Ruoss, M.D.) HHD221 Spring 2010 Page 36

the pulmonary capillary, the diffusion of CO is only limited by its diffusion characteristics and the surface area and thickness of the barrier. B. Perfusion Limitation – (e.g. Nitrous Oxide) 1. As also indicated in Figure 2, the partial pressure of Nitrous Oxide in pulmonary capillaries rises very rapidly, equilibrating with the alveolus within 0.1 sec of blood entering the capillary system. This occurs both because of the rapid diffusion characteristics of N2O and fact that N2Odoes not bind with hemoglobin. The rate of transfer of N2O across the alveolar-capillary membrane can be altered only by alterations in blood flow and is, therefore, perfusion limited. IV. DIFFUSION OF OXYGEN A. Under normal conditions, the transfer of Oxygen across the alveolar-capillary membrane is also perfusion-limited.Syllabus Although O2 obviously binds the hemoglobin, the avidity of binding is 200 fold less than for CO. However, under conditions of abnormal gas exchange, the transfer of O2 can become more diffusion-limited. B. Figure 3 illustrates differences in O2 transfer under multiple conditions, including abnormalities of gas exchange engendered by disease, with alveolar hypoxia, and with exercise. With extreme exercise, the time required for blood to traverse the pulmonary capillary system can decrease to as little as 0.25 seconds. Note that O2 transfer can become diffusion-limited even in healthy individuals during extreme(2010) exercise at altitude. V. DIFFUSION OF CARBON DIOXIDE A. Figure 4 illustrates the movement of Carbon Dioxide from capillary blood to alveolus, which resembles the kinetics of the reverse movement of O2 from alveolus to pulmonary capillary. Thus, the movement of CO2 is usually perfusion-limited, becoming more limited by diffusion under conditions of disease. VI. MEASUREMENT OF DIFFUSING CAPACITY A. Year's The diffusing capacity (or transfer factor) of the lungs is the rate at which a gas (i.e., oxygen or carbon monoxide) moves from the alveoli into pulmonary capillaries (in milliliters per minute) per unit of partial pressure gradient (in millimeters of mercury). Therefore, the diffusing capacity of the lung (DL) is equal to the uptake of the gas (V) divided by the difference between the alveolar and mean Last pulmonary capillary partial pressure of the gas: DL = VCO

Diffusion Of Gases – Peter Kao, M.D., Ph.D. (Stephen Ruoss, M.D.) HHD221 Spring 2010 Page 37

P1 – P2 B. This is merely a rearrangement of the Fick equation in which DL encompasses the area and thickness of the structure and the diffusivity of the gas. C. The partial pressure of carbon monoxide in pulmonary capillary blood is negligible (due to immediate binding with hemoglobin). Thus, the diffusion capacity for carbon monoxide (DLCO) may be written: DL = VCO PACO VII. REACTION RATES WITH HEMOGLOBIN A. For both oxygen and carbon monoxide, the total diffusing capacity is affected by the reaction with hemoglobin (Figure 5). The inverse of flow is resistance and the resistance to lung diffusing capacity includes the resistance of the alveolar membrane (DM)Syllabus and the binding of the gas to hemoglobin (θ · Vc): 1 = 1 + _1__ DL DM θ · Vc B. The rate of reaction of gas with hemoglobin is described by θ, i.e., the rate in ml per minute of gas which combines with 1 ml of blood per mm Hg partial pressure of gas. This is the “diffusing capacity” of 1 ml of blood and when multiplied by the volume of capillary blood (Vc) gives the “diffusing capacity” of the arte of reaction of gas with hemoglobin. In(2010) practice, the resistances of the membrane and blood components are approximately equal. Thus, a reduction of capillary blood volume by disease can reduce the diffusing capacity of the lung. VIII. INTERPRETATION OF DIFFUSING CAPACITY FOR CARBON MONOXIDE A. Clinically, the diffusing capacity of the lungs depend on: 1. The area and thickness of the blood-gas barrier; and Year's2. The volume of blood in the pulmonary capillaries. B. Increases in diffusing capacity will occur in conditions of increased pulmonary capillary blood volume or flow, i.e., 1. Polycythemia (increased red cells) 2. High Output States (increased flow) 3. Mitral Stenosis (obstruction to outflow) a. However, in clinical medicine, increases in diffusing Last capacity are rarely of significance.

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C. Decreases in diffusing capacity will occur with thickness of the surface for diffusion, reduction in the surface area for diffusion, or reduction in capillary blood volume, i.e., D. Conditions that Decrease the Diffusing Capacity 1. Thickening of the barrier a. Interstitial or alveolar edema b. Interstitial or alveolar fibrosis 1) Sarcoidosis 2) Scleroderma 2. Decreased surface area a. Emphysema b. Tumors c. Low pulmonary capillary blood volume 3. Decreased uptake by erythrocytes a. Anemia Syllabus b. Low pulmonary capillary blood volume 4. Ventilation-perfusion mismatch Figure 1

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E. Diffusion through a tissue sheet. The amount of gas transferred is proportional to the area (A), a diffusion constant (D), and the difference in partial pressure, and its inversely proportional to the Year'sthickness (T). The constant is proportional to the gas solubility (Sol) but inversely proportional to the square root of its molecular weight (MW). Last

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Figure 2

F. Uptake of carbon monoxide, nitrous oxide, and O2 along the pulmonary capillary. Note that the blood partial pressureSyllabus of nitrous oxide virtually reaches that of alveolar gas very early in the capillary so that the transfer of this gas is perfusion limited. By contrast, the partial pressure of carbon monoxide in the blood is almost unchanged so that its transfer is diffusion limited. O2 transfer can be perfusion limited or partly diffusion limited, depending on the conditions. Figure 3 (2010)

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G. Oxygen time courses in the pulmonary capillary when diffusion is normal and abnormal (for example, because of thickening of the alveolar membrane by disease). A shows time courses when the alveolar Po2 is normal. B shows slower oxygenation when the alveolar Po2 is abnormally low. Note that in both cases, severe exercise reduces the time available for oxygenation. Figure 4

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H. Calculated changes in Pco2 along the capillary when the diffusion properties are normal and abnormal (compare the time course of Po2 in Figure 3.3). (From PD Wagner and JB West: J Appl. Physiol. 33:62, 1972.) Figure 5 (2010)

Year's I. The diffusing capacity of the lung (DL) is made up of two components that due to the diffusion process itself and that attributable to the time taken for O2 (or CO) to react with hemoglobin. Last

Antibacterial Drugs 1 - James Whitlock, M.D. HHD221 Spring 2010 Page 41 Antibacterial Drugs 1

Assigned Reading: Katzung, Ch. 43

Learning objectives for drugs that target the bacterial cell wall: 1. Drug classes 2. Targets 3. Mechanisms of action 4. Anti-bacterial spectra 5, Adverse effects 6. Mechanisms of resistance 7. Pharmacokinetic issues 8. Uses Syllabus

TOPICS: A. Bacterial cell wall synthesis B Penicillin action C. Resistance to penicillin D. Adverse effects of penicillin (2010)

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Last Ventilation/ ABG Analysis - Ann Weinacker, M.D. HHD221 Spring 2010 Page 43 PULMONARY VENTILATION AND INTERPRETATION OF ARTERIAL BLOOD GASES

Assigned Reading: West, Respiratory Physiology, Chapter 2, 6;

I. INTRODUCTION A. Ventilation is the process by which fresh gas is brought into the respiratory system to replace a portion of the gas it contains. Carbon dioxide is eliminated from the body, and oxygen is brought in to replace the oxygen that has been taken up into the blood from the alveoli. II. NORMAL LUNG VOLUMES AND FLOWS Syllabus A. Normal tidal volume (the amount of air inhaled during a normal breath) is approximately 7 ml/kg of ideal body weight, and anatomic dead space (the portion of the tidal volume that does not participate in gas exchange in the lung) is approximately 2 ml/kg. The amount of gas that participates in gas exchange between the lungs and the blood is the tidal volume minus the dead space volume. Minute volume (or total volume) is the product of tidal volume and respiratory rate, and alveolar ventilation is the amount of gas that participates in gas exchange multiplied by the respiratory rate (in breaths per minute). Thus,(2010) in a 70 kg man in whom tidal volume and anatomic dead space are about 500 ml and 150 ml, respectively, if the respiratory rate is 15, the minute volume (total volume) is 7500 ml, and the alveolar ventilation is 5250 ml. B. Lung volumes and capacities (Figure 1) are often measured in clinical practice to determine whether ventilatory defects exist. Tidal volume and vital capacity (the amount of air exhaled from a maximal inspiration to a maximal expiration) are commonly measured with a spirometer (Figure 2), and from those measurements, inspiratory and expiratory reserve volumes can be Year'scalculated. Residual volume (the amount of air left in the lungs after a maximal expiration) cannot be measured with a spirometer, but can be determined after measurement of the functional residual volume. Last

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Figure 1 Syllabus

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Figure 2 C. Functional residual capacity (FRC) cannot be measured with conventional spirometry, but is typically measured indirectly in one of three ways: helium dilution, nitrogen washout, or body plethysmography. In the helium dilution method, the subject exhales to FRC, then breathes a known volume and concentration of helium from a special type of spirometer until the gas in the lungs Year'sis in equilibrium with the gas in the spirometer. The final concentration of helium is then measured in the spirometer and this concentration is used to calculate the FRC (Figure 3). Residual volume can then be calculated by subtracting the expiratory reserve volume from the FRC. Last

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Figure 3 D. In the nitrogen washout method, the subject exhales to FRC, then inhales 100% oxygen until the exhaled nitrogen concentrationSyllabus is zero. The total gas exhaled is collected, and the concentration of nitrogen in this gas is measured. FRC can then be calculated: 1. Vexh x % N2 = Vorig N2 in lungs 2. Vorig N2 in lungs x 1.25 = Vorig in lungs 3. (Vexh = volume of exhaled gas; Vorig = original volume of gas in the lungs.) E. In the plethysmograph ("body box") method, the subject sits in an airtight box and is asked to breathe against a closed valve (figure 4). The pressure at the(2010) mouth is measured, and the change in pressure in the box is used to calculate the FRC: 1. Body box: P1V1 = P2 (V1 - ΔV) 2. where P1 = the initial box pressure, V1 = the initial box volume, P2 = the box pressure when the subject inhales, and ΔV = the change in box volume when the subject inhales. 3. Subject: P3V2 = P4(V2+ΔV) 4. where P3 = pressure at the mouth before inspiration, P4 = Year'spressure at the mouth after inspiration, and V2 = FRC. Using ΔV calculated in the previous equation, FRC can be calculated. Last

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Syllabus

Figure 4 III. TOTAL AND ALVEOLAR VENTILATION Total ventilation (VE) (also called minute ventilation) is the total volume of gas exhaled per minute, and is the product of the tidal volume (VT) and the respiratory rate (RR). Alveolar volume (VA) is the volume of air entering alveoli and available for gas exchange and is equal to the tidal volume minus the dead space volume (VD). Alveolar ventilation is the product of alveolar volume and(2010) respiratory rate. IV. PARTIAL PRESSURES OF RESPIRATORY GASES A. It is clinically useful to know the partial pressures of gases, particularly oxygen and carbon dioxide, in the lungs (and in the blood). Dalton’s Law states that the pressure exerted by each gas in a space is independent of the pressures of the other gases in a mixture. Thus, the partial pressure of a gas in a mixture is equal to its fractional concentration times the total pressure of all gases in the mixture. When calculating the partial pressure of dry gas: Year's Pgas = fractional concentration of total gas x Ptot B. Thus, in dry atmospheric gas:

1. PO2 = .2093 x 760 mmHg = 159 mmHg

2. PCO2 = 0.0004 x 760 mmHg = 0.3 mmHg C. Where Pgas = the pressure of a gas; Last 1. Ptot = the total pressure of a gas mixture, 2. PO2 = the partial pressure of oxygen, and

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3. PCO2 = the partial pressure of carbon dioxide. D. In humidified air (inhaled gas in the lungs), the equation becomes:

PIgas = FIgas (PB - PH2O) E. Thus, in the lungs:

1. PIO2: 0.2093 x (760-47) = 149 mmHg

2. PICO2: 0.0004 x (760-47) = 0.29 mmHg F. where PIgas = the partial pressure of inspired gas; 1. PB = barometric pressure; 2. FIgas = the fractional concentration of inspired gas;

3. PH2O = the partial pressure of water vapor;

4. PIO2 = the partial pressure of oxygen, and

5. PCO2 = the partial pressure of carbon dioxide. G. The volume of alveolar gas (oxygen, carbon dioxide,Syllabus and nitrogen) is approximately 3.0 L at the end of a normal inspiration, and approximately 350 ml less at FRC. Approximately 300 ml of oxygen per minute diffuses from alveoli to capillaries (O2 consumption), and 250 ml of carbon dioxide diffuses from capillaries to alveoli each minute (CO2 production). The partial pressures of alveolar gases thus dependent least in part on the alveolar ventilation, O2 consumption, and CO2 production. At sea level, the partial pressures of alveolar gases at standard barometric pressure are: 1. PAO2 (2010) 104 mmHg 2. PACO2 40 mmHg

3. PAN2 569 mmHg

4. PAH2O 47 mmHg

where PAO2, PACO2, PAN2, and PAH2O are the partial pressures of oxygen, carbon dioxide, nitrogen, and water vapor. H. The partial pressure of carbon dioxide in the alveoli is determined by alveolar ventilation, CO2 production and delivery to the lungs. Carbon dioxide production varies as metabolic rate varies, e.g. with Year'sexercise (figure 5).

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Figure 5

I. The partial pressure of alveolar oxygen (PAO2) increases as alveolar ventilation increases, but the relationship not linear. The PAO2 depends on the inspired oxygen concentration (PIO2), the partial pressure of alveolar carbon dioxide (PACO2Syllabus), and the ratio of carbon dioxide production (VCO2) to oxygen consumption (VO2).

1. PAO2 = PIO2 - (PACO2/R) + F (usually ignored)

2. PAO2 = [FIO2 x (PB - PH2O)] - (PACO2/R)

3. (R = VCO2 / VO2 ≈ 0.8) J. This equation is called the alveolar gas equation, and will be discussed later in the discussion of arterial blood gases, since the partial pressure of arterial oxygen (PaO2) cannot be normal if the partial pressure of alveolar(2010) oxygen (PAO2) is not normal. V. ANATOMIC AND PHYSIOLOGIC DEAD SPACE A. Anatomic dead space has been briefly mentioned earlier. It is equal to the volume of the conducting airways, and air in the anatomic dead space does not reach gas exchange units in the lung. Although seldom measured in clinical practice, anatomic dead space can be measured by the single breath nitrogen test. For this test, the subject inhales a single breath of 100% oxygen, then exhales into a rapid nitrogen analyzer. The concentration of nitrogen in the initial portion of the exhaled breath is zero as the Year'soxygen in the anatomic dead space is exhaled. As alveolar gas begins to be exhaled, the nitrogen concentration increases, and eventually plateaus. The volume of exhaled gas at the midpoint of the transition phase between the exhalation of a high concentration of oxygen and the exhalation of a high concentration of nitrogen is Last equal to the anatomic dead space.

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B. A much more valuable measurement is the measurement of physiologic dead space. This is a functional measurement that reflects the efficiency of the lung at eliminating carbon dioxide. It is nearly the same as the anatomic dead space in normal lungs, but in diseased lungs it may be significantly higher. Physiologic dead space (VD/VT) is usually calculated using the Bohr equation, which states that VD/VT is equal to the partial pressure of alveolar carbon dioxide (PACO2) minus the partial pressure of expired carbon dioxide (PECO2), divided by the PACO2.

VD/VT = (PACO2 - PECO2)/PACO2 = = (PaCO2 - PECO2)/PaCO2 C. Since the partial pressures of alveolar and arterial carbon dioxide are in equilibrium, if the physiologic dead space is elevated, the partial pressure of arterial carbon dioxide (PaCO2), will be abnormally high. An understanding of the significance of the physiologic dead space is important to the interpretation of arterial blood gases. Syllabus VI. ARTERIAL BLOOD GASES Arterial blood gases are useful in many clinical situations. The values reported include the pH, PaCO2, PaO2, HCO3-, and SaO2 (percent saturation of hemoglobin with oxygen in arterial blood). The pH, PaCO2, and PaO2 are measured values, and the HCO3- and SaO2 are calculated values. The pH is the negative log of the hydrogen ion concentration, and in arterial blood is normally between 7.35 and 7.45, although severe metabolic derangements can decrease the pH to as low as 6.90 or increase it to as high as 7.80. The PaCO2 reflects alveolar ventilation, and is normally between 35-45(2010) mm Hg. Because carbon dioxide is readily diffusible, the partial pressure of arterial carbon dioxide (PaCO2) and the partial pressure of alveolar carbon dioxide (PACO2) are approximately equal. If anatomic or physiologic dead space is abnormally increased, the PaCO2 (and PACO2) will also be increased unless the patient can compensate by increasing minute ventilation. Normal values for PaO2 decrease with age, but are typically between 80 -100 mm Hg, resulting in SaO2 values between about 96-100%. Normal HCO3- values range betweenYear's 22-31 mmol/liter.

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VII. OXYGEN A. Although oxygen saturation can fairly accurately be determined noninvasively, accurate determination of the PaO2 requires direct measurement. Causes of abnormally low PaO2 include a decrease in partial pressure of inspired oxygen (as at high altitude), , diffusion limitation in the lungs, shunting of blood from the pulmonary circulation to the systemic circulation without allowing blood to be oxygenated in the lungs (can be an intrapulmonary or an intracardiac shunt), or mismatching between ventilation and perfusion. B. As previously mentioned, the alveolar gas equation allows calculation of the partial pressure of alveolar oxygen:

1. PAO2 = PIO2 - (PACO2/R) + F (usually ignored)

2. PAO2 = [FIO2 x (PB - PH2O)] - (PACO2/R) 3. (R = VCO2 / VO2 ≈ 0.8) Syllabus C. At sea level, the PIO2 is approximately 150 mm Hg (0.21 x [760- 47]). However: 1. In Denver, PIO2 = 0.21 (635-47) = 124 2. And on the summit of Mt. Everest, PIO2 = 0.21 (253-47) = 43! D. If the PACO2 is altered, the PAO2 will likewise be altered. E. The partial pressure of arterial oxygen (PaO2) can obviously never be higher than the partial pressure of alveolar oxygen (PAO2), so anything that will lower(2010) the PAO2 will lower the PaO2. Breathing room air at sea level, the normal difference between PAO2 and PaO2 is about 12. This difference, called the alveolar-arterial oxygen difference (A-a difference) is normally 10-15 mm Hg. (Note: Some people refer to this as the A-a gradient, but this is technically incorrect terminology.) F. Problem: What would the PAO2 be at the top of Mt. Everest if the PACO2 = 8 mm Hg? It is easy to see why one would need to Year'sbreathe supplemental oxygen to climb Everest!

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VIII. CARBON DIOXIDE A. Although the determination of the PaO2 is an important component of arterial blood gases, equally important (if not more important) information about the body’s acid base status can be determined. Approximately 15,000 mEq of acid are generated daily when proteins, phospholipids, nucleic acids, fats, and carbohydrates are metabolized. The kidneys eliminate only a fraction of the total acids generated, or about 1 mEq/kg of body weight per day. The lungs eliminate the rest, as the metabolism of fats and carbohydrates yields carbonic acid that can be eliminated as carbon dioxide: CO2 + H2O H2CO3  H+ + HCO3 B. The amount of carbon dioxide eliminated by the lungs depends on the alveolar ventilation, which changes in response to changes in pH, detected by chemoreceptors in the central nervous system and carotid bodies. The PaCO2 thus reflects a balance between carbon dioxide production and its elimination by alveolarSyllabus ventilation. IX. ACID-BASE STATUS A. Before proceeding with a discussion of acid-base abnormalities, it is useful to define the terms used when interpreting blood gases. Acidemia is a decrease in blood pH, and reflects an increase in hydrogen ion concentration. Alkalemia is an increase in blood pH, and reflects a decrease in hydrogen ion concentration. Acidosis is a process that lowers pH, and alkalosis is a process that raises pH. Although academia and alkalemia cannot coexist, acidosis and alkalosis can coexist. In practice, the terms acidosis and academia are often used interchangeably,(2010) as are the terms alkalosis and alkalemia, although strictly speaking, this is incorrect. B. Physiologically, cellular acidosis decreases myocardial contractility, arterial tone, and pulmonary vascular resistance. It also predisposes to cardiac arrhythmias, shifts the oxygen-hemoglobin dissociation curve to the right, impairs white blood cell and macrophage function, and causes an increase in bone resorption. Cellular alkalosis also predisposes to cardiac arrhythmias, and shifts the oxygen-hemoglobin dissociation curve to the left. It also Year'scauses cerebrovascular constriction and reduced cerebral blood flow, and alters neuromuscular membrane potentials causing paresthesias and predisposing to seizures. C. Acid-base disturbances can be simple or mixed. With simple disorders, the pH is usually brought to near-normal by compensatory mechanisms that are beyond the scope of this discussion. Simple disorders include: Last 1. metabolic acidosis, in which the pH is low and the [HCO3-] is also low

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2. metabolic alkalosis, in which the pH is high and the [HCO3-] is high 3. respiratory acidosis, in which the pH is low and the PaCO2 is high 4. respiratory alkalosis, in which the pH is high and the PaCO2 is low. D. Mixed disorders can include combinations of metabolic disorders (metabolic alkalosis and metabolic acidosis) or a combination of metabolic and respiratory disorders (metabolic acidosis and respiratory acidosis, metabolic acidosis and respiratory alkalosis, metabolic alkalosis and respiratory acidosis, or metabolic alkalosis and respiratory alkalosis). E. Once the type of acid-base disturbance is determined, the cause can be sought. Metabolic acidosis can be associated with either a normal or an elevated anion gap. Anion gap is calculated as the difference between the plasma sodium concentrationSyllabus and the sum of the chloride and bicarbonate concentrations: [Na+] – ([Cl-] + [HCO3-]) and is normally 10-14 because of the presence of anionic proteins. F. Metabolic acidosis associated with an elevated anion gap can be caused by a variety of disorders, and there are a number of mnemonics to help remember the differential diagnosis. One such mnemonic is SLUMPED: salicylate poisoning, lactic acidosis, uremia, methanol ingestion, paraldehyde ingestion, ethylene glycol ingestion, and diabetic (2010)(or other forms of) ketoacidosis. G. Metabolic acidosis associated with a normal anion gap can be caused by loss of HCO3- by the gastrointestinal tract (diarrhea, ileostomy, proximal colostomy) or the kidneys (proximal renal tubular acidosis, carbonic anhydrase inhibitors). Normal anion gap acidosis can also be caused by other types of renal tubular disease (acute tubular necrosis, type IV renal tubular acidosis, or hypoaldosteronism), or can be iatrogenic (total intravenous feeding, excessive administration of sodium chloride containing intravenous Year'sfluids). H. Metabolic alkalosis may be caused by renal loss of hydrogen ions (some diuretics, hypokalemia, primary hyperaldosteronism, primary hypercortisolism, ACTH excess, renin secreting tumors), gastrointestinal loss of hydrogen ions (vomiting, nasogastric suction, villous adenoma), or may be iatrogenic (overdose or Last overuse of sodium bicarbonate, massive blood transfusions).

Ventilation/ ABG Analysis - Ann Weinacker, M.D. HHD221 Spring 2010 Page 53

I. Respiratory acidosis is caused by a decrease in alveolar ventilation, and may be caused by chronic obstructive pulmonary disease, asthma, severe , upper airway obstruction, obesity-hypoventilation syndrome, sleep , muscle weakness, some drugs, or may be iatrogenic (inadequate mechanical ventilation). Respiratory alkalosis may be caused by hypoxemia, liver failure, pain, pregnancy, salicylate intoxication, and some central nervous system diseases. Respiratory alkalosis is the only acid-base disturbance that can be easily induced voluntarily, by . J. To approach the diagnosis of acid-base disorders, examine the blood gas and determine whether the pH represents acidemia or alkalemia. Then determine whether the primary disorder is metabolic or respiratory (look at the HCO3- and the PaCO2). Finally, calculate the anion gap to determine the cause of a metabolic acidosis, if present. Once the type of disturbance is determined, the potential causes of the disturbanceSyllabus (i.e. the differential diagnosis) can be determined. X. PRACTICE ACID-BASE PROBLEMS Case 1 A 42 year old woman presents with chills, , flank pain, and infected urine. Her blood pressure is 90/50, heart rate is 120, and respiratory rate is 25. Her blood gases and electrolytes are as follows: pH 7.55 Na 135 PaCO2 22 Cl (2010) 105 PaO2 108 HCO3 19

Case 2 A 68 year old man presents with profuse diarrhea for one week. His blood gases and electrolytes are as follows: pH 7.11 Na 133 PaCO2Year's 16 Cl 118 PaO2 90 HCO3 5

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Case 3 A 17 year old man with a seizure disorder that was previously well- controlled with phenobarbital (a drug with CNS and respiratory depressant effects) is brought to the Emergency Department, comatose. His blood gases and electrolytes are as follows: pH 7.12 Na 144 PaCO2 80 Cl 106 PaO2 38 HCO3 26

(Can you figure out why his PaO2 is so low?)

Case 4 A 35 year old woman ingested a full bottle of aspirin 6 hours prior to being brought to the Emergency Department. Her blood gases Syllabusand electrolytes are as follows: pH 7.54 Na 140 PaCO2 12 Cl 106 PaO2 113 HCO3 4

Case 5 A 65 year old obese ex-smoker(2010) presents to the Emergency Department with and . His blood gases and electrolytes are as follows: pH 7.49 Na 139 PaCO2 52 Cl 86 PaO2 38 HCO3 40

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PFT Test Analysis - Nayer Khazeni, M.D. HHD221 Spring 2010 Page 55 Interpretation of Pulmonary Function Tests

Assigned Reading: Respiratory Physiology (John West) - Chapter 10.

I. INDICATIONS FOR PULMONARY FUNCTION TESTS (PFTS) A. Evaluation for known or suspected B. Monitoring of disease progression and response to treatment C. Preoperative pulmonary evaluation D. Establishment of disability E. Early detection of COPD in smokers II. TYPES OF PFTS YOU WILL BE ABLE TO ORDER: Syllabus A. Spirometry B. Lung Volumes C. Diffusing Capacity D. Arterial Blood Gas E. Others (including maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP)) III. VOLUMES AND CAPACITIES(2010)

Year's

A. A capacity is a combination of two or more volumes 1. Tidal volume (VT): volume inhaled or exhaled in each breath during quiet breathing 2. Inspiratory reserve volume (IRV): maximal volume of air Last inhaled from the end of quiet inspiration

PFT Test Analysis - Nayer Khazeni, M.D. HHD221 Spring 2010 Page 56

3. Expiratory reserve volume (ERV): maximal volume of air exhaled from the end of quiet expiration 4. Residual volume (RV): volume that remains in the lungs after maximal exhalation 5. Total lung capacity (TLC) = VT + IRV + ERV + RV 6. Vital capacity (VC) = VT + IRV + ERV (75% of TLC) 7. Functional residual capacity (FRC) = ERV + RV (40% of TLC) 8. Inspiratory capacity (IC) = VT + IRV (60% of TLC) 9. Residual Volume (RV) remains in the lungs after a maximal exhalation B. Spirometry 1. Allows you to measure expiratory flows and any volume/capacity other than those including the RV (RV, TLC, FRC) Syllabus

(2010)

Year's2. Reference values adjusted for age, sex, race and height 3. Reproducibility: For normal individuals, FEV1 should not vary by more than 5% within a given day, by more than 12% week to week, or by more than 15% year to year

4. FEV1 declines with increasing age at rate of 20-30 mL/year in normal individuals and by 50-80 mL/year in susceptible smokers Last 5. Variation between different PFT labs may be as great as 20%, although methods have been standardized

PFT Test Analysis - Nayer Khazeni, M.D. HHD221 Spring 2010 Page 57

6. Requires correlation with other clinical information 7. Effort dependent (except at low lung volumes) 8. Bronchodilator response:

a. FEV1 increases by at least 12% (and by at least 200 mL) following administration of inhaled B2 agonist b. Identifies individuals with obstruction that is at least partly reversible, e.g. persons with asthma and minority of patients w/chronic C. Expiratory Flows

1. FEV1: forced expiratory volume in the first second of a forced vital capacity (FVC) maneuver 2. Peak expiratory flow rate (PEFR): the maximal forced expiratory flow achieved during a FVC maneuver

3. FEF25-75: mean forced expiratory flow during the middle half of a FVC maneuver Syllabus 4. Maximal voluntary ventilation (MVV): maximal amount of air expired in 12 or 15 seconds during repetitive maximal inspiratory and expiratory efforts and extrapolated to the minute IV. MEASUREMENTS A. Measurement of FRC (used to calculate RV and TLC) 1. Dilutional techniques (may underestimate FRC, and therefore TLC, in patients with emphysema) a. Helium dilution(2010) b. Nitrogen washout 2. Body plethysmography: measures all gas in the chest, including gas not in communication with the mouth, e.g. bullae B. Measurement of diffusing capacity (DCO) 1. Efficiency of gas transfer from mouth to alveolar capillary hemoglobin (“transfer factor”) 2. Reflects surface area available for gas transfer, as well as Year'spulmonary red blood cell mass. Thickness of alveolar capillary membrane is less important. 3. Reduced in emphysema, , sarcoidosis, , anemia 4. Increased in polycythemia, alveolar hemorrhage, early heart Last failure

PFT Test Analysis - Nayer Khazeni, M.D. HHD221 Spring 2010 Page 58

C. Measurement of respiratory muscle function 1. Maximal inspiratory pressure (MIP): > 50-75 cm H2O in normals 2. Maximal expiratory pressure (MEP): > 80-100 cm H2O in normals 3. Both are reduced in patients with neuromuscular disease and patients with respiratory muscle fatigue V. PATTERNS OF ABNORMALITIES IN PULMONARY DISEASE A. 1. Decreased expiratory flows

2. Decrease in FEV1 is out of proportion to decrease in FVC, so the ratio FEV1/FVC is reduced 3. TLC is normal or increased, due to hyperinflation 4. Examples: Syllabus a. Asthma: airway narrowing due to inflammation and mucus hypersecretion b. Emphysema: dynamic airways collapse due to reduction in elastic recoil and loss of alveolar tethering attachments (2010)

B. Restrictive lung disease (intrinsic, parenchymal disease or extrinsic, extra-parenchymal disease) Year's1. Decreased expiratory flows, although flows are NORMAL as a function of volume 2. Decreased TLC, decreased compliance 3. Examples: pulmonary fibrosis, , neuromuscular Last disease, kyphoscoliosis

PFT Test Analysis - Nayer Khazeni, M.D. HHD221 Spring 2010 Page 59

C. Pulmonary vascular disease 1. Increased pulmonary artery pressures, decreased diffusing capacity; spirometry and lung volumes typically normal 2. Examples: primary or secondary pulmonarySyllabus hypertension, pulmonary embolism, vasculitis D. Disorders of respiratory drive (abnormal control of breathing) 1. Spirometry and lung volumes typically normal 2. Examples: central sleep apnea, Cheyne-Stokes respiration E. Upper airway obstruction 1. Fixed obstruction, e.g. tracheal stricture 2. Variable obstruction (Intrathoracic, e.g. tracheal tumor or Extrathoracic, e.g.(2010) )

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PFT Test Analysis - Nayer Khazeni, M.D. HHD221 Spring 2010 Page 60

VI. DIAGNOSTIC ALGORITHM A. Assess technical quality 1. Free from artifact, cough, glottic closure, poor effort 2. Exhalation at least 6 seconds or plateau

3. Reproducibility (within 200cc) of FEV1 and FVC

B. Assess dynamic lung function (FEV1, FVC)

1. Reduced FEV1/FVC ratio is diagnostic for obstruction 2. Reduced FVC with normal ratio suggests restriction; reduced TLC is diagnostic of restriction. In restriction, expiratory flows are reduced in absolute terms but are normal for volume. 3. Reduced ratio and reduced FVC suggests severe obstruction or mixed obstruction and restriction C. Assess pattern of obstruction, if present Syllabus 1. Positive bronchodilator response suggests asthma, although partially reversible obstruction may be seen in COPD 2. Emphysema suggested by increased lung volumes, reduced diffusion, large volume of isoflow and preserved oxygenation at rest. SVC >> FVC indicates dynamic collapse of the airways. 3. Chronic bronchitis pattern suggested by smooth concavity on flow volume loop, normal or increased lung volumes, preserved diffusion and resting hypoxemia. D. Assess pattern of restriction,(2010) if present 1. Parenchymal causes of restriction (fibrosis) are associated with low TLC (especially IC), reduced diffusion and evidence of increased elastic recoil (supranormal FEV-1/FVC ratio) 2. Extraparenchymal causes of restriction (chest wall abnormalities, obesity, diaphragmatic paralysis, respiratory muscle weakness) are associated with low TLC (especially ERV) and normal diffusion a. Increased BMI suggests obesity Year'sb. Low Pimax and normal RV suggests inspiratory muscle weakness

c. Low Pemax and increased RV suggests expiratory muscle weakness d. FRC is typically increased in ankylosing spondylitis Last and decreased in kyphoscoliosis

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E. Assess diffusion and gas exchange 1. Abnormal diffusion and oxygenation with normal static and dynamic lung function seen in pulmonary vascular disease 2. Abnormal gas exchange (hypercarbia, hypoxemia) seen in severe OSA syndrome, hypoventilation, other disorders of respiratory drive

Syllabus

(2010)

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Last Antibacterial Drugs 2 - James Whitlock, M.D. HHD221 Spring 2010 Page 63 Antibacterial Drugs 2

Assigned Reading: Katzung, Ch. 43

LEARNING OBJECTIVES FOR DRUGS THAT TARGET THE BACTERIAL CELL WALL: 1. Drug classes 2. Targets 3. Mechanisms of action 4. Anti-bacterial spectra 5. Adverse effects 6. Mechanisms of resistance 7. Pharmacokinetic issues Syllabus 8. Uses TOPICS: A. Penicillins and cephalosporins B. Other beta-lactam drugs C. Vancomycin D. Daptomycin ) (2010)

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(2010)

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Last Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 65 Pulmonary Blood Flow

Assigned Reading: West, Respiratory Physiology, Chapter 4.

I. PULMONARY BLOOD FLOW A. Begins at the main pulmonary artery, carrying mixed venous blood pumped by right ventricle. B. Pulmonary arteries branch like the airways, and accompany the airways to the terminal bronchiole. C. Then branch into pulmonary capillary network that envelope the capillary. D. Some physiologists refer not to the capillary network, but rather as a sheet of flowing blood interrupted in places by posts – like an underground parking garage. Syllabus E. Oxygenated blood is collected from the capillary bed by the small pulmonary veins. The pulmonary veins run between the lobules and unite to form 4 large pulmonary veins that drain oxygenated blood into the left atrium. F. Important differences exist between the pulmonary and systemic circulations. (2010)

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Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 66

II. PRESSURES IN THE PULMONARY CIRCULATION ARE VERY LOW A. Pulmonary versus systemic pressures: PA 25/8 mean 15 mm Hg (vs aorta MAP 100) Pressure in right atrium is 2 mm Hg, in left atrium is 5 mm Pressure difference in Pulmonary Circulation = 15 – 5 = 10 mm Hg Pressure difference in Systemic Circulation = 100 – 2 = 98 mm Hg B. Identical cardiac output through pulmonary and systemic circulations: 5 LPM C. Pulmonary Blood Vessel walls are remarkably thin, Normally contain little smooth muscle D. Systemic arterioles are muscular with abundant smooth muscle E. Systemic circulation regulates blood flow to various organs More blood pressure is necessary to supply arm aboveSyllabus head F. Pulmonary circulation must accept the entire cardiac output at all times Pulmonary arterial blood pressure is as low as necessary to deliver blood to lung apex G. Low pulmonary blood pressures keep the work/strain on the right heart as low as possible H. Pulmonary capillary blood pressure is probable midway between PA and PV Hydrostatic effects affect(2010) pulmonary capillary pressures

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Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 67

III. PRESSURES AROUND THE PULMONARY BLOOD VESSELS VARY AS A FUNCTION OF LUNG VOLUMES A. Unique situation: pulmonary capillaries are surrounded by gas B. Capillaries are liable to collapse or distend, depending on surrounding gas pressure C. Usually the effective pressure around capillaries is the alveolar pressure D. Transmural pressure is the pressure difference between the inside and outside of capillaries. E. Pressure around pulmonary arteries and veins may be less than alveolar pressure Larger blood vessels may be pulled open by radial traction of lung parenchyma during expansion (inhalation). F. Alveolar vessels: Exposed to alveolar pressures – Syllabusinclude capillaries. Caliber determined by transmural pressure G. Extraalveolar vessels: Arteries and veins running through lung parenchyma. Caliber determined by lung volume H. Hilar vessels (large) are exposed to intrapleural pressures IV. PULMONARY VASCULAR RESISTANCE A. Vascular Resistance = (input – output pressure) / blood flow B. Pressure drop is approximately 10 mmHg, compared to 100 mmHg in systemic circulation (2010) C. Identical blood flows through pulmonary and systemic circulations D. Therefore, pulmonary vascular resistance is one-tenth that of systemic circulation E. PVR = (15 – 5) / 6 lpm = 1.7 mmHg /liter / min or ~ 100 dyne/ sec/ cm –5 F. Systemic vascular resistance is caused by the muscular arterioles, which regulate blood flow to the various organs G. Year's Pulmonary circulation has no muscular arterioles, and has as low a resistance as compatible with distributing the blood in a thin film over a vast area in the alveolar walls H. PVR can become even lower as the pulmonary pressure is raised: 1. Recruitment: Blood flows through new capillaries when pressure rises Last Chief mechanism for fall in PVR when pressure is raised from low levels

Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 68

2. Distension: Widening of the capillary segments, at higher pressures a. change in shape from flattened to circular b. chief mechanism of decreased PVR at high vascular pressures

Syllabus

V. LUNG VOLUMES AFFECTS PULMONARY VASCULAR RESISTANCE (PVR) A. At low lung volumes, extraalveolar vessels (arteries and veins) have a small caliber due(2010) to their intrinsic smooth muscle and elastic tissue. Capillaries are open. Overall high vascular resistance. B. The critical opening pressure is the pressure necessary to initiate blood flow through pulmonary vessels within a collapsed lung (several cm of H2O). C. At high lung volumes, increased alveolar stretching and alveolar pressure relative to capillary pressure leads to squashing of capillaries. But extraalveolar vessels are opened by radial traction. Overdistension of lung can increase vascular resistance. D. Year's Optimal (lowest) pulmonary vascular resistance occurs at functional residual capacity (FRC). E. Role of drugs in affecting PVR: 1. Smooth muscle vasoconstrictors increase PVR Serotonin, histamine, norepinephrine Last 2. Smooth muscle vasodilators: acetylcholine, isoproterenol

Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 69

VI. MEASUREMENT OF PULMONARY BLOOD FLOW Fick principle: Oxygen consumption is equal to amount of oxygen taken up by lungs

VO2 dot = Q dot (CaO2 – CvO2) or

Q dot = VO2 dot / (CaO2 – CvO2)

VO2 dot is measured by collecting expired gas and measuring its O2 concentration; mixed venous blood is sampled via catheter from the pulmonary artery, and arterial blood is sampled from the radial artery VII. DISTRIBUTION OF BLOOD FLOW A. Normal upright human lung, blood flow is much greater at the base than apex B. When supine, the distribution of blood flow from baseSyllabus to apex is more uniform C. On exercise, blood flow increases to apex and base, and regional differences decrease D. Uneven distribution of blood flow from base to apex is a consequence of hydrostatic pressure differences: E. Difference in pressure between bottom and top of lung 30 cm high will be 30 cm H20 or 23 mm Hg. This represents a large pressure difference for the low pressure(2010) pulmonary circulation ZONE 1 (TOP): PALVEOLAR > PARTERIAL > PVENOUS A. here, arterial pressure falls below alveolar pressure, and no blood flows B. not normal C. but may occur in hemorrhage (low arterial pressure), or during positive-pressure ventilation D. Represents ventilated but un-perfused lung – useless for gas Year'sexchange, alveolar dead space

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Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 70

ZONE 2 (MID LUNG ZONE): PARTERIAL > PALVEOLAR > PVENOUS A. more arterial blood pressure (less hydrostatic loss) B. blood flow is determined by arterial – alveolar pressure difference (not art-venous difference) C. Starling resistor, sluice, waterfall effect D. Moving down the zone, arterial pressure increases, alveolar pressure constant E. Increasing recruitment of capillaries occurs in zone 2 ZONE 3 (BASE OF LUNG): PARTERIAL > PVENOUS > PALVEOLAR A. venous pressure exceeds alveolar pressure B. Blood flow is determined by the arterial – venous pressure difference C. Increasing blood flow involves distension of capillariesSyllabus D. (Zone 4) (collapsed lung at bases): 1. High resistance to blood flow in extra alveolar vessels E. Other factors can contribute to uneven blood flow in lung 1. Periphery may receive less blood flow than central regions (2010)

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Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 71

VIII. ACTIVE CONTROL OF THE PULMONARY CIRCULATION A. Passive factors dominate vascular resistance and blood distribution normally B. Hypoxic pulmonary vasoconstriction (HPV): contraction of arteriole smooth muscle in hypoxic regions 1. Does not require central nervous system 2. Occurs in excised segment of pulmonary artery 3. Hypothesis: cells in the perivascular area release some vasoconstrictor in response to hypoxia, mediator not yet found 4. Principally the pO2 of the alveolar gas, not the arteriolar blood that determines the hypoxic vasoconstrictor response

C. HPV is a nonlinear response: when pO2 is reduced below 70 mmHg, marked vasoconstriction occurs; at very lowSyllabus pO2 local blood flow may be abolished D. Potassium channels may be involved in HPV, leading to increased calcium influx (promoting vasoconstriction) E. Nitric oxide, endothelium derived relaxing factor is formed from L- arginine 1. NO activates soluble guanylate cyclase, leads to synthesis of cGMP and smooth muscle relaxation 2. Inhibitors of NO augment hypoxic pulmonary vasoconstriction(2010) 3. Inhaled NO reduces hypoxic pulmonary vasoconstriction in humans F. Pulmonary endothelial cells release potent vasoconstrictors – endothelins G. Hypoxic vasoconstriction serves to direct blood flow away from hypoxic regions of lung. H. At high altitude, low inspired oxygen tension leads to generalized pulmonary vasoconstriction, and a rise in pulmonary arterial Year'spressure. I. Role of hypoxic pulmonary vasoconstriction is important in switching from fetal to neonatal circulation: J. During fetal life, pulmonary vascular resistance is very high, partly due to hypoxic vasoconstriction. Upon first breath of air into alveoli, the vascular resistance falls dramatically because of relaxation of Last smooth muscles, and pulmonary blood flow greatly increases.

Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 72

K. Low pH causes vasoconstriction, especially in conjunction with hypoxia.

Syllabus

IX. WATER BALANCE IN THE LUNG A. Problem of keeping the alveoli free of fluid is critical B. Starling’s Law: 1. Hydrostatic pressure capillary – interstitium 2. Colloid osmotic (2010)pressure capillary – interstitium a. σreflection coefficient b. K filtration coefficient 3. net fluid out = K [(Pc – Pi) - σ(πc−πi) C. Probable that the net pressure is outward causing a small flow of lymph, 20 ml/h D. Fluid that leaves capillaries and leaks into the interstitium 1. Can track through the interstitial space to the perivascular, Year'speribronchial space within the lung. 2. Numerous lymphatics run in the perivascular spaces, help transport fluid to the hilar lymph nodes E. Early Pulmonary edema: engorgement of peribronchial and perivascular spaces. F. Later Pulmonary edema: fluid may leak into alveolar spaces: Last 1. When the capacity for the interstitium to drain fluid is exceeded.

Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 73

2. Alveolar fluid is pumped out by a sodium/potassium ATPase in epithelia. 3. Alveolar edema is much more serious because it interferes with gas exchange G. Other Functions of the Pulmonary Circulation: 1. A reservoir for blood... lung can reduce its PVR as pressure is raised. 2. A filter for blood. Small thrombi are removed from circulation before they can reach the brain or other vital organs. White blood cells are trapped and later released from lung. X. METABOLIC FUNCTIONS OF THE LUNG A. Many vasoactive substances are metabolized by the lung: 1. Peptides: Angiotensin I (converted by ACE to Angiotensin II), 2. Bradykinin (80% inactivated by ACE) Syllabus 3. Amines: Serotonin (removed and stored), norepinephrine (30% removed) 4. Prostaglandins E2, F2alpha, leukotrienes (almost completely removed) B. Arachidonic acid metabolites: 1. formed by the action of phospholipase A2 on membrane phospholipids 2. Lipoxygenase produces leukotrienes – inflammatory mediators, contribute(2010) to asthma 3. Cyclooxygenases produce prostaglandins – potent vasoconstrictors or dilators C. Lung plays a role in clotting mechanisms of blood. D. Many mast cells containing heparin are present in the interstitium. E. Lung secretes IgA in the bronchial mucus, which contributes to host defense. F. Synthetic functions: Year's1. synthesis of dipalmitoyl phosphatidylcholine, component of pulmonary surfactant 2. Collagen and elastin proteins are important structural components of lung 3. Proteases can be released leading to breakdown of collagen and elastin leading to emphysema 4. Carbohydrate metabolism – elaboration of Last mucopolysaccharides of bronchial mucus.

Pulmonary Blood Flow - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 74

REVIEW QUESTIONS

1) A patient with pulmonary hypertension has mean pulmonary arterial and venous pressures of 33 and 3 mm Hg respectively. If we measure oxygen consumption to be 300 ml min-1 and oxygen concentration of the mixed venous and arterial blood to be 12 and 22 ml 100 ml-1, what is the patient’s pulmonary vascular resistance in mm Hg liters-1 min? A. 20 B. 2 C. 0.5 D. 1 E. 10 Syllabus 2) Which of the following does not contribute to increased blood flow in Zone 3 (base) of the lung? A. Increased arterial pressure B. Increased alveolar pressure C. Increased distension D. Recruitment E. Increased arterial – venous(2010) pressure difference

)E 2) B 1) E Answers: Year's

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Chest Imaging 2 - Ann Leung, M.D. HHD221 Spring 2010 Page 75 Chest Imaging 2

LEARNING OBJECTIVES: 1. Review types and costs of imaging studies most commonly ordered to evaluate lung disease 2. Review anatomy of visualized intrathoracic structures 3. Distinguish between normal and abnormal findings 4. Illustrate characteristic appearance of common (and some uncommon) lung diseases Syllabus

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Last Antibacterial Drugs 3 - James Whitlock, M.D. HHD221 Spring 2010 Page 77 Antibacterial Drugs 3

Assigned Reading: Katzung, Ch. 44 & 45

Learning objectives for drugs that inhibit bacterial protein synthesis: 1. Drug classes 2. Targets 3. Mechanisms of action 4. Anti-bacterial spectra 5. Adverse effects 6. Mechanisms of resistance 7. Pharmacokinetic issues 8. Uses Syllabus

TOPICS: A. Penicillins and cephalosporins B. Other beta-lactam drugs C. Vancomycin D. Daptomycin

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Last Structure And Function Of The Lung - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 79 VENTILATION - PERFUSION RELATIONS

Assigned Reading: West, Respiratory Physiology, Chapter 5.

I. OVERVIEW The Alveolar Gas Equation describes the relationship of gases in the alveoli

PAO2 = PIO2 – PaCO2 R R = respiratory quotient

= VCO2/VO2 Normal = 0.8-1.2 In this section, we will examine the factors that contributeSyllabus to the movement of gas from the alveolus to the alveolar capillary and back to the alveolus. • Diffusion • Variations in alveolar ventilation • Variations in alveolar perfusion • Variations in matching of ventilation to perfusion • Shunt II. DIFFUSION A. Oxygen moves from the(2010) alveolus to the pulmonary capillary by diffusion from the area of high partial pressure to lower partial pressure. A variation on the Fick equation illustrates this principle.

1. Fick Equation VO2 = DLO2 (PAO2 - PaO2)

B. DLO2 = coefficient of the diffusion capacity of the lung for oxygen. C. In the lung, diffusion is proportional to 1. solubility () divided by the square root of the molecular weight of the gas Year's2. the nature and the length of the diffusion pathway 3. the total capillary surface area available for diffusion. (70m2 in a normal lung). 4. the transit time of a red blood cell through the alveolar capillaries. (0.75 sec with normal cardiac output). Last

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D. Carbon dioxide also moves from the alveolar capillary to the alveolus via diffusion. Although CO2 is a larger molecule, it diffuses more readily than oxygen through the alveolar wall, due to its higher solubility (20:1) However, because the release of CO2 also depends on chemical conversion via carbonic anhydrase, and because the driving pressure of CO2 is lower, the exchange of CO2 may not actually occur faster than oxygen exchange. E. Variations in alveolar ventilation 1. In a normal lung, ventilation is greater in the bottom of the lung than the top of the lung. F. Variations in alveolar perfusion 1. In a normal lung, blood flow is greatest at the bottom and less at the top of the lung. These differences are governed by gravitational differences as well as other less well understood factors. The differences in perfusion from top to bottom are greater than the differences in ventilationSyllabus from top to bottom.

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Syllabus G. Variations in matching of ventilation to perfusion

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The sum total of arterial PaO2 is dependent upon a scatter of relationships between alveoli and accompanying alveolar Year'scapillaries. This is referred to as V/Q matching. The normal V/Q = 0.8 –1. Ventilation-perfusion matching is maintained because alveolar gas concentration leads to vasoregulation. Thus, hypoxic vasoconstriction serves to reduce blood flow to poorly ventilated alveoli. Last

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III. SHUNT A. Shunt is defined as a portion of blood that bypasses the usual path. For the discussion of gas transport, the focus will be on a “right-to- left” or a portion of blood that passes from the venous right side of the heart to the left arterial side of the heart without participating in gas exchange. A normal anatomic shunt exists as blood from the bronchial circulation returns directly to the pulmonary vein. In addition, blood from the coronary veins returns directly to the left ventricle. Normal anatomic shunt is 2-5%. Abnormal and clinically important shunts occur when blood bypasses the lungs through an intracardiac opening such as a ventricular septal defect. When portions of the lung collapse (atelectasis) or become filled with fluid or pus (pneumonia) blood may still flow pass these areas but no gas exchange can occur because there is no driving pressure from alveolar gas. A clinically important feature of shunt is that hypoxemia persists no matter how much oxygen is delivered to a patient. Thus, giving oxygen at FIO2 at 1.0 (100%)Syllabus and measuring PaO2 is a sensitive test for the presence of a shunt. Shunt does not usually result in elevated PaCO2 because chemoreceptors sense an increase PaCO2 and increase ventilation of unshunted blood. Shunt Equation: QS = Cc’O2 – Ca O2

QT Cc’O2 – Cv O2 (2010)

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Structure And Function Of The Lung - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 83

Syllabus

IV. ASSESSING OXYGENATION

A. Hypoxemia = low PaO2 (often defined as < 60mmHg or estimated normal) B. Hypoxia = clinical state of tissue deprivation of oxygen 1. Estimating a PaO(2010)2 for age: PaO2 = 103 – 0.4 x age (only at room air!!!) C. In an idealized cardiopulmonary system, the partial pressure of oxygen in arterial blood (PaO2) is perfectly equilibrated with the partial pressure of oxygen in alveoli (PAO2). However, our bodies are not always perfect, and even in normal persons there is a gap, called the alveolar-arterial difference or P(A-a)O2. This is also abbreviated in some texts as A-a Δ O2. P(A-a)O2 is helpful in the assessment of hypoxemia. P(A-a)OYear's2 = PAO2 – PaO 2 = 10 -15 mmHg at room air = 100 mmHg while breathing 100% oxygen

D. The alveolar-arterial difference can also be used to estimate shunt.

1. Est. shunt = P(A-a)O2 Last 20 a. But only on FIO2 = 1.00!

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V. CASES A 25 year old man with a head injury has an arterial blood gas of pH 7.28, PaCO2 = 56 mmHg, PaO2 = 68 mmHg. Is he hypoxemic? Does he have a widened P(A-a)O2? What explains this blood gas? What would you predict his response to supplemental oxygen will be?

A 4 year old child is brought to the emergency room with blue lips and fingertips. An arterial blood gas shows of pH 7.32, PaCO2 = 32 mmHg, PaO2 = 36 mmHg. Is the child hypoxemic? Does he have a widened P(A- a)O2? What explains this blood gas? What would you predict his response to supplemental oxygen will be?

After receiving oxygen at FIO2 =1.0 for 15 min. via a tight fitting mask, the child’s arterial blood gas shows pH 7.30, PaCO2 = 32 mmHg, PaO2 = 160 mmHg. What is his P(A-a)O2? What is the cause of his hypoxemia?Syllabus VI. OVERVIEW OF HYPOXEMIA AND HYPOXIA

A. Hypoxemia with normal P(A-a)O2 1. Decrease in ambient oxygen 2. Hypoventilation

B. Hypoxemia with increased P(A-a)O2 1. Ventilation-perfusion mismatch 2. Right-to-left shunt(2010) 3. (Diffusion limitation) C. Tissue hypoxia without hypoxemia 1. Inadequate oxygen carrying capacity (e.g. anemia) 2. Inadequate oxygen transport (e.g. low cardiac output) 3. Inadequate peripheral oxygen extraction (e.g. cyanide poisoning) Year's

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Structure And Function Of The Lung - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 87

REVIEW QUESTIONS 1) A 40 year old man survives a car crash but damages his chest wall leading to partial respiratory paralysis which decreases his ventilation by 60%. If prior to the car crash his arterial pCO2 was 40 mm Hg and his respiratory quotient is 1, what percentage of supplemental oxygen must be provided to maintain his arterial pO2 at 100 mm Hg? A. 84% B. 56% C. 100% D. 21% E. 28%

2) Calculate the shunt of a patient with an arteriovenous pulmonarySyllabus fistula if at cardiac catheterization he is found to have an arterial O2 concentration -1 of 17 ml x 100 ml , a mixed venous blood O2 concentration of 14 ml x 100 -1 ml , and O2 concentration of blood exiting the pulmonary capillaries of 20 ml x 100 ml-1. A. 40% B. 50% C. 60% D. 70% E. 80% (2010)

3) Which of the following statements is false regarding gas exchange in the lung? A. V/Q ratio is highest at the apex B. Ventilation is highest at the base C. Blood flow increases more rapidly from top to bottom than Year'sventilation D. pH is lower toward the base of the lung

E. Alveolar pCO2 is higher at the apex of the lung 3) E 2) B 1) E Answers:

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Last Gas Transport And Exchange - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 89 GAS TRANSPORT AND EXCHANGE

Assigned Reading: West Ch. 6.

GOAL: To examine how oxygen and carbon dioxide are stored and transported in blood. Gas circulates in the body in one of three ways: A. Dissolved in solution B. Bound to a protein C. Chemically converted I. GAS TRANSPORT AS DISSOLVED IN SOLUTION A. Background: The concept of partial pressures Syllabus

1. PAIR = PN + PCO2 + PO2 + PH20

2. At 37C, PH20 = 47mmHg and at sea level, PB = 760 mmHg 3. 21% oxygen, 79% nitrogen regardless of temp or barometric pressure

4. PIO2 = FIO2 ( PB - PH20) = 0.21 (760 – 47) = 150 mmHg *Calculate the partial pressure of inspired nitrogen *Calculate the partial pressure of inspired(2010) oxygen on Mt. Everest, PB = 253mmHg

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a. Fig. 1 Partial pressure of O2: room air to mitochondria Last at sea level

Gas Transport And Exchange - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 90

B. Henry’s Law: Gases are carried in physical solution in the blood proportional to their partial pressure. The solubility coefficient of any gas in a liquid will vary with temperature as well; at higher temperatures, solubility decreases. C =  P C = content or concentration  = solubility factor (mL/100mL blood/mmHg) P = partial pressure of the gas (mmHg)

1. CO2 = .003 x 100mmHg = 0.3mL/100mL blood

2. CCO2 = 0.072 x 40 mmHg = 2.9 mL/100mL blood C. However, our body consumes oxygen at about 300mL/minute. If we relied on dissolved oxygen, the heart would need to pump 100L/min or 20x the normal cardiac output to meet demand. II. GAS TRANSPORT WHEN BOUND TO PROTEIN A. Hemoglobin Syllabus 1. Hemoglobin is a complex protein made of 4 polypeptide chains; each molecule has 4 heme groups capable of binding a molecule of oxygen.

2. 4 moles O2 = 4 x 22.4 L O2 = 1.39 mL O2 per gram of Hgb 1 mole Hgb 64,458 gm 3. With normal Hgb = 15gm/100mL blood, Hgb can carry 20.85 mL/100mL blood, or 70x the amount of dissolved gas! B. Hemoglobin Saturation(2010) 1. Above we calculated how much oxygen Hgb could carry, but in usual conditions, the hemoglobin sites are not all bound with oxygen 2. “% saturation of hemoglobin” refers to the total oxygen binding sites actually bound by oxygen. Oxygen bound hemoglobin is called oxyhemoglobin.

a. % saturation = actual Hgb-O2 content

total Hgb O2 capacity

3. The relationship between PO2 and % saturation is non- Year'slinear. The S-shaped hemoglobin-oxygen dissociation curve has physiologic advantages. In the normal range of arterial PO2, the curve is almost flat, so that a moderate decrease in arterial PO2 is associated with only a small decrement in % saturation of Hgb. Last

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Figure 2. The hemoglobin-oxygen (Hb-O2) dissociation curve shows the % saturation of hemoglobin at each PO2. When the hemoglobin concentration is known the content of O2 can be calculated. The total content includes the small amount of O2 in solution which becomes significant at high levels of PO2. The saturation scale on the left applies only to the Hb-O2 line. The scale on the right shows content values for a normal hemoglobin of 15gm/100ml.(2010) C. Influences on Hemoglobin Binding to Oxygen 1. Decreased affinity to oxygen results in a shift of the oxygen- Hgb dissociation curve to the right, and improved unloading of oxygen in tissues. A decreased affinity means that blood leaving the alveoli will have a slightly lower oxygen content, but not much (remember the S-shaped curve!) and will give up oxygen to tissues at higher PO2. 2. Factors that decrease affinity: Decreased pH ( H+) Year's PCO2  Temperature  2,3 diphosphoglycerate (DPG)

Remember: hot exercising muscles need O2! Last

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3. Increased affinity to oxygen results in a shift of the oxygen- Hgb dissociation curve to the left, and enhances loading of Hgb sites. An increased affinity means that the blood leaving the alveoli will have a higher O2 content, but will not give it up to the tissues as easily. 4. Factors that increase affinity:

Unloading of CO2 in the lung, CO (carbon monoxide)

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Figure 3. The Oxygen-Hemoglobin Dissociation Curve D. Unusual Circumstances 1. Carbon monoxide: CO has an affinity for Hgb 250 times greater than oxygen. Thus, CO will bind to a Hgb site and HOLD on, thus functionally decreasing the number of Hgb sites available to bind O2. It also causes an effective increase in affinity of oxygen to Hgb. Carboxyhemoglobin is Year'sthe term for CO bound Hgb. 2. Different hemoglobins will have different oxygen affinities. (e.g. Human fetal Hgb has a P50 = 20 mmHg compared to 27mmHgb for adult Hgb A. ) 3. Changes in 2,3 DPG occur over 6-24 hrs and play an adaptive role at altitude, during acid-base abnormalities, and Last with anemia.

Gas Transport And Exchange - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 93

E. Arterial Blood Oxygen Content

1. CaO = [carrying capacity of Hgb X gms of Hgb

X % oxygen sat] + [ x PaO2] a. For a healthy person at sea level,

2. CaO = [1.39 ml x 15 gm HgB x 0.97] + [0.003 X 100mmHg] 3. = ~20mL /100mL of blood Calculate what happens in the following situations: A patient with anemia, Hgb = 8 A patient with polycythemia and a Hgb of 20 A firefighter exposed to CO whose % oxygen saturation is 80% A mountain climber on top of Mt. Everest F. Venous Blood Oxygen Content Syllabus 1. Oxygen is extracted in different tissues at different rates. Extraction is also dependent upon the rate of blood flow through the tissue. Thus, venous blood returning from the tissues does not always have the same amount of unused oxygen. The term “mixed venous blood” refers to the pooled blood returned to the right heart and on its way to the lungs via the pulmonary arteries.

a. VO2 = oxygen consumption (normal ~ 250 mL/min) b. Q = blood flow or cardiac output (normal ~ 5L/min) c. CvO2 = oxygen(2010) content of mixed venous blood

G. The Fick Equation VO2 = Q(CaO2 –CvO2) 1. This equation shows that with constant blood flow, increased oxygen demand leads to a greater arterial-venous oxygen difference. Similarly, increased blood flow and unchanged oxygen demand leads to a decreased arterial-venous difference. 2. Rearranging the Fick Equation (and using normal values),

a. CaO2 –CvO2 = VO2/Q = 250/5 = 50 mL O2/L of blood Year'sor 5 mL/ 100mL blood b. From above, normal CaO2 = 20 mL/100mL blood

1) Thus, CvO2 = 15 ml/100ml c. Looking to the Oxygen-Hemoglobin Dissociation Last Curve, PvO2 = 40 mmHg

Gas Transport And Exchange - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 94

III. GAS TRANSPORT VIA CHEMICAL CONVERSION A. Oxygen is not transported through a process of chemical conversion, but the great majority of carbon dioxide is transported this way.

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(2010) B. Some CO2 is dissolved in solution and CO2 has its own solubility factor. Since the solubility of CO2 is about 20x greater than that of O2, a greater amount of CO2 is carried at physiologic partial pressures. Still, at 2.9mL/100mL blood, this represents only ~6% of CO2 in the body. C. CO2 binds to hemoglobin as well, in a complex, curvilinear relationship. This is called carbamino, and at 2.1mL/100mL blood, represents ~4% of the CO2 in the body. Formation of carbamino weakens Hgb-O2 affinity (right shift) and the presence of higher Year'sPO2 decreases carbamino formation. This phenomenon is called the Haldane Effect. It is highly adaptive for Hgb loading of CO2 in the muscles and unloading in the lungs. D. Importantly, 90% of CO2 is found in the plasma chemically converted to bicarbonate. In plasma, CO2 rapidly combines with water to form carbonic acid which then dissociates to form bicarbonate and a hydrogen ion. Last + 1. CO2 + H20  H2CO3  HCO3 + H

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E. The conversion of CO2 to bicarbonate is facilitated by the presence of the enzyme carbonic anhydrase. Thus, the reaction occurs slowly in plasma where no enzyme is available, but rapidly in certain cells such as red blood cells. Hgb buffers the H+ and the Hgb-O2 dissociation curve shifts to the right. As bicarbonate diffuses out of the cell, Cl- diffuses into the cell to maintain charge neutrality.

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Fig 5

F. The arterial content of CO2 is a balance between CO2 production and alveolar ventilation. Under normal conditions, Pa CO2 =40 mmHg,. The Ca CO2 can be calculated and is 47 mL/100mL blood. Substituting the difference between CO2 production and excretion, Cv CO2 – Ca CO2 allows one to derive that Cv CO2 is 51 mL/100mL blood and from the CO(2010)2 dissociation curve, Pv CO 2 = 46mmHg.

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Gas Transport And Exchange - Peter Kao, M.D., Ph.D. HHD221 Spring 2010 Page 96

REVIEW QUESTIONS

1) A 60 year old man presents to the hospital with anemia due to GI blood loss from colon adenocarcinoma. His hemoglobin is 8 gm x 100 ml-1, and his oxygen saturation breathing room air is 96%. What is this patient’s –1 total oxygen concentration in ml O2 x 100 ml ? A. 9 B. 10 C. 11 D. 12 E. 13

2) All of the following conditions contribute to the Haldane effect,Syllabus EXCEPT which one? A. The ability of reduced hemoglobin to bind H+ B. The increased tendency of reduced hemoglobin to form carbamino hemoglobin C. An increase in the deoxygenation of blood increases the blood’s affinity to carry CO2 D. The increased tendency of reduced hemoglobin to bind 2,3 DPG (2010)

2) D 1) C Answers: Year's

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Antibacterial Drugs 4 - James Whitlock, M.D. HHD221 Spring 2009 Page 97 Antibacterial Drugs 4

Assigned Reading: Katzung, Ch. 46 & 47

Learning objectives for inhibitors of folic acid synthesis, fluoroquinolones, and anti-TB drugs: 1. Drug classes 2. Targets 3. Mechanisms of action 4. Anti-bacterial spectra 5. Adverse effects 6. Mechanisms of resistance TOPICS: Syllabus A. Sulfonamides & trimethoprim B. Fluoroquinolones C. Antimycobacterial drugs D. Isoniazid E. Rifampin F. Ethambutol G. Pyrazinamide (2010)

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Last Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 99 Airflow Obstruction

I. BASIC FLOW-VOLUME LOOP OBTAINED WHEN YOU REQUEST “SPIROMETRY.” (“FULL PFTS” INCLUDE LUNG VOLUMES AND DLCO)

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II. SOME EQUATIONS OF RELEVANCE FOR UNDERSTANDING AIRFLOW OBSTRUCTION A. Laminar Flow (in a tube) = Driving pressure / Resistance B. Poiseuille’s Law: 1. Resistance = 8 x viscosity x tube length Year's π x tube radius4 2. Thus, tube radius is the dominant factor in determining resistance to airflow. C. Bernoulli’s principle (based on conservation of energy): Last 1. Total mechanical energy = kinetic energy + potential energy

Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 100

2. Total energy is conserved during exhalation b/c air travels in a continuous stream = constant flow rate (not to be confused with velocity, which varies tremendously throughout exhalation, as apparent from shape of expiratory limb of flow-volume loop). III. BERNOULLI’S EFFECT IS RELEVANT FOR UNDERSTANDING WHY MOST OF FORCED EXPIRATION IS “EFFORT-INDEPENDENT”

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A. The pressure at "1" is higher than at "2" because the fluid speed at "1" is lower than at "2". B. Bernoulli's principle can be derived from the principle of conservation of energy. This states that in a steady flow the sum of all forms of mechanical energy in a fluid along a streamline is the same at all points on that streamline. This requires that the sum of kinetic energy and potential energy remain constant…If a fluid is flowing horizontally and(2010) along a section of a streamline, where the speed increases it can only be because the fluid on that section has moved from a region of higher pressure to a region of lower pressure; and if its speed decreases, it can only be because it has moved from a region of lower pressure to a region of higher pressure. Consequently, within a fluid flowing horizontally, the highest speed occurs where the pressure is lowest, and the lowest speed occurs where the pressure is highest. Year's

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IV. AIRFLOW OBSTRUCTION IN A NUTSHELL A. The importance of the Bernoulli effect with respect to PFTs is that during an exhalation, gas velocity must increase dramatically as flow travels toward the trachea, because the total cross-sectional airway area decreases. This causes the hydrostatic pressure to fall within the airways, an effect that becomes very important during forceful exhalations, when large airways (which are intrinsically floppy) collapse at points where the pressure outside of them exceeds the inside (hydrostatic) pressure. The localized sites in the airways where this occurs are called “choke points” and they result in expiratory flow limitation. This is analogous to what happens when attempting to drink a milkshake through a low quality (non-rigid) straw. If you draw too forcefully on the straw, the pressure inside becomes negative with respect to ambient pressure and the straw collapses. B. This effect explains why after the very brief initial, effort-dependent portion of a forced exhalation (the Peak Flow), expiratorySyllabus flow becomes effort-independent, since no matter how much expiratory effort you exert (just like however more forcefully you try to draw in on the straw), the flow will not increase. C. The major factor contributing to a positive intra-airway pressure is a high lung static recoil pressure (high lung volume). Factors that reduce intra-airway pressure during expiration (thus promoting flow limitation) are 1) the resistive drop in driving pressure with airflow from alveoli toward the mouth; 2) the Bernoulli reduction in hydrostatic (intra-airway) pressure caused by increased velocity due to the reduction in (2010)total cross-sectional airway area in more proximal airway generations; and 3) loss of mechanical tethering of central airways as the exit from the lung parenchyma. D. Because with COPD there is both decreased elastic recoil (reduced driving pressure) and alveolar destruction (reduced axial tension tethering bronchial tubes), the Bernoulli effect occurs at higher lung volumes than normal with the development of choke points in more distal airways and consequent air-trapping, hyper-inflation (high TLC, “barrel chest”), and expiratory airflow limitation (low FEV1/FVC, prolonged expiratory phase). With asthma, the elastic Year'srecoil is not reduced and tethering is normal, so the main issue is more expiratory airflow limitation (due to reduced airway diameter from airway bronchoconstriction and mucous secretion) rather than air-trapping. With , expiratory airflow limitation results from airway narrowing due to tenacious secretions, and if you have a compressing goiter, aspirate a chicken bone, etc. you will locally decrease the airway diameter with consequent massive increase in Last resistance to airflow

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E. Incidentally, it may seem paradoxical that the velocity is greatest in larger caliber airways and slow in terminal bronchioles since, after all, Bernoulli’s principle states that the narrower the tube, the more rapid the velocity (and the lower the “distending” pressure in the bronchial tube). Wouldn’t you expect that the narrowest (most distal) tubes in the bronchial tree would have the highest velocity? F. The explanation has to do with the fact that: Velocity (cm/s) = Flow (ml/sec) / cross-sectional area (cm2) G. Since Flow is constant in the expiratory air-stream, and since the total cross-sectional area increases with each successive generation of airways (b/c the number of tubes increases dramatically), the velocity in distal bronchi is much lower (and therefore hydrostatic pressure is greater). V. AIR-TRAPPING IN COPD (“CHOKE POINTS”) Syllabus

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A. Left. The equal-pressure-point (EPP) model. At top, pleural (Ppl), alveolar (Palv) and intra-airways pressures at end-inspiration. At bottom, corresponding values during a forced expiration, in which the expiratory muscles generated an expiratory pressure of 20 cm Year'sH2O. B. Right. Numerical examples of an active, yet not maximal, expiration from the same lung volume, in a subject with normal lung recoil of 3 cm H2O (top), and in a patient with emphysema, with lung recoil of only 1 cm H2O (bottom). In this latter case, EPP is very close to the most peripheral airways. Last

Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 103

VI. UPPER AIRWAY (= FROM MOUTH TO LOWER TRACHEA)

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VII. SYMPTOMS BEGIN WHEN FEV1 GETS BELOW A THRESHOLD. SMOKING ACCELERATES RATE OF LOSS OF LUNG FXN (CURVE D) (2010)

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Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 104

VIII. “NOT ALL THAT IS ASTHMA” Causes of Wheezing Based on anatomic site of obstruction: Extrathoracic Upper Airway Intrathoracic Upper Airway Lower Airway Obstruction Obstruction Obstruction Postnasal drip syndrome Tracheal stenosis Asthma Paroxysmal vocal cord motion Aspiration COPD Hypertrophied Malignancies Pulmonary Edema supraglottitis Intrathoracic goiter Aspiration Laryngeal edema Pulmonary embolism Laryngostenosis Acquired Postextubation granuloma Herpetic tracheobronchitis Cystic fibrosis Retropharyngeal Right sided aortic arch Carcinoid syndrome Benign airway tumors BronchiectasisSyllabus Anaphylaxis Lymphangitic carcinomatosis Malignancy Parasitic infections Obesity Klebsiella rhinoscleroma Mobile supraglottic soft tissue Relapsing polychondritis Laryngocele Abnormal arytenoid movement (2010) Vocal cord hematoma Bilateral vocal cord paralysis Cricoarytenoid arthritis Wegener’s granulomatosis Year's

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Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 105

IX. CAUSES OF AIRFLOW OBSTRUCTION IN ADULTS Differential Diagnosis of COPD: Diagnosis Suggestive Features Onset in mid-life Symptoms slowly progress COPD Long Smoking history Dyspnea during exercise Largely irreversible airflow limitation

Onset early in life (often childhood) Symptoms vary from day to day Symptoms at night/ early morning Asthma Allergy, , and/or eczema also present Family history of asthma Largely reversible airflow limitation

Fine basilar on Chest X-ray shows dilated heart, pulmonary edema Heart Failure Pulmonary function tests indicate volume restriction,Syllabus not airflow limitation

Large volumes of purulent Commonly associated with bacterial infection Coarse crackles. Clubbing on auscultation Chest X-ray/ CT shows bronchial dilation, bronchial wall thickening

Onset all ages Chest X-ray shows lung infiltrate Microbiological confirmation(2010) High local prevalence of tuberculosis

Onset younger age, non-smokers Obliterative May have history of rheumatoid arthritis or fume exposure bronchiolitis CT on expiration shows hypodense areas

Most patients are male and non-smokers Diffuse Almost have chronic panbronchiolitisYear's Chest X-ray and HRCT show diffuse small centrilobular nodular opacities and hyperinflation

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X. GRADING ASTHMA SEVERITY (BEFORE INITIATING THERAPY)

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Last Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 107

XI. “STEPWISE” PHARMACOLOGIC TREATMENT OF ASTHMA (DON’T IGNORE ENVIRONMENTAL COMPONENTS, THOUGH!)

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Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 108 XII. EVALUATING ASTHMA FLARES

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XIII. MEDICINES FOR ASTHMA ARE HIGHLY EFFECTIVE FOR MOST PEOPLE, SO ADDITIONAL FACTORS OFTEN CONTRIBUTE TO FATALITY Risk factors for Death from Asthma: Asthma Year'sHistory Previous severe exacerbation (e.g., intubation or ICU admission for asthma) Two or more hospitalizations for asthma in the past year Two or more ED visits for asthma in the past year Hospitalizations or ED visit for asthma in the past month Using >2 canisters of SABA per month Difficulty perceiving asthma symptoms or severity of exacerbations Other risk factors: lack of written asthma action plan, sensitivity to Alternaria Last

Airway Obstruction – Tushar Desai, M.D. HHD221 Spring 2010 Page 109 Social History Low socioeconomic status or inner-city residence Illicit drug use Major psychosocial problems

Co-morbidities Cardiovascular disease Other chronic lung disease Chronic psychiatric disease

XIV. CONSIDER OCCUPATIONAL CAUSES OF ASTHMA WHEN APPROPRIATE (AVOIDANCE OF EXPOSURE IS A CORNERSTONE OF THERAPY) Evaluation and management of work aggravated asthma and occupational asthma: Evaluation Potential for workplace-related symptoms: Recognize sensitizers (e.g., isocyanates, plant, or animal products) Irritants or physical stimuli (e.g., cold/heat, dust, humidity) Syllabus Coworkers may have similar symptoms Patterns of Symptoms (in relation to work exposures): Improvement occurs during vacations or days off (may take a week or more) Symptoms may be immediate (<1 hour), delayed (most commonly, 2-8 hours after exposure), or nocturnal Initial symptoms may occur after high-level exposure (e.g., spill) Documentation of work-relatedness of airflow limitation: Serial charting for 2-3 weeks (2 weeks at work and up to 1 week off, as needed to identify or exclude work related changed in PEF) Record when symptoms and exposures occur Record when bronchodilator is used Measure and record peak flow (or FEV1)(2010) every 2 hours awake Immunological tests Referral for further confirmatory evaluation (e.g., bronchial challenges) Management Work-aggravated asthma: Work with onsite health care providers or managers/supervisors Discuss avoidance, ventilation, respiratory protection, tobacco smoke-free environment. Occupationally induced asthma: Recommend complete cessation of exposure to irritating agent Year's

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XV. MANY PATIENTS WILL NOT BE WILLING TO CONSIDER GIVING UP A PET (AND JUST ABOUT ALL PATIENTS WILL REMAIN FULLY CONVINCED THAT THEY ARE NOT ALLERGIC TO THEIR PET, NO MATTER WHAT YOU TELL THEM) Avoidance measures for animal dander: Removing animals from the house: Keep animals outside, e.g., in garage or kennel; restricting animals to certain rooms has not been shown to be effective. Once animal has been removed, the premises should be cleaned thoroughly. Controlling allergen with an animal in the house: Difficult because the animal contains 10-50 mg of major allergen, while the quantities of airborne allergen are only 5-20 ng/m3. Using an air filter can only reduce airborne allergen. Reduce reservoirs: remove carpets, reduce upholstered furniture to a minimum, replace drapes with blinds, or/and vacuum weekly using vacuum with good filtration, ie, double thickness bags and/or HPA filtration Room air filtrations: HEPA or electrostatic (maintenance data are better defined for EPA) Washing cats does not reduce allergen levels significantly. Washing dogs twice a week may help. Syllabus

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XVI. THIS IS A GREAT CHECKLIST OF ITEMS TO COVER DURING INITIAL EVALUATION OF ALL PATIENTS WITH ASTHMA ASSESSMENT QUESTIONS* FOR ENVIRONMENTAL AND OTHER FACTORS THAT CAN MAKE ASTHMA WORSE

Inhalant Allergens Workplace Exposures Does the patient have symptoms year round? (If yes, ■ Does the patient cough or during the week, ask the following questions. If no, see next set of but not on weekends when away from work? questions.) ■ Do the patient’s eyes and nasal passages get irritated ■ Does the patient keep pets indoors? What type? soon after arriving at work? ■ Does the patient have moisture or dampness in any ■ Do coworkers have similar symptoms? room of his or her home (e.g., basement)? (Suggests house-dust mites, molds.) ■ What substances are used in the patient’s worksite? (Assess for sensitizers.) ■ Does the patient have mold visible in any part of his or her home? (Suggests molds.) Rhinitis ■ Has the patient seen cockroaches or rodents in his or ■ Does the patient have constant or seasonal nasal her home in the past month? (Suggests significant congestion, runny nose, and/or postnasal drip? cockroach exposure.) Gastroesophageal Reflux Disease (GERD) ■ Assume exposure to house-dust mites unless patient ■ Does the patient have heartburn? lives in a semiarid region. However, if a patient living Syllabus in a semiarid region uses a swamp cooler, exposure ■ Does food sometimes come up into the patient’s to house-dust mites must still be assumed. throat? Do symptoms get worse at certain times of the year? (If ■ Has the patient had coughing, wheezing, or shortness yes, ask when symptoms occur.) of breath at night in the past 4 weeks? ■ Early spring? (trees) ■ Does the infant vomit, followed by cough, or have wheezy cough at night? Are symptoms worse after ■ Late spring? (grasses feeding? ■ Late summer to autumn? (weeds) Sulfite Sensitivity ■ Summer and fall? (Alternaria, Cladosporium, mites) ■ Does the patient have wheezing, coughing, or ■ Cold months in temperate climates? (animal shortness of breath after eating shrimp, dried fruit, or dander) (2010)processed potatoes or after drinking beer or wine? Tobacco Smoke Medication Sensitivities and Contraindications ■ Does the patient smoke? _ Does anyone smoke at ■ What medications does the patient use now home or work? (prescription and nonprescription)? ■ Does anyone smoke at the child’s daycare? ■ Does the patient use eyedrops? What type? Indoor/Outdoor Pollutants and Irritants ■ Does the patient use any medications that contain beta-blockers? ■ Is a wood-burning stove or fireplace used in the patient’s home? ■ Does the patient ever take aspirin or other nonsteroidal anti-inflammatory drugs? ■ Are there un-vented stoves or heaters in the patient’s home? ■ Has the patient ever had symptoms of asthma after Year's taking any of these medications? ■ Does the patient have contact with other smells or fumes from perfumes, cleaning agents, or sprays? *These questions are examples and do not represent a standardized assessment or diagnostic instrument. The validity and reliability of ■ Have there been recent renovations or painting in the these questions have not been assessed. home? [ www.nhlbi.nih.gov/guidelines/asthma ] Last

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XVII. AAT DEFICIENCY IS A RARE AND NOT PARTICULARLY TREATABLE CAUSE OF COPD (It is exceedingly important to encourage smoking cessation to minimize further loss of lung function, especially in young, symptomatic patients.) Indications of severe-alpha-1-antitrypsin deficiency: Emphysema in a young individual (ie, less than or equal to 45 years) Emphysema in a non-smoker or minimal smoker Emphysema characterized by predominant basilar changes on the chest X-ray A family history of emphysema and/or liver disease, especially unexplained cirrhosis or hepatoma Clinical findings or history of panniculitis Clinical findings or history of unexplained chronic liver disease

XVIII. POLLEN Peak pollen periods in United States Syllabus

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XIX. IMPORTANT ADJUNCT TO MEDICAL THERAPIES FOR ASTHMA IS ENVIRONMENTAL MEASURES Basic measures to control exposure to indoor allergens: Indoor Allergen Recommendations for reducing exposure Animal dander Remove animal from house, or at minimum, keep animal out of patient’s bedroom. Keep pet in a room with a HEPA filter and clean the filter frequently. Cover air ducts that lead to bedroom with filters Use air filters and vacuums with HEPA filters. Clean filters frequently. Dust mites Less costly: Encase mattress, pillows, and box-spring in allergen-impermeable covers. Finely woven covers for pillows plus duvets are preferable. Wash bedding weekly in warm water with detergent or use electric dryer on hot setting Reduce indoor humidity to <50% More costly: Remove carpets from the bedroom Replace old upholstered furniture with leather, vinyl,Syllabus or wood Cockroaches Use poison bait or traps to control. Consult professional exterminator for severe infestation. Periodically clean home thoroughly Secure food and garbage Fix water leaks Indoor Mold Clean moldy surfaces with dilute bleach solution Fix water leaks Reduce humidity to <50 percent. Avoid use of humidifiers. Clean swamp (evaporative) coolers Rodents Consult a professional exterminator Periodically clean home thoroughly Secure food and(2010) garbage Repair holes in walls, doors, floors, and block other entry points

XX. WASHING A. Washing sheets in hot water every week, dust mite encasements for non-washable bedding (like pillows & mattresses), and HEPA or equivalent filtration on your vacuum cleaner can be very helpful. B. Avoidance measures for dust mites: First: Bedrooms Cover pillows and mattresses with zippered covers which are impermeable to mites and allergens.Year's Wash sheets, pillowcases, and blankets in warm water with detergent or dry in an electric dryer on the hot setting weekly; when necessary, blankets should be replaced with those that can be washed. Comforters should be removed. Use washable, vinyl, or roll-type window covers. Remove clutter, soft toys, and upholstered furniture. Where possible, carpets should be removed or replaced with area rugs that can be cleaned/washed. Second: Rest of house Last Reduce upholstered furniture, particularly old sofas. Replace carpets with polished flooring where possible. Carpets on concrete slabs or

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over poorly ventilated crawl spaces are a problem and should be replaced with polished flooring if possible. Vacuum weekly using cleaner with a HEPA filtration system. Window coverings should be washable, vinyl, or roll type. Control humidity to <50 percent relative humidity at normal temperatures, ie. 68 to 72 degrees F. Third: Changing houses In general, allergy sufferers should not be encouraged to move from their home except in those cases where they are living in basements or overtly damp housing. Individuals who are allergic to mites (or molds) should be advised about the potential benefit of moving to an apartment (2nd floor or higher) or a house with 2nd floor bedrooms and wooden floors.

XXI. INHALERS How to use your metered-dose inhaler Using an inhaler seems simple, but most patients do not use it the right way. When you use your inhaler the wrong way, less medicine gets to your lungs. For the next few days, read these steps aloud as you do them or ask someone to read them to you. Ask your doctor, nurse, other health care provider, or pharmacist to check how well you are using your inhaler. Syllabus Use your inhaler in one of the three ways pictured below (A or B are best, but C can be used if you have trouble with A and B). (Your doctor may give you other types of inhalers.) Steps for Using Your Inhaler Getting ready 1. Take off the cap and shake the inhaler. 2. Breathe out all the way. 3. Hold your inhaler the way your doctor said (A, B, or C below). Breathe in slowly 4. As you start breathing in slowly through your mouth, press down on the inhaler one time. (If you use(2010) a holding chamber, first press down on the inhaler. Within5 seconds, begin to breathe in slowly.) 5. Keep breathing in slowly, as deeply as you can. Hold your breath 6. Hold your breath as you count to 10 slowly, if you can. 7. For inhaled quick-relief medicine (short-acting beta2 agonists), wait about 15–30 seconds between puffs. There is no need to wait between puffs for other medicines. A. Hold inhaler 1 to 2 B. Use a spacer/holding C. Put the inhaler in your inches in front of your chamber. These come in mouth. Do not use for mouth (about the width of many shapes and can be steroids. two fingers).Year's useful to any patient.

Clean your inhaler as needed, and know when to replace your inhaler. For instructions, read the Lastpackage insert or talk to your doctor, other health care provider, or pharmacist.

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XXII. FEV1 IS THE BEST SINGLE PREDICTOR OF MORTALITY IN COPD (BUT THIS STAGING OBVIOUSLY IGNORES OTHER PARAMETERS LIKE SMOKING STATUS) Classification of severity of COPD Stage Characteristics FEV1/FVC <70 percent I: Mild COPD FEV1 ≤80 percent predicted FEV1/FVC <70 percent II: Moderate COPD 50 percent ≤FEV1 <80 percent predicted FEV1/FVC <70 percent III: Severe COPD 30 percent ≤FEV1 <50 percent predicted FEV1/FVC <70 percent IV: Very Severe COPD FEV1 <30 percent predicted or FEV1 <50 percent predicted plus chronic respiratory failure FEV1: forced expiratory volume in one second; FVC: forced vital capacity; : arterial partial pressure of oxygen (PaO2) less than 60 mm Hg (8.0 kPa) with or without arterial partial pressure of CO2 (PaCO2) greater than 50 mm Hg (6.7 kPa) while breathing air at sea level. Reproduced from the Global Initiative for ChronicSyllabus Obstructive Pulmonary Disease, Executive Summary: Global Strategy for the Diagnosis, Management, and Prevention of COPD, 2006, www.goldcopd.com (Accessed March 13, 2007).

XXIII. BODE INDEX A. The BODE index is a multi-dimensional predictor of survival with COPD Variables and Point Values Used for the Computation of the Body-Mass Index, Degree of Airflow Obstruction and Dyspnea, a(2010)nd Exercise Capacity (BODE) Index.* Variable Points on BODE scale 0 1 2 3 FEV1 (% of predicted)† ≥65 50–64 36–49 ≤35 Distance walked in 6 min ≥350 250–349 150–249 ≤149 (m) MMRC dyspnea scale ‡ 0-1 2 3 4 Body-mass index § >21 ≤21 * The cutoff values for the assignment of points are shown for each variable. The total possible values range from 0 to 10. FEV 1 denotes forced expiratory volume in one second.Year's † The FEV 1 categories are based on stages identified by the American Thoracic Society. ‡ Scores on the modified Medical Research Council (MMRC) dyspnea scale can range from 0 to 4, with a score of 4 indicating that the patient is too breathless to leave the house or becomes breathless when dressing or undressing. § The values for body-mass index were 0 or 1 because of the inflection point in the inverse relation between survival and body-mass index at a value of 21. Last

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B. BODE prognosis Total 4 year points survival 0-2 80% 3-4 67% 5-6 57% 7-10 18%

XXIV. “STEPWISE” APPROACH TO TREATMENT OF COPD Syllabus

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COPD/ Asthma - Charles Lombard, M.D. HHD221 Spring 2010 Page 117 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

ASSIGNED READING: Robbins pages 717-728.

I. OVERVIEW A. An endstage inflammatory process involving airways and alveoli occurring in older patients nearly all of whom have significant smoking histories. These patients frequently present in clinics with advanced disease characterized by: Clinical > chronic cough, expectoration, dyspnea Physiologic > airflow obstruction (Decreased FEV1, usually <1.24 L) > mostly irreversible by bronchodilatorsSyllabus Pathology > damage to airways and alveoli 1. Note: Chronic obstructive lung disease traditionally includes: a. Chronic bronchitis b. Emphysema c. Asthma d. Bronchiectasis B. However, modern use of this term generally refers to chronic bronchitis and emphysema.(2010) C. Chronic bronchitis and emphysema frequently occur together with overlapping pathology and clinical syndromes. However, it is conceptually useful to think of them in their "pure" forms. II. COPD: EPIDEMIOLOGY A. 15-20 percent of Caucasians who smoke are susceptible B. only 5% of Asians who smoke are susceptible—why??? 1. Dutch hypothesis: airway hyperreactivity diathesis Year's2. English hypothesis: mucus hypersecretion diathesis C. COPD is a growing worldwide problem III. PATHOLOGY OF EMPHYSEMA A. Emphysema - abnormal permanent enlargement of the air spaces distal to the terminal bronchiole accompanied by destruction of their Last walls. 1. Note: Emphysema is defined pathologically.

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B. Subtypes: 1. Centroacinar emphysema - predominant involvement at level of respiratory bronchiole. Upper lobes more severely affected. Strong association with cigarette smoking. 2. Panacinar emphysema - destruction affects respiratory bronchioles and alveolar air spaces uniformly. Bases of lung more severely affected. Most cases associated with Alpha- 1-antitrypsin deficiency. 3. Paraseptal emphysema - predominant Involvement of distal air spaces but gross anatomic location in subpleural locations is most important finding. Occurs in young people. Is not smoking related but is probably a congenital abnormality. May lead to spontaneous but is otherwise physiologically insignificant in most cases. C. Emphysema is best diagnosed grossly in inflated specimens where one can document the enlarged air spaces. MicroscopicallySyllabus one sees enlarged alveoli with thin, attenuated septae. Many of these are avascular and have a minimal degree of fibrosis. It appears as if alveolar septae have been "dissolved away." IV. PATHOGENESIS OF EMPHYSEMA: A. Protease—anti-protease hypothesis 1. unrestrained proto-lytic activity destroys elastin 2. cigarettes recruit neutrophils to lung and activate macrophages 3. cigarettes inside(2010) release of digestive enzymes 4. cigarettes inhibit slashed and activate alpha one antitrypsin B. Inflammation—repair hypothesis 1. initial degradation of lung is followed by repair 2. inflammation and collagen synthesis ensues C. These two mechanisms overlap 1. [ALPHA-1-ANTITRYPSIN DEFICIENCY] a. Alpha-1-antitrypsin (Alpha-1-AT) is an important Year'sproteinase inhibitor which helps protect the lung from autodigestion. There are many different alleles coding for this inhibitor, the most common is PiM. A variant abnormal allele PiZ codes for an ineffective product. Patients homozygous for the allele PiZZ are at great risk to develop severe emphysema. 60-75% of non-smokers and nearly all (95%) smokers are Last afflicted. In addition, they have a much earlier onset of disease, usually at 30-40 years of age. 2-3% of all

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cases of emphysema are associated with this deficiency. V. AIRWAY OBSTRUCTION IN EMPHYSEMA A. Loss of elastic recoil 1. Loss of alveolar attachments correlate with the severity of obstruction 2. Loss of recoil is marked in PLE and uneven in CLE B. Inflammation, fibrosis, and hypertrophy of airway smooth muscle 1. Deforms and narrows airway C. Changes are greater in PLE than CLE D. Emphysema is the most important anatomic association with airflow obstruction in patients with COPD. Syllabus Normal In elastic Emphysema recoil loss of keeps normal recoil airway leads to open airway narrowing

VI. PATHOGENESIS OF EMPHYSEMA(2010)

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VII. CHRONIC BRONCHITIS A. Clinical definition is any patient who has a persistent cough with sputum production for at least 3 months in at least 2 consecutive years. This definition has great limitations in that it includes patients without airflow obstruction. In addition, these symptoms may be present in patients without chronic bronchitis. Most physicians use chronic bronchitis to refer to patients with: 1. Chronic productive cough 2. Obstructive PFTs 3. Appropriate CXR, ABGs B. These patients are almost always heavy smokers. C. Pathologic findings in large airways 1. Hypersecretion of mucus 2. Hypertrophy of bronchial submucosal glands 3. Goblet cell hyperplasia (decreased ciliated cells)Syllabus 4. Chronic inflammation in bronchial walls 5. Squamous metaplasia (decreased ciliated cells) D. In large airways an increased "Reid Ratio” is a good marker for chronic bronchitis.

Bronchial Epithelium RR = A Thickness of glands B bronchial basement submucosal (2010)membrane to glands cartilage surface AB RR (Reid Ratio): cartilage Normal < .35 Indeterminant .35 - .55 Chronic Bronchitis > .55

E. Pathologic alterations in small airways (<3mm) are of most Year'sphysiologic importance in producing airway obstruction. Important pathologic changes include: 1. Goblet cell metaplasia - mucus hypersecretion 2. Chronic inflammation/edema - bronchiolar narrowing 3. Bronchiolar muscular hypertrophy - hyperreactivity Last 4. Decrease in ciliated cells - poor clearance of secretions

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VIII. CHRONIC BRONCHITIS: PATHOGENESIS A. Chronic irritant toxic to airway lining cells 1. cigarette smoke, pollution, other B. Recurrent infection 1. bacterial, viral C. Chronic hypoxia 1. Cor pulmonale 2. Erythrocytosis

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D. Cor pulmonale in Emphysema: 1. Late in course of disease 2. Secondary to extensive destruction of capillary network E. Cor pulmonale in Chronic bronchitis: 1. occurs earlier in course of disease 2. related to chronic hypoxia Year's3. complicated by erythrocytosis F. Symptoms: 1. dyspnea, , peripheral edema G. Hypoxic constriction of pulmonary arteries 1. unique property of pulmonary artery smooth muscle cells Last due to hypoxia-induced inhibition of membrane K+ channel

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IX. TREATMENT OF COPD A. Smoking cessation B. Bronchodilators C. Inhaled steroids D. Pulmonary rehabilitation E. Antimicrobial therapy F. Oxygen therapy G. The natural history of COPD runs a time course of about 30 years in most cases. However, early in the course of the disease, symptoms are mild and are frequently ignored. Patients usually do not present to physicians until they have advanced stages of disease. Once symptomatic, patients suffer a steadily progressive loss of lung function despite medical therapy and cessation of smoking. Syllabus X. CAUSES OF DEATH IN PATIENTS WITH COPD Progressive COPD 40% Cor pulmonale 25% Pneumonia 10% Myocardial infarction 8% Lung cancer 8% Suicide (2010)5% As noted above, chronic bronchitis and emphysema frequently occur together with significant overlapping of both pathologic and clinical findings. Relatively "pure" forms do occur and the following examples will demonstrate characteristic findings for relatively pure chronic bronchitis and emphysematous patients. Year's

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XI. CASE 1: EMPHYSEMA A 67 year old man presented to a pulmonary rehabilitation clinic with the history of about 8 years of progressive, unrelenting dyspnea. Cough was minimal. He denied past histories of chest infections, pedal edema, or the need for phlebotomies. The patient lived a sedentary life and 2 years ago had given up his only sport, golf, because of the excessive dyspnea it caused him. He had smoked 1 - 2 packs of cigarettes per day for 47 years. The patient was thin and dyspneic. His chest was "barrel-shaped" and breath sounds were very faint. Heart sounds were also faint. There was no jugular venous distension, hepatomegaly, or pedal edema. CXR: slender cardiac silhouette, decreased lung markings, flat diaphragms and hyperinflation. ABG: pO2 77; PCO2 40; pH 7.46 HCT: 44% PFT: FVC 2.3 (3.6); FEV1 0.9 (2.8) The patient stopped smoking and was given breathing instructions.Syllabus However, dyspnea progressed and he required home O2 therapy one year later. Six months later he developed increasing dyspnea at rest and mild pedal edema. He improved slightly on diuretics but two months later developed pneumonia and expired. XII. CASE 2: CHRONIC BRONCHITIS 50 year old male presented with 10 year history of productive cough and progressive dyspnea. He began smoking at age 14 and averaged 2 packs per day. His past history was remarkable for repeated bouts of bronchitis, successfully treated with antibiotics. The patient was obese, appeared cyanotic(2010), and had pedal edema. ECG showed right ventricular hypertrophy. CXR showed an enlarged cardiac silhouette, increased bronchovascular markers, and no signs of hyperinflation. ABG: pO2 67; pCO2 50; pH 7.31 HCT: 52% PFT: FVC 2.8 (4.2); FEV1 1.2 (3.1) Treatment: diuretics, salt restriction, bronchodilators, O2 by nasal prongs at night, phlebotomy. Patient improvedYear's for 3 years but then developed pneumonia (successfully treated) and was admitted three times over the next year for acute respiratory failure. The patient's status deteriorated such that he needed continuous low flow oxygen and became dyspneic with minimal physical effort. The patient expired in acute respiratory failure at the age of 54. Last

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XIII. SUMMARY OF CLINICAL DIFFERENCES A. Features of two clinical types of COPD Chronic Bronchitis Emphysema “Blue Bloaters’ “Pink Puffers”

Major Symptom Cough > Dyspnea Dyspnea > Cough

Airflow Obstruction Present Present

Hyperinflation little to moderate moderate to severe

Air/blood interface somewhat abnormal severely abnormal Syllabus cor pulmonale relatively early stage relatively late stage

2° polycythemia moderate to severe none or mild

Respiratory Drive low High

Infections frequent Occasional

TLC increased + (2010)++

RV increased ++ ++

DLCO decreased - ++

pO2 decreased ++ +

pCO2 increasedYear's + Nl

pH decreased + Nl

CXR Increased bronchovascular Hyperinflation Last markings

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A major difference between pure chronic bronchitis and pure emphysema is the "responsiveness" of the respiratory center in the brain stem to hypoxia. The chronic bronchitis patient has an impaired respiratory drive in response to hypoxia. This appears to be an inherited determinant. XIV. ASTHMA A. DEFINITION: 1. Reversible (either spontaneous or with therapy) airway obstruction in patients with hyperreactive airways ("twitchy lungs"). Hyperreactive airways can be detected by the methacholine or histamine inhalation challenge test, but is usually not clinically necessary. B. CLINICAL CLASSIFICATION: 1. Immunologic-IgE mediated (extrinsic) asthma. Acute episodes of bronchoconstriction usually occur in association with a specific agent. Common examples include:Syllabus cats, dogs, pollens, molds, insects, wood dusts, foods (shellfish, fish, soybeans, peanuts, strawberries...). Patients frequently have a personal or family history of allergic disease (, asthma, eczema, hives). Patients usually present in childhood. Be aware that patients with IgE mediated asthma may also suffer exacerbations of their asthma on exposure to the precipitants of asthma in patients with intrinsic asthma (see below). 2. Non-immunologic, intrinsic, cryptogenic asthma. No specific immunologic/allergic(2010) cause identified. IgE level normal, skin test for allergens negative. Symptoms precipitated by: a. non-specific irritants: odors/smells, cigarette smoke, hair spray b. happy or sad emotional events c. exercise/cold air d. viral infections (RSV, parainfluenza, adenovirus, rhinovirus). 3. Most patients present after childhood. Year'sa. Note: Aspirin sensitivity with nasal polyps occurs in 2- 4% of patients with intrinsic asthma. These patients experience asthma, frequently severe, on ingestion of aspirin. They frequently have similar bouts of wheezing with other non-steroidal anti-inflammatory agents and the yellow food dye (tartrazine). Last

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4. More recently a similar sensitivity to the preservative sodium metabisulfite has been described. This is commonly found in fruits, beer, wine and is widely used on vegetables at salad bars. C. Occupational/Industrial Asthma 1. In certain industries asthma is relatively frequent (e.g., isocyanate industry). While it is thought that most cases are idiosyncratic, there is some evidence that implicates a dose- response relationship to the sensitizing agent. Symptoms may be immediate or delayed, and may persist/recur for several days after one exposure (grain dust sensitivity). XV. OF ASTHMA A. Episodic difficult breathing frequently associated with wheezing. Cough, chest tightness are common. Cough may produce tenacious mucus and mucus plugs. With mild obstruction one can appreciate a prolonged expiratory phase of respirationSyllabus on auscultation of the chest. Patients are invariably hyperventilating. As obstruction increases wheezing generally becomes more audible. However, if obstruction is extremely severe and the patient is unable to move much air, wheezing may be inaudible. B. Clinically asthmatic attacks can be divided into immediate phase reactions and late phase reactions. About 50% of asthmatics have late phase reactions. Features of Immediate and Late Phase Asthmatic Responses (2010)

Immediate Phase Late Phase Onset after exposure 15-30 min few-several hours Resolution Few hours several hours-days Response to epinephrine + 0 Response to beta-2 adrenergics + 0 ResponseYear's to steroids 0 + Response to cromolyn + +

XVI. PATHOLOGY OF ASTHMA A. Sputum Cytology 1. Clumps of epithelial cells (Creola Bodies) Last 2. Mucus casts of airways (Curschmann's spirals)

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3. Numerous eosinophils 4. Charcot-Leydig Crystals (clumped crystals of eosinophils) B. Lung Pathology 1. Smooth muscle hypertrophy/hyperplasia 2. Bronchial submucosal gland hyperplasia 3. Goblet cell metaplasia 4. Intraluminal mucus plugs 5. Chronic inflammation and edema with prominent number of eosinophils 6. Thickened basement membrane XVII. PATHOGENESIS OF ASTHMA A. The mast cell is felt by most to be of central importance in the pathogenesis of asthma. In allergic individuals, inhalation of allergens leads to IgE mediated mast cell degranulation.Syllabus Although less well studied, it is apparent that mast cells become activated and degranulate under non-immunologic stimulation such as exposure to cold dry air. There are many mast cell derived mediators of inflammation and they can account for most of the physiologic and morphologic changes associated with asthma. Mediators of the late phase reactions include other inflammatory cells such as eosinophils, neutrophils, basophils, and lymphocytes. XVIII. ASTHMA: EPIDEMIOLOGY A. Personal/family history(2010) of activity B. Genetic risk C. Cigarette smoke exposure D. ? Lack of early exposure to micro-organisms E. Increased incidence of asthma in clean “westernized” areas F. Decreased incidence in rural/farming environment G. Decreased in houses with dogs H. Decreased in younger siblings--Especially those with an older Year'sbrother I. Airway Hyperreactivity 1. Only 25% of sensitizing atopic patients develop asthma (Why???) 2. Airway hyperreactivity is a key feature of persistent asthma in response to specific allergens Last 3. In response to nonspecific stimuli, cold air, exercise, viruses

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XIX. TREATMENT OF ASTHMA A. Relax airway smooth muscle 1. Theophylline, beta 2 adrenergic agents a. Decrease inflammation b. Steroids 2. Block parasympathetic nerve stimulation a. Atropine 3. Stabilize mast cells a. Cromolyn 4. Desensitization immunotherapy 5. New therapies a. Leukotriene synthesis inhibitors and leukotriene receptor antagonists XX. STATUS ASTHMATICUS Syllabus A. , not relieved by the usual treatment (not well defined!). Clinically, patients have decreasing pO2 (usually <50), and increasing pCO2 (>45), with little or no response to maximum bronchodilator therapy at one hour. Frequently they have altered consciousness. 1. Complications: a. Cardiopulmonary arrest b. Pneumothorax/ B. Pathology is similar to asthma,(2010) but more severe. In particular there are numerous thick tenacious mucus casts which plug and obstruct the patient's airways. XXI. PROGNOSIS IN ASTHMA: A. Parents will frequently ask how long asthma will persist in their children. A longitudinal study of children diagnosed with asthma (NEJM 349:1414-22;2003) indicated that by early adulthood: 1. 27 % never reported wheezing (probably never had Year'sasthma) 2. 21 % reported rare bout of transient wheezing 3. 12 % had intermittent childhood wheezing that disappeared in adulthood 4. 15 % had persistent wheezing into adulthood B. Factors associated with persistent asthma: parental history of asthma, young age at onset, history of atopy, cigarette smoking, Last cat/dust mite allergy, female sex.

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XXII. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS A. History of asthma B. Eosinophilia C. Increased IgE titers D. Hypersensitivity to aspergillus E. Fleeting pulmonary infiltrates F. Steroid responsive G. Pathology 1. Mucus impaction in bronchus a. allergic mucus (degenerating eosinophils, Charcot Leyden crystals, scattered fungal organisms) b. Surrounding eosinophil-rich and/ or granulomatous inflammation in lung parenchyma Syllabus c. Bronchiectasis may ensue XXIII. A. Definition: 1. Pulmonary disease characterized pathologically by alveolar filling with histiocytes and large numbers of eosinophils. B. Classification of Pulmonary Eosinophilia 1. CLINICAL SYNDROMES a. Acute Eosinophilic(2010) Pneumonia b. Chronic Eosinophilic Pneumonia (Carrington’s Pneumonia) C. SPECIFIC ETIOLOGIES/DISEASES 1. Infection-related Eosinophilic Pneumonia 2. Drug-related Eosinophilic Pneumonia 3. Allergic Bronchopulmonary Aspergillosis 4. Vasculitis-associated Eosinophilic Pneumonia Year's5. Hypereosinophilic syndrome 6. Miscellaneous (Including Idiopathic Cases) D. Chronic Eosinophilic Pneumonia (idiopathic): 1. Clinical presentation: Females: >80% Dyspnea: 70% Last Fever: 90%

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Weight loss: 60% Night sweats: 70% : 10% Cough: 70% History of asthma 30% 2. Most, but not all, have an allergic history including: asthma, hay fever, drug allergies, atopic skin, etc. 3. Most, but not all, have eosinophilia. 4. Always exclude known associations including parasitic infections, allergic reactions to fungi (especially aspergillus), drugs and chemicals. 5. Pathology: a. Alveoli filled with histiocytes, eosinophils. b. Scattered giant cells, granulomas. Syllabus c. Bronchiolitis ± obliterans. d. Interstitial infiltrate. E. Course/Treatment: 1. Dramatic clinical/radiographic response to steroid therapy. XXIV. DRUG REACTIONS A. Drugs are an increasing cause of interstitial lung disease, both acute and chronic. There are probably two basic reactions, but differentiation between(2010) these two is not always clear-cut. B. Toxic reactions (may be dose related). Many of these reactions represent a which may progress to extensive fibrosis and even honeycombing if the drug is not stopped. Chemotherapeutic agents are often the culprits but this recognition has led to a decrease in the number of iatrogenic deaths due to chemotherapy-induced respiratory failure. C. Hypersensitivity reactions: 1. Eosinophilic pneumonia, allergic alveolitis-like lung disease, Year'sas well as a number of other nonspecific allergic patterns may be produced by drugs. a. *Note: The histologic patterns of disease caused by drugs mimic naturally occurring disease. Therefore, a careful drug history should be taken in all patients and Last the possibility of a drug reaction should be considered.

Allergic/ Sarcoidosis - Charles Lombard, M.D. HHD221 Spring 2010 Page 131 ALLERGIC LUNG DISEASES

ASSIGNED READING: Robbins pages 712-716, 737-741

I. EXTRINSIC ALLERGIC ALVEOLITIS (EAA) A. This term includes a number of diseases defined as pulmonary allergic reactions to inhaled biological dusts/organic antigens. Many of these are occupational diseases in that exposure to the antigen occurs at work. B. COMMON EXAMPLES: ANTIGEN

Farmer's lung Microsporum faeni (in moldy hay) Syllabus

Humidifier lung Thermophilic actinomyces

Bird fancier's lung Pigeon, parakeet, feathers, excrement, serum

Sequoiosis, other wood workers Moldy wood with a variety of fungi II. CLINICAL PRESENTATION (2010) A. Signs and symptoms in Hypersensitivity Pneumonia 1. ACUTE ALLERGIC ALVEOLITIS: a. Symptoms: 1) 2) fever 3) cough 4) shortness of breath Year's5) onset: rapid, 4-12 hrs following exposure b. Lab: 1) CBC: leukocytosis (neutrophils) 2) PE: rales 3) X-ray: patchy alveolar infiltrates 4) Sputum: usually none Last 2. CHRONIC ALLERGIC ALVEOLITIS: a. Symptoms:

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1) malaise 2) weight loss 3) progressive breathlessness 4) onset: variable, usually insidious i. *Note similarity to presentation of other CISLD's Patients may or may not have a history of recurrent acute attacks. History taking should focus on recurrent or chronic exposure to possible sensitizing antigens. (Patients frequently do not make the connection between this exposure and their respiratory symptoms). b. Lab: 1) CBC: normal WBC Syllabus 2) PE: widespread rales 3) X-ray: interstitial fibrosis 4) Lavage: lymphocytosis 5) Physiology: decreased diffusion capacity, restrictive lung disease III. DIAGNOSIS OF EAA A. Demonstration of periodic or continuous exposure to a sensitizing antigen (2010) B. Signs and symptoms compatible with disease C. Appropriate PFTs and pathology D. Evidence of immunologic sensitive station radial immunodiffusion for precipitating antibodies E. Inhalational challenge testing IV. PATHOLOGY OF EAA: A. Year'sCellular bronchiolitis 1. Interstitial pneumonia a. lymphocytes, plasma cells 2. Small noncaseating granulomas 3. Other: a. bronchiolitis obliterans Last b. scattered giant cells

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V. COURSE/TREATMENT A. Acute disease if etiology identified and antigen removed, outcome is usually complete recovery. B. Chronic disease frequently unrecognized and may develop progressive pulmonary fibrosis with respiratory failure. C. In severe disease without excessive fibrosis, steroid therapy leads to dramatic, rapid resolution of illness. D. In farmer's lung following acute episode of hypersensitivity , about one-half will have disabling recurrent pulmonary disease if exposure continues. In this group, 10-15% will expire from respiratory failure. VI. PATHOGENESIS: A. It is likely that both immune complex and cell mediated immunologic hypersensitivity reactions are involved.Syllabus

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Last Allergic/ Sarcoidosis - Charles Lombard, M.D. HHD221 Spring 2010 Page 135 SARCOIDOSIS

ASSIGNED READING: Robbins pages 734-735

I. DEFINITION: A. Sarcoidosis is a systemic granulomatous disease of unknown etiology. II. EPIDEMIOLOGY: A. Young adults - American Blacks, N. Europeans whites. Definite familial aggregations may occur at any age but peaks 30-40 Present most commonly in winter-spring. Incidence in U.S. 10/100,000 (whites); 35/100,000 (blacks). Blacks have more severe disease. III. CLINICAL MANIFESTATIONS: Syllabus A. Nearly universal involvement of the lung. Hilar lymphadenopathy +/- parenchymal infiltrates. B. Any organ may be involved. C. Constitutional symptoms: fever, fatigue, anorexia, weight loss (1/3) IV. SELECTED SITES OF DISEASE: A. Lungs: 1. 50-70% present with dyspnea, cough 2. 20-30% are asymptomatic,(2010) but have an abnormal chest x- ray 3. < 5% have a normal chest x-ray 4. These are 4 radiographic stages of sarcoidosis: a. Bilateral hilar lymphadenopathy (BHL) and no infiltrates b. BHL + interstitial (IS) infiltrates c. IS infiltrates alone Year'sd. honeycomb lung 5. In stage one PFTs are frequently normal. As disease progresses there is decreased DLCO, decreased TLC, decreased pO2 on exercise. Significant functional impairment develops in less than 1/3 of patients. In these there is a progressive decrease in VC, and in severe chronic cases there is resting hypoxemia and a chronic respiratory alkalosis. Diffusing capacity is markedly abnormal. Last Abnormalities of airflow occur late and only in severe cases.

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Endstage is a small, scarred, noncompliant lung, and this occurs in less than 5% of cases. B. Heart: 1. Primary involvement: heart block, arrhythmia, failure 2. Secondary: cor pulmonale C. Gastrointestinal: Hepatic granulomas, isolated increased alkaline phosphatase other - rare D. Genitourinary: Hypercalcemia - nephrocalcinosis other - uncommon E. Ocular: Uveitis + retinopathy (15%) Blurred vision, eye pain, blindness F. Skin: 1. Early: Erythema nodosum, Erythema multiforme -- (good prognosis); Syllabus 2. Chronic: Plaque-like nodules, facial nodules-(progressive disease) G. Nervous System: 1. Peripheral neuropathy: as part of generalized progressive sarcoidosis 2. CNS: cerebrum, cerebellum, brain stem, spinal cord lesions frequently with minimal or no evidence of thoracic/other disease. H. Endocrine: (2010) 1. Hypercalcemia 2. Pituitary - hypopituitarism 3. Hypothalamus - Diabetes Insipidus I. Skeletal: Arthritis, arthralgia; Bone cysts IV. PATHOLOGY: A. Chronic inflammatory reaction characterized by noncaseating epithelioid granulomas. Negative special stain for organisms. Year'sVarious non-specific inclusions: Schaumann bodies, asteroid bodies. In the lung, involvement initially follows lymphatic routes. Inflammation eventually spills over into the alveoli with progressive disease leading to fibrosis and restructuring of lung. Lymph nodes may be focally or completely replaced by granulomas. Despite extensive attempts, no organisms have been cultured and there Last are no consistent serologic abnormalities.

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V. DIAGNOSIS: A. Tissue biopsies demonstrating typical pathology (noncaseating granulomas): 1. open lung 100% 2. mediastinal LN 96% 3. transbronchial 90% 4. liver 70% 5. conjunctival 50% B. Clinical correlation with pathologic findings: 1. Exclusion of other granulomatous disease a. Culture for infectious organisms (TB, Fungi, bacteria) b. Clinical history and c. Radiologic studies C. Positive (reagent generally unavailable)Syllabus VI. PROGNOSIS: A. BHL (75%) : 60-70% --> Resolution to normal (12-18 months) B. BHL + infiltrates (20%) :40%-- > Resolution to normal C. Infiltrates alone (5%) : 20% --> Resolution to normal D. Of those with residual CXR evidence of disease, survival is generally prolonged with variable evidence of progressive lung disease/clinical symptoms. E. Endstage honeycomb lung(2010) develops in small percentage (5%). VII. TREATMENT: A. Most Require No Therapy. B. Steroids for: 1. Pulmonary involvement in: a. Symptomatic patients b. Evidence for active alveolitis Year's1) High angiotensin converting enzyme (ACE) 2) + Gallium scan 3) [These tests are useful for following activity of disease] c. Significant hypoxemia at rest C. Ocular involvement LastD. Cardiac involvement

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E. Neurologic involvement VIII. ETIOLOGY: A. While still unknown, there is increasing evidence that perhaps in some way mycobacterium tuberculosis is in some way associated with the disease. PCR studies have identified TB DNA in about one-half of patients with sarcoidosis. Whether or not this subset of patients would benefit from modern anti-TB therapy is untested. The clinical manifestations of disease in these patients is unlike that of typical TB infection and the significance of the finding of TB-DNA by PCR in these patients remains unclear. There appears to be a component of abnormal immunologic reactivity to this disease as indicated by the favorable response to steroid therapy. Whether this reaction is in response to exposure to a defective TB organism (cell wall deficient) or to another or multiple antigensSyllabus is unknown.

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Pulmonary Mechanics - Norman Rizk, M.D. HHD221 Spring 2010 Page 139 Mechanics of Ventilation / Static Lung Mechanics

Assigned Reading: West, Respiratory Physiology, Chapter 7 A. Normal quiet inspirations is achieved by diaphragm actively descending, accounts for 3-5% of total energy expenditure B. Normal quiet expiration is passive C. During rapid or labored breathing, external intercostals and strap muscles aid inspiration; the internal intercostals and abdominal recti muscles aid expiration. D. During labored breathing and in pathologic states, work of breathing may account for 50% of energy expendituresSyllabus I. MUSCLES OF RESPIRATION MECHANICS A. Muscles of Respiration

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II. DISTENDING PRESSURES OF THE RESPIRATORY STRUCTURES

III. STATIC LUNG INFLATION AND COMPLIANCE A. Pressure that inflates the lung is the pressure acrossSyllabus it, i.e., the difference between alveolar pressure and pleural pressure = “transpulmonary pressure” B. Compliance is a measure of distensibility and is defined as ∆ volume/ ∆ pressure. C. Compliance averages 200 ml per cm of H2O in normal human lungs (without chest wall). IV. PRESSURE-VOLUME CURVE(2010) OF THE EXCISED LUNG

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V. SALINE VS. AIR INFLATION OF THE LUNG

VI. LUNG INFLATION AND COLLAPSE Syllabus A. Distending transpulmonary pressure of the lung is opposed by the tendency of the lung to collapse due to: 1. elastic recoil of tissue elements (1/3 of whole) 2. surface tension (2/3 of the whole) caused by air-liquid interface in alveoli a. surface tension accounts for the difference in pressure required to inflate air-filled vs. saline filled lungs (2010) VII. SURFACE TENSION A. Surface tension is due to intermolecular forces (hydrogen bonds) acting at the air-liquid interface, and is defined as the force acting across an imaginary 1 cm line on a liquid surface. B. Surface tension causes the “rounding up” tendency of water on a waxed (low resistance) surface, and the tendency of soap bubbles to collapse. C. Fluid at an air-liquid interface tends to diminish its surface area in Year'scontact with air because of it.

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VIII. SURFACE TENSION

IX. INTERMOLECULAR FORCES AT THE AIR-WATER INTERFACESyllabus

(2010) X. SURFACE TENSION OF LIQUIDS Air-Liquid Surface Tension of Some Common Liquids Liquid Surface Tension Water 70 Plasma 50-60 Lung surface-active material <5-50 (28 at equilibrium) DetergentYear's solution 30 95% ethanol 22

XI. SURFACE TENSION-EFFECTS ON LUNG A. Increases markedly pressure required to inflate the lung (accounts Last for 2/3 of it).

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B. Causes geometric instability because smaller alveoli, if connected by airways to larger alveoli, tend to empty their gas volume into them. C. Pressure within a sphere generated by surface tension: P= 4T/r XII. SURFACE TENSION IN PLANES AND SPHERES

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XIII. SURFACE TENSION MEASUREMENT

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XIV. SURFACE TENSION OF WATER, SERUM AND LUNG

XV. SURFACTANT PRODUCTION Syllabus

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XVI. SURFACTANT A. Complex mixture of proteins and phospholipids, mainly dipalmitoyl phosphatidylcholine. B. Secreted by type 2 pneumocytes, which are metabolically sensitive Year'sto blood flow. C. Production begins in the third trimester. If deficient at birth because of fetal prematurity, it can be artificially replaced in neonates. D. Concentration of it at surface determines its effect on surface tension. Last

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XVII. CHEST WALL COMPLIANCE AND INTERACTION A. Chest wall has its own compliance characteristics, and is coupled to the lung’s compliance by the vacuum between them, the pleural space. B. Uncoupling the chest wall and lung by disrupting the vacuum causes the lung to collapse and the chest wall to move out, i.e. a pneumothorax. C. Addition of compliance curves of the two structures yields the compliance of the entire respiratory system. XVIII. ADDITION OF CHEST WALL AND LUNG PRESSURE-VOLUME CURVES Syllabus

XIX. PNEUMOTHORAX- UNCOUPLI(2010)NG THE LUNG AND CHEST WALL

XX. ALVEOLARYear's INTERDEPENDENCE A. Another important geometric consideration is the way alveoli are connected via interalveolar septa- they are not just isolated spheres. B. Collapse of one area tends to tether open other adjacent areas. Last

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XXI. ALVEOLAR INTERDEPENDENCE

XXII. PLEURAL PRESSURE GRADIENTS AND REGIONAL VENTILATION A. In upright animal, pleural pressure is more negative at the apex than at the base due to effects of gravity on the lung. B. Non-dependent (apical) regions are more inflated thanSyllabus dependent ones (Ptp= Palv-Ppl). C. Alveoli in dependent regions, although less inflated, are more compliant and receive more ventilation with each breath because of their better compliance. D. Regional differences in ventilation (2010)

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E. Compliance in health and disease

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Last Pulmonary Mechanics - Norman Rizk, M.D. HHD221 Spring 2010 Page 149 MECHANICS OF VENTILATION Dynamic Lung Mechanics

I. PATTERNS OF AIRFLOW IN TUBES

Syllabus

II. TYPES OF AIRFLOW- LAMINAR FLOW A. Laminar airflow is an orderly, uniform, bulk flow that predominates in the lower airways. B. Resistance is directly proportional to gas viscosity (n) and airway length(l) but inversely proportional to the fourth power of radius, i.e. 1. R= 8nl/ π r4 (2010) III. TYPES OF AIRFLOW- TURBULENT FLOW A. Chaotic disorganized bulk flow in larger airways; resistance dependent upon gas flow and density but little affected by viscosity. B. Whether flow is laminar or turbulent may be predicted by Reynold’s number (Re): 1. Re= 2rvd/n C. Where v= velocity, d=density, r=radius, and n=viscosity of gas. Year'sRe>2000 >> turbulent flow IV. OVERALL AIRFLOW A. Because of the mixtures of airflow in the lung, driving pressure is roughly proportional to both flow rate and the square of the flow rate: P =K V+K V2 Last 1 2

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V. CONFIGURATIONS OF REAL AIRWAYS

VI. SITES OF AIRFLOW RESISTANCE Syllabus A. Because turbulent flow causes most airflow resistance, 70-80% of it occurs in upper airway and airways > 2mm in size B. Small airway resistance is less important because of huge number of them (>30K terminal bronchioles) and parallel tube arrangement:

1. 1/R = 1/R1+1/R2+1/R3….1/RN i.e. resistance is added reciprocally VII. SITES OF AIRWAY RESISTANCE(2010)

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VIII. CONDUCTING AND RESPIRATORY ZONES OF THE LUNG

IX. LUNG VOLUME AND AIRWAY RESISTANCE Syllabus A. Airway resistance increases parabolically as lung volume declines, particularly below normal resting lung volume ,i.e. below FRC B. Normal individuals breathing above FRC do very little resistance work, mainly elastic work C. Conductance, the inverse of resistance (1/R), increases linearly with lung volume X. AIRWAY CONDUCTANCE AND(2010) RESISTANCE

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A. Relationship of airway caliber to lung volume- radial traction

XI. LIMITATIONS TO MAXIMAL EXPIRATORY FLOW A. Maximal airflow rates are limited not only by the strength of the driving pressure generated by the individual, but also by the tendency of small airways to be compressed by high pleural pressures. Syllabus B. The higher the pleural pressure generated, the more compression of airways- they cancel each other’s effects on flow! C. Because of this, the force of elastic recoil and the airway resistance of each individual, i.e. intrinsic mechanical properties of the lungs, determine the airflow rate in health and disease-especially at mid- lung volumes. D. Airway and pleural pressures(2010) during quiet expiration.

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E. “Equal pressure point” limitation during forced expiration

F. Equal pressure points in emphysematous lungs- airSyllabus trapping

G. Maximum flow-volume (2010)curves

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H. Flow-volume curves

Syllabus I. Maximal flow-volume curves in obstruction and restriction

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XII. PATHOLOGIC STATES AND LUNG MECHANICS A. Fibrosing diseases increase elastic recoil>> low volume, high flow for volume, large work of breathing. B. Obstructive diseases increase airflow resistance>> low flow, high Year'svolume (air trapping), large work of breathing. C. Dyspnea supervenes before hypoxemia because of the work of breathing!

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Mechanical Ventilation - Norman Rizk, M.D. HHD221 Spring 2010 Page 155 Mechanical Ventilation

Assigned Readings: West, Pulmonary Physiology and Pathophysiology, Chapter 9

I. DEFINITIONS AND INDICATIONS A. Mechanical ventilation is indicated for severe acute respiratory failure. It is useful conceptually to divide respiratory failure into: 1. Ventilatory failure- characterized by elevated pCO2 and acid pH. The elevated pCO2 is due to hypoventilation according to the formula: V a. paCO2= CO2 VA k b. Where paCO2 represents arterial pCO2, VCO2 is CO2 production, VA is alveolar ventilation and k is a constant. Syllabus c. Patients with ventilatory failure are either too weak, too stiff (decreased lung or chest wall compliance), or too obstructed to ventilate themselves adequately. 2. Oxygenation failure- characterized by an abnormal A-a DO2 and arterial hypoxemia due to either V/Q mismatching or shunting. If coexisting ventilatory failure does not exist, the pCO2 is normal or low. Mechanical ventilation can be used to create a closed system for high oxygen concentration administration or to diminish the V/Q mismatching and shunting by further(2010) inflating the lung. II. TYPES OF VENTILATORS A. Pressure cycled ventilators terminate the inspiratory phase when a preset pressure is achieved. The tidal volume is determined indirectly by the patient’s compliance and airway resistance. B. Volume cycled ventilators terminate the inspiratory phase when the preset tidal volume is delivered. The airway pressure is determined indirectly by the patient’s compliance and airway resistance. C. Year's Setting Ventilator Parameters 1. Tidal volumes (Vt) are frequently set at 7-15 ml/kg, higher than the 6-8ml/kg of normal spontaneous breathing. The higher Vt is subjectively more comfortable and helps to prevent microatelectasis that results from monotonous small Vt ventilation. However if Vt are too high, non-dependent parts of the lung may become over-stretched and injured, Last “volutrauma”. Controlled trials in patients with diffuse lung

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injury have shown that lower tidal volumes are associated with increased survival in these patients. 2. Frequency (f) or rate is initially selected based on a clinical estimate of the patient’s overall minute ventilation (f times Vt = minute ventilation) needs to maintain eucapnia. It can then be adjusted after the pCO2 is assayed. 3. Inspiratory to expiratory ratio (I:E ratio) is important to assess. If expiratory time is too short, the patient will not be able to exhale completely before the next breath and will become hyperinflated due to “breath-stacking”. Inspiratory flow rates (Q) influence this. For any given Vt and f, higher inspiratory flow rates will shorten inspiration and lengthen expiration, allowing more time for exhalation. However higher flow rates also cause higher peak inspiratory pressures, promoting barotrauma. III. VENTILATOR MODES USED TO TREAT VENTILATORYSyllabus FAILURE A. Controlled mechanical ventilation. A mode in which a preset tidal volume is delivered at a specified rate, regardless of patient status. This is suitable only for sedated or paralyzed patients, since it is not an interactive mode. B. Assist control ventilation. A mode in which the patient initiates the delivery of each preset tidal volume by inspiring from the ventilator circuit, with a back-up rate set in case the patient fails to breathe. The patient sets (“triggers”) the rate and hence the minute ventilation (VE), but this mode can facilitate hyperventilation if the patient has an abnormally(2010) high drive to breathe. C. Synchronized intermittent mandatory ventilation. The ventilator senses the patient’s respiratory pattern and delivers preset tidal volumes in between normal spontaneous breaths. This is in effect partial mechanical ventilation. It can be used as a graded method to wean the patient from the ventilator, but also can prolong that process, since it requires continually turning down of the ventilator rate. It exercises respiratory muscles during spontaneous breaths but can cause diaphragmatic fatigue, since it is a partial mode of Year'sventilation. D. Pressure support ventilation. The ventilator delivers whatever flow is required to achieve the preset pressure, and gas flow is maintained only as long as the patient continues to inspire. Each breath is triggered by the patient, as in assist control ventilation. The patient can therefore set the f, Vt, Q and VE . At low levels of pressure ventilation, the mode can be used just to overcome the resistance of the endotracheal tube and ventilator circuitry demand Last valves.

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E. Pressure control ventilation. The delivers whatever flow is required to achieve the preset pressure but the rate and duration of the breath is preset. This is not a triggered mode. The patient does not control the Vt or f. This mode is suitable only for anesthetized or sedated patients, since it does not allow patient interaction. IV. VENTILATOR MODES USED TO TREAT OXYGENATION FAILURE A. Positive end-expiratory pressure (PEEP). Acute diffuse lung injuries are usually accompanied by low lung volumes, due to low compliance states. Dependent lung zones tend to be partially or wholly collapsed. PEEP maintains a persistently positive preset airway pressure, even at the end of expiration, to provide a kind of pneumatic stint to inflate the lung and return its lung volume back to a normal level. In so doing, it re-expands collapsed zones and hence diminishes V/Q mismatching and shunting. There are some problems associated with injudicious use of PEEP’s continual application of airway pressure: Syllabus 1. PEEP diminished venous return to the thorax and hence left ventricular filling and cardiac output, due to the positive intrathoracic pressure 2. PEEP also compresses the pulmonary capillary bed, increasing right ventricular afterload, which can cause a intraventricular septal shift and hence less left ventricular filling 3. PEEP can cause so much compression of capillary bed that areas of the lung may not be perfused- this occurs in areas where intraalveolar(2010) pressure exceeds capillary pressure, usually in non-dependent lung zones where hydrostatic capillary pressure is lowest 4. PEEP should only be used in low lung volume states, since overinflation puts patients at a mechanical disadvantage in compliance and in respiratory muscle strength 5. PEEP, by elevating overall airway pressure, predisposes to barotrauma- this is caused by air rupturing into the bronchovascular bundle, tracking back into the , and then either into the pleural space (pneumothorax) or into Year'ssubcutaneous tissues (subcutaneous emphysema). V. DISCONTINUING MECHANICAL VENTILATION A. Patients are ready to be liberated when their ventilatory or oxygenation failure has resolved sufficiently to permit them to breathe spontaneously. Criteria to judge sufficient resolution of respiratory failure have been developed to assist in decision- Last making.

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B. For ventilatory failure, patients should normally: 1. Have a forced vital capacity of at least 12-15 ml/kg, considerably below normal levels of 60-80 ml/kg. 2. Maintain eucapnia or normal pH, with less than 10 liters of minute ventilation, since higher amounts of ventilation represent an onerous respiratory muscle load 3. Be able to generate at least 25 cmH20 subatmospheric pressure on a maximal inspiratory pressure test when inhaling maximally against an aneroid manometer 4. Evidence a spontaneous breathing pattern that is not too rapid or shallow, i.e. breathe in a pattern for which the rate divided by the tidal volume does not exceed ~ 105. This test, the rapid index, correlates best of all of the tests for ventilatory failure with patients who have adequate strength and respiratory mechanics to breathe spontaneously off of a ventilator. Syllabus C. For oxygenation failure, patients should have an adequate paO2 while inspiring less than 45% O2 while on 5 cmH2O or less of PEEP. Higher oxygen or PEEP requirements to maintain oxygenation ordinarily mean the patient is not ready to be removed from the ventilator. VI. CONCLUSIONS Mechanical ventilation is a life-saving therapeutic modality designed to treat ventilatory or oxygenation failure. Ventilatory failure is treated with the form of positive pressure therapy(2010) that mostly closely matches the patient’s needs and physiologic status. Positive pressure ventilation can also diminish the V/Q mismatching and shunting responsible for severe oxygenation defects. A working knowledge of normal and pathologic respiratory physiology is essential in selecting modes of ventilation and setting parameters on mechanical ventilators in order to provide these therapies safely and efficaciously.

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Anti-Fungal Agents – Richard Roth, M.D. HHD221 Spring 2010 Page 159 ANTIFUNGAL AGENTS

Required Reading: Katzung, Chapter 48.

The objective of this lecture is to cover the drugs used for both systemic and topical fungal infections. TOPICS 1. Polyene antibiotics (Nystatin, amphotericin B and amphotericin B in liposomes, candicidin) 2. Azoles (ketoconazole, fluconazole, itraconazole, miconazole, voriconazole, butoconazole, Posaconazole) 3. Echinocandins (caspofungin, micafungin and anidulafungin 4. Allylamines (naftifine, terbinafine, butenafine) 5. Others (flucytosine, haloprogin, ciclopirox, griseofulvin)Syllabus

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Assigned Reading: Katzung, Ch. 20

LEARNING OBJECTIVES: 1. Understand the factors that affect the lung as a drug delivery system 2. Understand the inflammatory and broncho-constrictive aspects of asthma and chronic obstructive pulmonary disease (COPD) and the similarities and differences between the two diseases. 3. Understand the pharmacology of corticosteroids, bronchodilators, and other drugs used to treat asthma and COPD. TOPICS: A. The lung as a drug delivery system Syllabus B. Drugs for asthma C. Drugs for COPD

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Last HHD Lab Instructions HHD221 Spring 2010 Page 163 Lab Instructions The format of each HHD small group session is the same, unless you are notified in advance: 1. The small group session dates are specified in the course schedule, and each lab lasts two hours. 2. The class is divided into 8 rooms in the Fleischmann laboratories, with three small groups in each room, and 3-4 students assigned to each small group. 3. Attendance at small group sessions is mandatory; an absence must come with written permission from the Dean’s office. 4. The small group sessions will consist of presentations by YOU to your fellow students. Syllabus 5. You need to read and think about all three cases, but your small group will only need to prepare a presentation for your assigned case. 6. Make sure all members of your group are involved in the preparation and presentation. Each member of a small group should be prepared to assume any role in the presentation of your case. Instructors will be evaluating your performance. 7. The case histories and related questions are printed in your syllabus. 8. Additional digital photographs for the cases are posted on CWP>HHD>Lab Materials. (2010) 9. Glass slides for the cases are in your white slide boxes in your locker. 10. Group 1 covers Case 1; Group 2 covers Case 2; Group 3 covers Case 3. 11. The lab rooms have LCD projectors/screens, so plan to use PowerPoint to give your presentation. 12. Use the video-microscope in your room to display the histopathology and anyYear's relevant normal histology. 13. A summary handout for your case is appreciated by the other students in your room. The standard is one page, black and white (additional embellishments will not improve your evaluation). 14. Physicians who specialize in the material covered by your cases will be in the lab rooms to provide guidance/discussion during your presentation. Last15. Use of materials from other groups in your class, or any materials from a prior year, is not allowed.

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Last Lung Lab 1 – Faculty HHD221 Spring 2010 Page 165 LUNG LAB 1

CASE 1 A 32-year-old man arrives at the ER at 3 a.m. with dramatically increased difficulty breathing over the last hour, accompanied by feelings of severe chest tightness. He has been treated before for similar episodes.

Physical examination: The patient has difficulty speaking because of rapid breathing, punctuated by coughing. The patient is diaphoretic, but afebrile. Resp. Rate is 20; BP 140/80; Pulse 160 and regular. A pulsus paradoxus of 20 mm Hg is detected, however, the patient is unable to lie down for more than a few seconds because of exacerbation of his dyspnea.

The patient is audibly wheezing. On auscultation of the chest, the breath sounds are acoustically faint. reveals no areasSyllabus of dullness. An ABG showed: pO2 55, pCO2 45, and pH 7.4

QUESTIONS: 1. What is your initial assessment?

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2. How would you manage the patient now?

Year's 3. What is the pathogenesis of this disease?

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4. How is this disease managed chronically and what is the mechanism of action of the medications?

Ten minutes into the patient’s ER visit he reports feeling faint and then begins speaking incoherently. Intubation is attempted, however, the patient suffers a cardiopulmonary arrest. Resuscitation is unsuccessful. 5. What factors are associated with a fatal outcome of this disease? Syllabus

Examine slide #141 6. What are the pathologic features(2010) of this disease? Which do you see on this slide?

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CASE 2 A 62 year old administrator describes a 5 year history of unrelenting dyspnea. She first noted it while playing tennis but did not find it bothersome until recently. She has no significant cough and there is no past history of pneumonia. She has smoked 2 pkg. of cigarettes each day since the age of 18. Physical examination: Remarkably thin, nearly cachectic appearing woman. Enlarged chest with decreased breath sounds and increased tympany on percussion. LABS: CXR [See CWP LungLab1_Case2_CXR; also _CT from similar patient]. observed predicted PFTs: FVC (L) 2.0 3.2 Syllabus FEVl (L) 0.6 2.9 MMEF (L/Sec) 0.2 3.0 ABGs: pH 7.43 pO2 72, pCO2 38 QUESTIONS: 1. What is your clinical diagnosis?

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2. Look at slide #133. Describe the pathologic features.

3. How does this differ from "honeycomb lung?"?

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4. How do you account for the pattern seen in this patient's PFTs?

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5. What would be an etiologic consideration if this patient were only 30 years old?Year's Would the pathology look any different?

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CASE 3: () [SLIDE #136] A 66 year old man was brought to the hospital in late December because of cough, fever, and chest pain. The history revealed that he had the onset of fever, muscle aches, and headache approximately 4 days prior to admission. A dry cough ensued. The day before admission he had chills and the cough became productive with purulent sputum. He also noted dyspnea and pleuritic chest pain.

On admission to the hospital, the vital signs showed BP 110/80 supine, pulse 110, respiratory rate 30, and temperature of 103°F. He appeared to be in moderate respiratory distress.

On physical exam his was supple and there were no signs of meningitis. Exam of the chest revealed coarse rales at the R lung base, and there was a friction rub. Breath sounds were reduced and there was . Syllabus CBC: WBC count 16,000 with 70% PMN, 15% bands. Chest X-Ray: [See CWP LungLab2_Case3_CXR]

QUESTIONS: 1. What is the syndrome the patient had initially (with the fever, sore throat, and headache)? (2010)

2. What is the most likely single clinical diagnosis at the time of admission?

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3. How would your differential diagnosis change if the patient were an infant? If he had a recent bone marrow transplantation for leukemia?

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4. Examine Slide #136 from your Pathology Study Set. Describe your findings (Is the abnormal process centered on any particular structure? Why?

5. What is your anatomic diagnosis?

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6. At what stage of resolution or organization is the abnormal process demonstrated in this slide?

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Control Of Ventilation - Frank Kagawa, M.D. HHD221 Spring 2010 Page 171 CONTROL OF VENTILATION

Assigned Reading: West, Respiratory Physiology, Chapter 8.

LEARNING OBJECTIVES A. Identify the basic components and structures involved in control of ventilation. B. Understand the basic integrated responses to hypoxemia, , acidosis and exercise. I. FUNCTIONS OF THE RESPIRATORY SYSTEM A. Supply O2 / remove CO2 B. Acid-base homeostasis Syllabus C. Speech D. Defecation/micturition II. CONTROL OF VENTILATION The Overview: SENSORS CENTRAL CONTROLLER

EFFECTORS (2010) III. PART 1- THE CENTRAL CONTROLLER MAJOR COMPONENTS: BRAINSTEM Involuntary Control CORTEX Volitional Control LIMBIC/HYPOTHALAMUS Emotional Control

A. The brainstem Year's1. The brainstem is organized into groups of neurons designated “respiratory centers”. a. Medullary Respiratory Center b. Apneustic Center (lower pons) c. Pneumotaxic Center (upper pons) LastB. Medullary Respiratory Center 1. Dorsal respiratory group

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a. Chiefly inspiration, includes possible “pacemaker” area. Activity “ramps” up. Ramp can be prematurely shortened by the pneumotaxic center.

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2. Ventral respiratory group a. Chiefly expiration. Normally not active (expiration is passive), except at high ventilatory levels. (2010)

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C. Apneustic Center Last 1. Apneuses = prolonged inspiratory gasps 2. Located in lower pons

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3. Thought to have an excitatory effect on the inspiratory areas of the medulla in animals, influence in humans is unknown.

D. Pneumotaxic Center 1. Located in upper pons 2. Functions as an “off switch” 3. By shortening inspiration, increases the respiratory rate. 4. Probably fine tunes the respiratory rhythm

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(2010) E. QUESTION The following statements are true regarding the central controller, except which one? 1. DRG function is primarily inspiratory activity 2. VRG function is primarily expiratory activity 3. The apneustic center inhibits the inspiratory activity of the medullary respiratory centers 4. The pneumotaxic center shuts off inspiration and “fine tunes” Year'sthe respiratory rhythm Answer: 3 Last

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IV. PART 2- THE EFFECTORS A. Muscles involved in respiration include: 1. Diaphragm 2. Intercostals 3. Abdominal muscles 4. Accessory muscles B. QUESTION The following statements regarding the effectors are true, except which one? 1. Paradoxical abdominal movement suggests diaphragmatic fatigue or work overload 2. In the quadriplegic patient respiratory mechanics are improved when they are upright 3. Use of accessory muscles suggests that theSyllabus workload is likely to cause respiratory muscle fatigue Answer: 2 V. PART 3- THE SENSORS A. Central Chemoreceptors B. Peripheral Chemoreceptors C. Lung receptors D. Other receptors (2010) VI. CENTRAL CHEMORECEPTORS A. Located near the ventral surface of the medulla B. Responds to changes in CO2 indirectly via effects on [H+] ion concentration of the CSF C. Adaption to chronic hypercapnia occurs due to transport of bicarb across the blood-brain barrier via anion channels Year's

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Central Chemoreceptor region (yellow) Syllabus

Blood brain barrier blocks H+, but not CO2 VII. PERIPHERAL CHEMORECEPTORS(2010) A. AORTIC BODY B. CAROTID BODY 1. Account for all of the hypoxic drive, but only 20% of the hypercapnic drive Year's

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VIII. AORTIC BODY Syllabus A. Located between ascending aorta and pulmonary artery B. Senses pCO2, pO2 (O2 content as well as pO2) C. Transmits via the vagus D. Simultaneous changes in pO2, pCO2 cause an augmented response IX. CAROTID BODIES A. Located at bifurcation of(2010) the common carotid B. Carotid>>Aortic in CNS influence C. Senses pCO2 and pH in addition to pO2 D. Extremely high blood flow keeps pO2 near arterial level E. Hyperbolic response to pO2 F. Simultaneous changes in pO2, pH or pCO2 cause an augmented response Year's

Last Location of the carotid body

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X. QUESTION The following statements about chemoreceptors are true, except which one? 1. The peripheral chemoreceptors account for all of the hypoxic drive, but only 20% of the hypercapnic drive. 2. The carotid body senses pH and pCO2 in addition to pO2. 3. Carotid bodies have less CNS influence than the aortic body. 4. The central chemoreceptor responds to pCO2 via changes in CSF pH. Answer: 2

XI. THE LUNG RECEPTORS A. There are three main types of receptors in the lungs: 1. Irritant receptors Syllabus 2. Stretch receptors 3. J receptors

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(green= irritant, blue=stretch, purple= j) XII. IRRITANTYear's RECEPTORS A. Located near carina and large bronchi B. Rapidly adapting receptors (RAR) C. Responsible for irritant reflexes D. Cough reflex: cough, bronchospasm, mucus production, E. Stimulated by noxious gases, cigarette smoke, inhaled dusts, and Last cold air, as well as mechanical stimuli

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XIII. STRETCH RECEPTORS A. Located in the smooth muscle of bronchi and posterior trachea B. Slowly adapting receptors (SAR) C. Presumed mediators of the Hering-Breuer reflex (Early termination of inspiration by increasing lung volumes) D. Respond to mechanical stimulus (stretch), clinically in humans, VT must exceed 800-1000 cc XIV. J RECEPTORS A. C-fibers (unmyelinated afferents) B. The majority of afferent fibers C. 2 classes: pulmonary “juxta-pulmonary capillary” or J-receptors, and bronchial D. Excited by both chemical and mechanical stimuli - SyllabusHistamine, prostaglandins, bradykinin, serotonin, - vascular distention, increased interstitial fluid E. Stimulation results in rapid shallow breathing, bronchoconstriction and mucus production XV. OTHER RECEPTORS A. Nose and upper airway B. Joint and muscle C. Gamma system (2010) D. Arterial baroreceptors XVI. QUESTION The following are true statements about regarding the lung receptors, except which one? 1. Irritant receptors are known as SAR receptors and are located in the large airways. 2. Stretch receptors are in the smooth muscle of the airways, Year'sand are the presumed mediators of the Hering-Breuer reflex. 3. J receptors are responsible for the rapid shallow breathing seen with CHF and interstitial lung disease. Answer: 1 XVIII. PART 4 - THE INTEGRATED RESPONSE A. Stimuli with clinically important integrated responses include: Last 1. Carbon dioxide

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2. Oxygen 3. pH 4. Exercise XIX. CARBON DIOXIDE A. Linear response B. Primarily due to central chemoreceptors C. Increased by hypoxia due to effects on peripheral chemoreceptors D. Often measured by the Read rebreathing method—usually 2-4 liters per minute per mm pCO2. Varies with age, height, weight, sex. Syllabus

Note: 1) linear response 2) augmentation by low O2 XX. OXYGEN (2010) A. Hyperbolic response B. Much less ventilatory response than pCO2 C. Resulting hyperventilation causes pCO2 to fall, thus decreasing overall response D. Very little role in normal subjects E. Very important in those patients with severe lung disease or normal Year'ssubjects at altitude.

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Note: little effect until PAO2 <60 mmHg XXI. pH A. Mainly due to peripheral chemoreceptor stimulation, but central effects as well B. Less response than to iso pH change with CO2 (HyperventilationSyllabus decreases CO2 which drops central chemoreceptor output) C. Acidosis increases CO2 sensitivity:

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Note the weak response to pH vs CO2 XXII. EXERCISE A. Ventilation increase promptly and can reach very high levels. B. Year's pO2, pCO2, and pH often remain normal through all but the most strenuous exertion. C. Exact mechanism controlling this increase remains unknown. Last

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QUESTION The following statements about the integrated response are true, except which one? 1. The response to CO2 is linear and often measured by rebreathing CO2. 2. The response to O2 is hyperbolic, and may be important in patients with severe lung disease. 3. pH is less potent stimulus than CO2 for an equal change in pH. 4. The ventilatory response to exercise is caused by lactic acidosis. Answer: 4

TAKE HOME POINTS Syllabus A. The central controller, peripheral sensors and effectors form a feedback loop. B. Inspiratory and expiratory control are divided between different groups of neurons. C. Effective respiration requires coordination of multiple groups of effector muscles, not just the diaphragma. D. The hypercapnic (CO2) sensors are mainly central, and hypoxemic (O2) sensors are peripheral. E. Integrated ventilatory responses(2010) are effected by concurrent changes in the level of hypoxemia (O2), hypercapnia (CO2) and pH (H+). The strongest of the integrated ventilatory responses is to hypercapnia.

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Last ARDS - Ann Weinacker, M.D. HHD221 Spring 2010 Page 183 THE ACUTE RESPIRATORY DISTRESS SYNDROME: Physiology and New Management Strategies

Assigned Reading: West, Pulmonary Physiology and Pathophysiology, Chapter 9.

I. INTRODUCTION The acute respiratory distress syndrome (ARDS) has been recognized as a cause of respiratory failure in patients with a variety of illnesses for more than three decades. It has been known by a variety of other names, including the adult respiratory distress syndrome, shock lung,Syllabus capillary leak syndrome, adult hyaline membrane disease, non-cardiogenic pulmonary edema, and diffuse alveolar damage. Clinically, it is characterized by pulmonary edema, refractory hypoxemia, diffuse pulmonary infiltrates, and altered lung compliance. Pathologically, it is distinguished by infiltration of the lungs with inflammatory cells, interstitial and alveolar edema, hyaline membrane formation, and ultimately fibrosis. The exact incidence of ARDS is unknown, but was estimated by the National Institutes of Health in 1972 to be as high as 75 per 100,000 population annually in the United States. Numerous risk factors for the development of ARDS have been identified, and are related to both direct and indirect causes of lung injury.(2010) Direct causes include aspiration, pneumonia, pulmonary contusion, toxic inhalation, and near-drowning. Indirect causes include , shock, severe extrathoracic trauma, multiple fractures, drug overdose, multiple transfusions, and cardiopulmonary bypass. Other indirect causes include eclampsia, burns, disseminated intravascular coagulation, pancreatitis, and air or amniotic fluid emboli. ARDS was first described in a heterogeneous group of patients in 1967, by a surgeon, Dr. Ashbaugh. Since that time, the definition, pathophysiology,Year's and treatment of ARDS have evolved considerably. Ashbaugh described a dozen patients who were dyspneic and tachypneic, and had refractory hypoxemia, decreased lung compliance, and diffuse alveolar infiltrates on chest radiographs. He was the first to recognize that a variety of insults can result in the syndrome he described. For the next two decades, a number of definitions were used to describe the syndrome of acute respiratory distress, making comparison of studies of patients Lastwith ARDS difficult.

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In 1988 John Murray proposed an expanded definition of ARDS to facilitate approaches to studying and treating acute lung injury. The expanded definition addressed the chronicity and severity of the injury, and emphasized the importance of looking for the cause of ARDS. Murray also proposed a four-point lung injury score based on the extent of chest radiographic abnormalities, severity of hypoxemia, lung compliance, and the amount of positive end expiratory pressure (PEEP) employed in mechanically ventilated patients. The severity of hypoxemia was assessed by the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2). This lung injury score is still very useful in defining the severity of ARDS in clinical studies.

In 1994 the American-European Consensus Conference Committee proposed the currently used definition of ARDS, and suggested that the term acute respiratory distress syndrome replace the term adult respiratory distress syndrome, since occurrence of the syndrome is not limited to adults. They described ARDS as a "syndrome of inflammation and increased permeability" and suggested the term acuteSyllabus lung injury (ALI) to describe the continuum of pathologic responses to pulmonary parenchymal injury. The criteria to diagnose both ALI and ARDS included an acute onset, bilateral infiltrates on frontal chest radiographs, and either a pulmonary capillary wedge pressure of ≤ 18 mm Hg or the absence of clinical evidence of elevated left atrial pressure. They defined ARDS as a more severe form of ALI, and proposed that the difference between ALI and ARDS was the degree of disturbance of oxygenation. ALI is defined by a PaO2/FiO2 of ≤ 300 mm Hg (regardless of the level of PEEP), whereas in ARDS the PaO2/FiO(2010)2 is ≤ 200 mm Hg. II. PATHOPHYSIOLOGY A. The forces affecting fluid shifts in the lungs can be explained by the Starling equation:

Qf = K[(Pc - Pi) - σπχ−πι

1. Qf = Net Flow Out Of Capillary

2. Kf = Capillary Filtration Coefficient

3. Pc = Capillary Hydrostatic Pressure Year's4. Pi = Interstitial Hydrostatic Pressure 5. σ = Reflection Coefficient

6. πC = Capillary Oncotic Pressure

7. πI = Interstitial Oncotic Pressure Last

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B. An imbalance in these forces may result in pulmonary edema. (See table, below.) Pulmonary edema can be due to cardiac causes (cardiogenic) or noncardiac causes (non-cardiogenic). Cardiogenic pulmonary edema is the result of increased hydrostatic pressure, which occurs when there is failure of the left ventricle. Non-cardiogenic pulmonary edema, such as ARDS, is the result of injury to the alveolar capillaries and the alveolar epithelium. Pulmonary capillary hydrostatic pressure is not typically elevated in non-cardiogenic pulmonary edema. Factors predisposing to pulmonary edema Increased capillary permeability ARDS Oxygen toxicity Toxins (inhaled, circulating) Increased capillary permeability Increased left atrial pressure Myocardial infarction Syllabus Mitral stenosis Fluid overload Pulmonary veno-occlusive disease Decreased interstitial Rapid removal of pleural fluid or air hydrostatic pressure Decreased alveolar surfactant Decreased capillary oncotic Dilution of blood proteins pressure Crystalloid(2010) IV solutions Protein loss

C. The normal alveolus (left side) and the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome (right side). Year's

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1. In the acute phase(2010) of the syndrome (right side), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting cytokines, interleukin-1, 6, 8, and 10, (IL-1, 6, 8, and 10) and tumor necrosis factor (alpha) (TNF-(alpha)), which act locally to stimulate Year'schemotaxis and activate neutrophils. Macrophages also secrete other cytokines, including interleukin-1, 6, and 10. Interleukin-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of antiinflammatory mediators are also present in the Last alveolar milieu, including interleukin-1-receptor antagonist, soluble tumor necrosis factor receptor, autoantibodies

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against interleukin-8, and cytokines such as interleukin-10 and 11 (not shown). The influx of protein-rich edema fluid into the alveolus has led to the inactivation of surfactant. MIF denotes macrophage inhibitory factor. From Ware LB, Matthay MA. 2000. The acute respiratory distress syndrome. New England Journal of Medicine 342: 1334-49. Used with permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. D. Clinically, ARDS is classically described as comprising four phases, although in an individual patient the progression through distinct phases is difficult to recognize. The first phase occurs at the time of acute injury. The only derangement that may be seen during the phase of acute injury is the development of respiratory alkalosis. The acute phase is followed by a latent period that may last from several hours to 2 days, during which there is gradual development of patchy, ill-defined radiographic infiltrates and the physical examination finding of fine rales. The chest radiographicSyllabus picture in the acute phase is often similar to that of cardiogenic pulmonary edema, except that the heart size is usually normal and the infiltrates tend to be more peripheral in ARDS. E. Following the latent period, acute respiratory failure develops, with progressive dyspnea, tachypnea, hypoxemia, and decreasing lung compliance. The physical examination worsens, and diffuse rales are apparent. Chest radiographic abnormalities become progressively more pronounced, and patchy infiltrates coalesce. Air bronchograms are often apparent in diffuse air-space consolidation. Pleural (2010)effusions in simple ARDS are relatively uncommon, and suggest additional pathology. F. The final clinical phase of ARDS is characterized by "severe physiologic abnormalities" including intrapulmonary shunting leading to refractory hypoxemia, and concomitant metabolic and respiratory acidosis. Chest radiographic infiltrates begin to take on a more reticular pattern that may represent the beginnings of fibrosis. G. Pathologically, three stages that roughly correlate with the clinical phases are described. The pathologic changes seen throughout Year'sthe three stages constitute a pattern of injury called diffuse alveolar damage. During the initial exudative stage, there is engorgement of pulmonary microvasculature and perturbed pulmonary endothelial and epithelial permeability. Protein-rich edema fluid leaks into the interstitium and into the alveoli themselves. Surfactant abnormalities lead to increased surface tension within the alveoli and cause atelectasis, particularly in dependent regions Last of the lung. The lungs appear hemorrhagic, and there is an influx of neutrophils and monocytes into the interstitium.

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H. The neutrophils in the lungs are both responders to the inflammatory process, and contributors to it. They are recruited into the interstitium in response to cellular adhesion molecules including selectins and beta-2 integrins, and are activated by complement and a variety of cytokines, including tumor necrosis factor (TNF) alpha, and interleukins (IL)-1, 6, 8, and 10. Once activated, they themselves begin to elaborate a variety of cytokines and other inflammatory mediators. Although neutrophils appear to play a large role in the inflammatory process in ARDS, they are not crucial for the development of acute lung injury, as evidenced by the fact that neutropenic patients can develop ARDS. I. Alveolar macrophages also play a role in ARDS, elaborating cytokines that contribute to the inflammatory response, but also by clearing senescent neutrophils and red blood cells from the alveoli. In fact, macrophages appear to be important in the resolution of ARDS, and an increased number of macrophages recovered in bronchoalveolar lavage fluid has been associated withSyllabus improved survival. J. During the exudative phase of ARDS, type II alveolar pneumocytes become hyperplastic. Type I pneumocytes that comprise the normal alveolar epithelium slough, denuding the basement membrane, and plasma proteins and fibrin accumulate on the denuded basement membrane to form hyaline membranes. K. Concomitant with these airway changes, platelet aggregation and fibrin-rich microthrombi formation within the vasculature cause increased pulmonary vascular resistance and pulmonary hypertension. Hypoxic(2010) pulmonary vasoconstriction and endogenous vasoconstrictors also contribute to the development of pulmonary hypertension in patients with ARDS. L. After approximately three to ten days the fibroproliferative or organizing stage begins, characterized by infiltration of the interstitium with fibroblasts and continued exuberant infiltration with inflammatory cells. Type II pneumocytes proliferate and replace the type I pneumocytes on the denuded basement membrane. Hyaline membranes are no longer formed in the organizing stage, but fibroblasts begin to deposit collagen, thickening the alveolar Year'swalls. Macrophages phagocytose the hyaline membranes and other cellular debris. Following the fibroproliferative stage, the final stage of ARDS is manifest by fibrosis, scarring and cyst formation. Throughout the three stages of ARDS, involvement of the lungs is inhomogeneous, with some areas of the lungs relatively spared Last while others are profoundly disturbed.

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M. For reasons that may have to do with causative factors, patient factors, or both, not all patients progress through all of these stages. Many of the treatment approaches have therefore been directed at preventing this progression from the acute phase to fibro-proliferation and scarring. III. TREATMENT STRATEGIES A. Lung protective mechanical ventilation 1. Mechanical ventilation is the central supportive intervention in the management of ARDS. The traditional approach to ARDS ventilation is rooted in the management of the postoperative patient and aims at normalizing arterial blood gases and pH. This has traditionally been achieved by ventilating with high tidal volumes (10 - 15 ml/kg). However, in the face of inhomogeneously decreased pulmonary compliance and extensive shunt physiology, large tidal volumes are associated with high peak inspiratorySyllabus airway pressures and may be harmful to lungs profoundly disturbed by ARDS. 2. Indeed, animal studies have shown that high tidal volume ventilation releases inflammatory mediators and disrupts pulmonary alveolar epithelium and endothelium, leading to acute lung injury with hyaline membrane formation. In humans, plasma concentrations of key pro-inflammatory cytokines TNF-alpha, IL-6 and IL-8 increase over time and severe damage to small bronchioles occurs in most acute lung injury patients(2010) treated with conventional, high tidal volume ventilation. 3. Lung damage is not caused by high peak inspiratory pressure alone, however, but rather by stretching of the alveoli between the end-expiratory and end-inspiratory trans- alveolar pressures. Hence the term "volutrauma" has been suggested as a more appropriate term than "barotrauma" to describe the alveolar over-stretching. In poorly compliant lungs, intense shearing forces develop in the alveolar walls as a result of the high pressures required to separate the Year'scollapsed walls of small airways and alveoli during each inspiration. The compound effect of cyclic shearing and over-stretching is local injury and subsequent local and systemic inflammatory response. Thus, the paradigm of ventilator management of ALI/ARDS has thus recently shifted towards "lung protective" ventilation strategies. Last

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4. A recent large ARDSNet trial compared traditional mechanical ventilation with ventilation at a lower tidal volume. Conventional ventilation used an initial tidal volume of 12 ml/kg with a plateau pressure of 50 cm H2O or less. Patients who were ventilated with the low tidal volume strategy received an initial tidal volume of 6 ml/kg and a plateau pressure of 30 cm H2O or less. The trial was stopped after the enrollment of 861 patients because mortality was 22% lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0% vs. 39.8%). This was the first study to convincingly demonstrate a survival advantage with a proposed treatment strategy for ARDS, and has significantly altered practice patterns in caring for ARDS patients. 5. Maneuvers that recruit collapsed alveoli can be used to complement the protective ventilation strategy. Periodic sustained inflation of the lungs using a pressureSyllabus of 30 to 45 cm H2O for 20 seconds improved oxygenation in a recent study of 14 patients with ARDS. Changing body position from supine to lateral decubitus or prone has been called the "ultimate recruitment maneuver" and can improve oxygenation through several possible mechanisms. Functional residual capacity is increased and blood flow and ventilation are redistributed, thereby improving the mismatch between ventilation and perfusion in ARDS. Prone positioning shifts the weight of the heart from the dorsal lung regions to the sternum and anterior rib cage, thus decreasing compressive(2010) atelectasis. Prone positioning is not always successful in improving oxygenation, however, and response rates are extremely variable. 6. An additional lung protective strategy is inverse ratio ventilation, in which the usual ratio of inspiratory time to expiratory time is reversed. The goal of inverse ratio ventilation is to improve oxygenation, but it may take several hours to achieve the maximal benefits. Inverse ratio ventilation is an uncomfortable mode of ventilation, and usually mandates the use of neuromuscular blocking agents Year'sand the liberal use of sedatives. It is another tool in the armamentarium to treat patients with ARDS and refractory hypoxemia, but has not been shown to improve survival. B. Nitric oxide 1. Inhaled nitric oxide is a potent vasodilator that reduces pulmonary artery pressure and in high doses reverses Last hypoxic pulmonary vasoconstriction without causing systemic hypotension. It is a very lipophilic gas that rapidly

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diffuses across endothelial cells in ventilated lung units to the smooth muscle cells of the pulmonary vasculature. In smooth muscle cells it activates the enzyme guanylate cyclase, which then produces cyclic guanosine 3',5'- monophosphate (cGMP). Cyclic GMP in turn mediates vascular smooth muscle relaxation. Nitric oxide is quickly inactivated when it reacts with hemoglobin in the intravascular space to form methemoglobin, and thus does not exert vasodilating effects systemically. 2. Nitric oxide has other beneficial effects, including inhibition of platelet aggregation and leukocyte adhesion, and possible antiinflammatory effects. In spite of its beneficial effects, however, three large multicenter studies of the use of nitric oxide in ARDS have shown no survival benefit. Potential dangers of the use of nitric oxide include the development of methemoglobinemia, and the production of nitrogen dioxide and the peroxy-nitrite ion, two toxic nitrogenSyllabus oxides. C. Corticosteroids 1. Inflammatory dysregulation is a major feature of ARDS, and it is intuitively appealing to use anti-inflammatory agents (particularly corticosteroids) to limit the acute manifestations and the long-term sequelae of ARDS. Even since the earliest descriptions of ARDS, investigators have felt that corticosteroids would be beneficial in the treatment of the syndrome. However, short courses of high-dose corticosteroid therapy administered early in the course of disease to patients(2010) at risk for ARDS have been ineffective in preventing ARDS. Attempts to improve survival by administering steroids in the early stages of ARDS have also been unsuccessful. 2. Recent trials have been directed at treating the later, fibrosing phase of ARDS. A randomized, double-blind, placebo-controlled study of methylprednisolone was undertaken in 24 patients whose ARDS was not resolving one week after the onset of respiratory failure. Patients who did not respond by day 10 of the study were blindly crossed Year'sover into the alternative treatment group. This study demonstrated improvement in lung injury and organ dysfunction scores and a marked reduction in mortality (12% vs 62%) in the methylprednisolone recipients when compared to the placebo group. This small study is often used as the basis for corticosteroid use in the treatment of Last unrelenting ARDS.

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3. Although the use of corticosteroids remains theoretically very attractive, currently available data do not convincingly support the efficacy and safety of their use in persistent ARDS. However, a large multicenter ARDSNet trial of high dose corticosteroids in late ARDS is currently underway to address this issue again. Future research will also need to identify the patient subgroup(s) most likely to benefit from corticosteroids, and the optimal timing and duration of the intervention. IV. OTHER THERAPIES AND FUTURE DIRECTIONS A. Many other therapeutic interventions have been investigated in the treatment of ARDS. Partial liquid ventilation is an experimental ventilation technique that utilizes perfluorocarbons to maintain open lung units and improve oxygenation. It has been evaluated in animal and human studies, but there are not sufficient data available to draw conclusions as to the utility of thisSyllabus modality. B. Ketoconazole is an imidazole antifungal agent with antiinflammatory properties that has recently been studied in an ARDSNet trial to determine its effect in reducing morbidity or mortality from ARDS. Two hundred and thirty-four patients with ARDS or ALI were randomized to receive a three week course of ketoconazole or placebo within 36 hours of meeting study criteria. There were no differences in mortality, pulmonary physiology, ventilator-free days, or organ failure-free days between the two treatment groups. C. Exogenous surfactant replacemen(2010)t therapy, delivered as an aerosol or instilled through an endotracheal tube is an attractive treatment option in ARDS, and has been shown to be safe. However, a large clinical trial was unable to demonstrate the efficacy of this treatment. Studies of surfactant replacement therapies are ongoing, however. D. Fluid management has long been controversial in the treatment of ARDS. Many believe that restricting fluids improves the pulmonary edema and gas exchange in patients with ARDS, and use pulmonary artery catheters to help guide fluid management. A Year'srecent ARDSNet study investigated liberal versus conservative fluid therapy, and the utility of pulmonary artery catheters versus central venous catheters in guiding fluid therapy. The results of that study support the use of a conservative strategy of fluid management in patients with acute lung injury, although there was no significant difference in the primary outcome of 60-day mortality. The conservative strategy of fluid management did, however, improve lung function and shorten the duration of mechanical ventilation and Last intensive care without increasing other organ failures.

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E. In addition to these individual treatment strategies, various investigators are combining strategies such as proning and nitric oxide or liquid ventilation and surfactant replacement. The results of large trials of these therapies will be interesting, and will hopefully guide our therapy in the future. V. OUTCOMES A. Although the overall mortality due to ARDS has declined in the past two decades, mortality remains high. Most investigators report mortality rates between 40 and 68 percent. Sepsis and multiple organ system failure are the most common causes of death. Unrelenting respiratory failure is the cause of death in a minority of patients with ARDS. Survival is associated with age, comorbidities, and severity of underlying illness. B. In most patients who survive ARDS, there is some decrement in lung function, although many recover completely. However, a number of recent studies have shown that health-relatedSyllabus quality of life is severely compromised in survivors of ARDS. Many patients report cough and dyspnea, and altered physical function after hospital discharge. One to two years after the onset of ARDS, survivors have significantly altered quality of life, comparable to patients with chronic illnesses. Cognitive function and affect may be impaired in almost 80% even one year after hospital discharge. VI. CONCLUSION ARDS is a syndrome of inflammation and increased pulmonary vascular permeability that results in pulm(2010)onary edema, refractory hypoxemia and damage to lung parenchyma. In part because of the heterogeneity of patients with ARDS, strategies designed to reduce inflammation and lung injury have been disappointing on the whole. Lung protective ventilation with low tidal volumes appears to offer a distinct survival advantage. Multicenter ARDSNet trials may give us more insight into effective treatments for ARDS in the future.

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Last Respiratory Distress Syndrome - Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 195 Respiratory Distress Syndrome Pathology

I. ACUTE RESPIRATORY DISTRESS SYNDROME: A CLINICAL SYNDROME A. Acute onset of respiratory failure B. Bilateral diffuse infiltrates on CXR C. Severe hypoxia (PaO2/FiO2 <200) D. Non-hemodynamic mechanism (normal PCWP and oncotic pressure II. DIFFUSE ALVEOLAR DAMAGE: THE PATHOLOGY UNDERLYING ARDS A. Due to diffuse acute lung insult Syllabus B. Injury of alveolar epithelium or capillary endothelium affects fragile permeability barrier C. DAD Site of Injury: Alveolar endothelial/epithelial interface

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Respiratory Distress Syndrome - Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 196

Syllabus III. ARDS: PATHOGENESIS A. Endothelial injury with increased vascular permeability B. Epithelial injury (alveolar lining cells) 1. Loss of barrier to fluid 2. Disrupts normal epithelial fluid transport 3. Reduces surfactant turnover/production 4. Increased risk of septic shock 5. Disorganized repair(2010) may lead to fibrosis

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Respiratory Distress Syndrome - Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 197

C. Etiologies of the Adult Respiratory Distress Syndrome 1. Pneumonia a. b. SARS c. Hanta virus d. Other 2. Sepsis 3. Aspiration of gastric contents 4. Inhalational injury a. Smoke, toxic gases b. High Fi02 5. Drug/Toxin-associated 6. Shock 7. Trauma Syllabus 8. Emboli a. Fat b. Diffuse thromboemboli 9. Near drowning 10. Acute pancreatitis 11. Radiation 12. Idiopathic (Acute Interstitial Pneumonia) IV. ARDS: PHASES OF EVOLUTION(2010) A. Phases Overview 1. Exudative phase a. Begins within 1st 24 hours of insult b. Last through 1st week 2. Proliferative phase: Begins around day 7 3. Fibrotic phase (variable) :Begins around day 10 4. Recovery phase: Weeks to months B. Year'sExudative phase (1st week) 1. Lungs are heavy and feel consolidated 2. Epithelial and endothelial damage 3. Fibrin rich edema fluid, hemorrhage 4. Hyaline membrane formation 5. Inconspicuous inflammation: Few scattered neutrophils LastC. Proliferative phase (begins around day 7) 1. Proliferation of type II alveolar lining cells

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2. Interstitial fibroblastic proliferation 3. Airspace fibroblastic proliferation 4. Organization of hyaline membranes 5. Clearing of alveolar debris D. Fibrotic phase (begins around day 10) 1. “Fibrosis” is predominantly cellular fibroblasts but with some increase in collagen. 2. Lung is markedly and abnormally restructured 3. But in most cases, this does not appear permanent E. Recovery phase 1. The pathology is surprisingly reversible. 2. If patients survive ARDS, they have remarkably good respiratory function by 6 months 3. Severity of initial ALI and the rapidity of its resolutionSyllabus correlate with long term outcome 4. Only a few develop progressive fibrosis (see Interstitial lung disease lecture) V. NEONATAL RESPIRATORY DISTRESS SYNDROME, AKA: HYALINE MEMBRANE DISEASE A. Definition: 1. Respiratory distress in a newborn infant within the first few hours of life 2. Due to a deficiency(2010) in Pulmonary surfactant B. Neonatal RDS 1. 60-70,000 cases annually 2. Increasing incidence 3. Incidence depends on gestational age of infant at birth a. < 28 weeks : 80 % risk b. > 39 weeks : < 1 % risk C. Year's Pathophysiology of Neonatal RDS 1. Surfactant Deficiency 2. Predisposes to collapse of alveoli 3. Surface tension without SF: 72 dynes/cm 4. Surface tension with SF: 25 dynes/cm D. Risk Factors for Neonatal RDS Last 1. Prematurity 2. Increased M:F ratio both in incidence and severity

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3. Cesarean section delivery 4. Maternal Diabetes E. Prenatal detection of risk for Neonatal RDS 1. Lecithin/Sphingomyelin ratio (L/S ratio): Ratio > 2 indicates lung maturity 2. Presence of Phosphatidylglycerol (PG): Presence of PG indicates lung maturity F. Clinical Manifestations 1. Tachypnea, chest wall retraction, expiratory grunting, 2. Hypoxia and hypercarbia 3. Diffuse infiltrates on CXR G. Pathology of nRDS 1. Gross: Heavy, dark, consolidated lungs Syllabus 2. Microscopic: Hyaline membranes form within 3 hours H. Complications of neonatal RDS 1. Acute: a. Interstitial emphysema (air dissection): Pneumothorax, pneumomediastinum, etc. b. Superimposed pneumonia 2. Chronic: Bronchopulmonary dysplasia 3. Prematurity (2010) a. Intraventricular hemorrhage b. PDA with CHF c. Retinopathy VI. BRONCHOPULMONARY DYSPLASIA: CHRONIC LUNG DISEASE OF INFANCY A. Remodeling and long-term damage to the premature lung due to high ventilatory pressures and high FiO2 being given to lungs with low surfactant levels. B. Year's “Classic” BPD findings: 1. Atelectasis 2. Squamous metaplasia 3. Alveolar epithelial cell hyperplasia 4. Interstitial fibrosis Last 5. Airway smooth muscle hypertrophy 6. Pulmonary vascular hypertensive change

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C. “New” Bronchopulmonary Dysplasia” (Gentler ventilation with surfactant) 1. Decreased alveolarization of lung 2. Less interstitial fibrosis 3. Less pulmonary hypertensive change 4. Less epithelial airway disease 5. Prominent airway hyperreactivity 6. Long term consequences not fully defined.

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Interstitial Lung Disease – Paul Mohabir, M.D. HHD221 Spring 2010 Page 201 SURFACTANT/ INTERSTITIAL LUNG DISEASE

Assigned Reading: West, Pulmonary Physiology and Pathophysiology, Chapter 5.

I. DEFINITION: Diverse group of lung diseases of lower marked by lung infiltration of the interstitium and disruptions of alveolar structures. A. Alveolar wall: 1. Normally contains scant macrophages, fibroblasts and few myofibroblasts (fibroblasts with muscle-like phenotype, i.e., contractile and motile). B. In Interstitial Lung Disease (ILD): Syllabus 1. Alveolar wall anatomically altered: a. Inflammatory cell infiltrate b. Hyperplastic alveolar epithelial cells c. Proliferating myofibroblasts 1) disordered collagen deposition and fibrotic scar C. Pathologic changes reflect final common pathway after diverse insults 1. Because lung has(2010) only a limited repertoire of repair after injury- heal with scar instead of resolution D. Incidence (per Schwartz, "ILD"): 100,000 admissions / year 1. 30-40 cases per 100,000 II. WHAT IS INTERSTITIUM? A. Normal Alveolus: 1. 300 x 106 alveoli in normal lung Year's2. Grape-like structures, branching off terminal bronchioles 3. Walls are 5-10 microns thick B. Lined with alveolar epithelial cells: 1. Type I: pancake-like, delicate, cover 90% area 2. Type II: secrete surfactant: a. lowers surface tension, prevents collapse (atelectasis) Last b. host defense (opsonization)

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C. Epithelial cells attached to Basement Membrane D. Capillary endothelial cells: line capillary network around alveoli E. Endothelial cells attached to Basement Membrane F. Basement membranes fused together = Sites of Gas Exchange G. Interstitium: 1. A thin layer between basement membranes 2. Normally contains scant fibroblasts, connective tissue (collagens) 3. Alveolar Macrophages III. CHARACTERISTICS OF INTERSTITIAL LUNG DISEASE A. INTERSTITIUM becomes thickened: 1. With edema fluid 2. cellular infiltrate Syllabus 3. increased connective tissue B. ALVEOLI can also be involved: 1. Alveolar infiltrates 2. Cellular (e.g. DIP, Eosinophilic Pneumonia) 3. Hemorrhagic (Alveolar Hemorrhage, Goodpasture's, Vasculitides, diffuse alveolar hemorrhage, eg, bone marrow transplant recipients) 4. Pulmonary Alveolar(2010) Proteinosis IV. ILD PATHOGENESIS: INFLAMMATION AND REPAIR A. INFLAMMATION: ALVEOLITIS 1. Initiated by injury to alveolar lining epithelium (Type I and Type II cells) 2. Exposure of basement membrane 3. Immune Effector Cells: 4. Normally 80 cells per alveolus: Year'sa. 90% Macrophages, 10% lymphs < 1% neutrophils b. Normally, resting, non-activated, No cytokine production B. ALVEOLITIS: 1. Marked increase in number of effector cells Last 2. Recruitment to lung, and local proliferation

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C. FILL INTERSTITIUM AND ENTER ALVEOLI 1. Marked alteration in proportions of effector cells: a. Idiopathic Pulmonary Fibrosis (IPF) 1) PMNs, T-cells and Macrophages b. Sarcoidosis: T-cells, CD4 helper and Macrophages c. Hypersensitivity Pneumonitis: T-cells, CD8 d. Eosinophilic Granuloma: Langerhans cells and macrophages 2. Effector cells are activated: Secreting cytokines and growth factors which enhance fibrogenesis. D. NEUTROPHILS CAUSE MOST DAMAGE DURING ACUTE INJURY 1. Reactive oxygen metabolites, and proteases V. ILD PATHOGENESIS: INFLAMMATION AND REPAIRSyllabus A. DYSREGULATED REPAIR LEADS TO FIBROSIS 1. Alveoli have limited capacity to repair 2. Type I epithelial cells are replaced by dedifferentiated Type II cells 3. If severe denudation of Type I cells, a. then bronchiolar epithelium migrates in replacing type I cells and disrupting gas exchange B. EPITHELIAL RE-POPULATION DEPENDS UPON INTACT BASEMENT MEMBRANE(2010) 1. If very damaged, then no surface for epithelial migration 2. reconstruction is impossible but persistent damage and/or inadequate repair leads to scarring C. FIBROSIS FOLLOWS 1. Increased number of myofibroblasts producing collagen 2. Disordered collagen deposition 3. Alveolar wall function damaged Year's4. Stiff, non-compliant lungs (restriction on PFTs) 5. Fibroblasts controlled by alveolar macrophages a. Secreting PDGF, TGF-β, fibronectin VI. DIFFUSE ALVEOLAR DAMAGE (DAD) A. Pathologic lesion occurring in Adult Respiratory Distress Syndrome Last (ARDS)

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B. Causes: Infection (Sepsis) / Toxic inhalation (oxygen) / Circulating Toxins/Radiation C. Acute or Exudative Stage: (1st week) 1. Edema 2. Hyaline Membranes 3. Cellular infiltrate (neutrophils, then lymphs, macrophages) D. Proliferative or Organizing Stage: (after 7 days) 1. Fibroblast proliferation, dramatic 2. Type II cell hyperplasia and atypia E. Rule out infectious causes of DAD (e.g. , Cytomegalovirus) F. ACUTE INTERSTITIAL PNEUMONITIS (Hamman-Rich syndrome) 1. Fulminant progressive respiratory failure over weeks 2. Clinically like ARDS, but without obvious causeSyllabus 3. Pathologically like organizing DAD a. Mural incorporation: Type II cells proliferate on top of alveolar exudates, causing septal thickening VII. CHRONIC INTERSTITIAL PNEUMONITIS A. Idiopathic Pulmonary Fibrosis (UIP) 1. Definition: chronic fibrosing interstitial pneumonia associated with the histologic appearance of usual interstitial pneumonia (UIP)(2010) on surgical lung biopsy. 2. Major criteria: a. exclusion of drug toxicities, environmental exposures, connective tissue diseases b. Abnormal PFTs with restrictive pattern, decreased diffusion c. Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT 3. Minor Criteria: Year'sa. age over 50 b. insidious onset of dyspnea on exertion c. illness over 3 months d. bibasilar dry crackles B. Etiology: Unknown LastC. Epidemiology 1. 30-40/100,000

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2. 40-70 yr. old; males > females D. Risk Factors ? 1. cigarette smoking 2. chronic aspiration 3. environmental 4. infectious agents 5. genetic predisposition, 5% of IPF is familial with autosomal dominant pattern of inheritance E. Diagnosis 1. History: insidious onset dry cough, SOB (rapid, shallow breathing pattern), clubbing, weight loss, malaise, fatigue 2. Laboratory: may have +ANA or rheumatoid factor but with lower titers (rule out 'rheumatoid lung”, i.e., interstitial lung disease resulting from rheumatoid arthritis) 3. Chest x-ray: Syllabus a. basal, peripheral reticular opacities b. decreased lung volumes F. HRCT: 1. Nodular pattern: not characteristic of IPF 2. Linear (reticular opacities): a. Reticular opacities seen in IPF because of parenchymal fibrosis due to intralobular interstitial thickening(2010) b. as fibrosis progresses, bronchi become dilated and tortuous causing what is known as traction bronchiectasis c. honeycomb or endstage lung is seen as numerous cystic spaces; honeycombing on HRCT sensitive and specific for diagnosis of IPF. d. fibrosis due to UIP is predominately peripheral, subpleural and basilar 3. Cysts: air-containing lesions seen in end-stage or Year'shoneycomb lung 4. Parenchymal opacification: a. "ground glass" implies a potentially reversible disease 1) extensive ground glass uncommon in patients with IPF but is more commonly observed in Last nonspecific interstitial pneumonia (NSIP).

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b. A hallmark of IPF on HRCT is patchy distribution with areas of both mild and severe fibrosis, and normal lung seen in the same patient. G. Pulmonary Function Testing: Restrictive Pattern 1. Flow rates may be normal or increased due to increased recoil. If pt. is a smoker, they will be decreased as in obstructive lung disease 2. reduced vital capacity (VC), total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) due to stiffening of lung 3. reduced diffusion capacity (DLCO); may occur before decrease in lung volumes 4. normal or low arterial oxygen levels (Pao2) due to mismatch of ventilation and perfusion. Increased desaturation with exercise. H. Lung Biopsy Syllabus 1. Usual interstitial pneumonia (UIP) is diagnosed by surgical lung biopsy either with open thoracotomy or video-assisted thoracoscopy (VATS). Pathology shows interstitial inflammation with lymphocytes and plasma cells, fibroblastic foci (composed of myofibroblasts producing collagen), areas of fibrosis composed of dense collagen and honeycombing caused by cystic and fibrotic areas distorting alveolus. “Spatial and temporal heterogeneity” (areas of normal lung interspersed with disease areas at different pathologic stages) is hallmark(2010) of disease and helps distinguish from nonspecific interstitial pneumonitis (NSIP) which is more homogeneous and disease of similar age. Pathology can be similar in interstitial fibrosis associated with collagen vascular disease (RA, MCTD, Scleroderma, Dermatomyositis) or drug reactions (Nitrofurantoin, Busulfan, Bleomycin, Methotrexate) or () but is often more like NSIP. Also, use blood tests (e.g. RF, ANA, anti-nuclear antibodies, Scl-70) and history to distinguish. Year's2. Biopsy helps to exclude other interstitial lung diseases: a. desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis interstitial lung disease (RBILD)- associate with smoking. b. nonspecific interstitial pneumonia (NSIP) c. lymphoid interstitial pneumonia (LIP)- increased Last lymph nodes and proliferation of lymphocytes d. acute interstitial pneumonia (AIP)

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e. bronchiolitis obliterans organizing pneumonia (BOOP) I. Transbronchial biopsy (TBB) cannot diagnose UIP primarily due to the small amount of tissue obtained, but can be used to diagnose malignancy, infections, sarcoidosis, occasionally hypersensitivity pneumonitis, BOOP, eosinophilic pneumonia, or pulmonary histiocytosis X. VIII. TREATMENT OF IPF: A. Median survival ranges from 4-5yrs. Likely to increase with earlier diagnosis. B. Treatment based on the premise that inflammation leads to injury and fibrosis, so treatment has primarily included antiinflammatory medications and transplantation. C. Corticosteroids: 1. 10-30% pts. respond with improvement whereas up to 40% respond on the basis of subjective or undefinedSyllabus assessment criteria. Responses are usually partial and transient with few cures. 2. Treat with .5mg/kg/day po x 4 weeks, then taper to .25mg/kg/day for 8 weeks, then 0.125 mg/kg/day D. Azathioprine (Imuran) at 2-3 mg/kg day plus corticosteroids associated with modest improvement and in combination with N- acetylcysteine (NAC). E. Cyclophosphamide (Cytoxan) 2 mg/kg/day Response is determined(2010) after 3-6 months on therapy by assessing symptoms, radiologic findings and physiologic findings. F. Interferon Gamma (IFN- )- Phase III trial results show potential survival benefit in patients treated with IFN- but no significant effect on disease progression- ?enhance immune function, ability to fight viral and bacterial infection G. Active trials of pirfenidone, Gleevec, bosentan and. Lung Transplantation- approximate 40% 5-year survival in IPF patients. IX. CHRONICYear's INTERSTITIAL PNEUMONITIS A. DESQUAMATIVE INTERSTITIAL PNEUMONITIS (DIP) 1. A misnomer, not desquamation of alveolar epithelial cells- associated with smoking in 90% of cases. 2. Rather a cellular infiltrate of mononuclear inflammatory cells 3. Monotonous cellular infiltrate in alveolar space 4. Seen in hypersensitivity pneumonitis, also in eosinophilic Last pneumonia

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B. BRONCHIOLITIS OBLITERANS WITH ORGANIZING PNEUMONIA (BOOP) 1. Associated with the Organizing Phase of acute lung injury 2. Clinically, can occur after recovery from viral illness. Fever, cough, dyspnea 3. Marked by polypoid tufts of organizing connective tissue in bronchioles, alveolar ducts. a. Plugs of granulation tissue 4. Excellent response to steroids but may relapse following steroid taper. X. GRANULOMATOUS INFLAMMATION A. SARCOID 1. Nonnecrotizing granulomas. 2. Lymphatic distribution (subpleural, bronchovascularSyllabus bundles) 3. Compact, well circumscribed epithelioid histiocytes with multinucleated giant cells surrounded by rim of lymphs and collagen fibrosis 4. Chronic bronchiolitis 5. Loose granulomas 6. Late fibrosis which can mimic IPF 7. May respond to steroids or immunosuppressives early in disease during inflammatory(2010) phase. XI. EXTRINSIC ALLERGIC ALVEOLITIS (HYPERSENSITIVITY PNEUMONITIS) ACUTE: A. Allergic reaction to inhaled organic dust and bronchiolocentric B. CLINICAL: Middle-age, recent onset dyspnea (DOE), cough, fever C. PE: Malaise. Fine crackles at bases D. Labs: ESR, ANA, RF, anemia non-specific Serum precipitins, if Year'santigen is suspected E. PFTs: Restriction. Decreased diffusion. Hypoxemia worse with exercise F. CXR: Fine interstitial infiltrates, mid-lung fields G. HRCT: Ground glass densities suggestive of alveolitis LastH. BX: BAL: Marked lymphocytosis CD8 > CD4 TBBX ok: DIP, cellular infiltrate with loose granulomas

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I. RX: Antigen avoidance (difficult for farmers and bird breeders) J. Steroids: Prednisone 60 mg/d. Slow taper to off. K. Prognosis: Good, especially if diagnosed and treated before CHRONIC: A. Exposure history may be remote B. Impairment in wound healing likely C. Can mimic IPF D. Cellular inflammatory interstitial infiltrate (CD8+ lymphocytes on BAL) E. Relatively unresponsive to treatment XII. ILD: SUMMARY A. Defined Interstitium: Compartment normally very thin, scant cellularity for gas exchange and maintain lung architecture.Syllabus B. ILD: Cellular infiltration of interstitium and alveolar space after epithelial injury. Initiates repair processes. Fibrosis occurs if repair too exuberant, disorganized, persistent and unregulated. C. Pathology: DAD (acute, organizing) 1. UIP (temporal heterogeneity: normal, cellular, fibrotic, honeycomb) 2. DIP (cellular infiltrate in alveolar spaces) 3. NSIP(cellular or (2010)fibrotic)- more homogeneous than IPF and more responsive to immunosuppressive therapy. 4. BOOP (polypoid tufts of granulation tissue in alveolar ducts)- steroid responsive 5. Granulomas (Sarcoid, HP) D. Presentation of 1. IPF and ILD form connective tissue disease 2. HP E. Year'sTherapies 1. Steroid-based, anti-inflammatory and immunosuppressive 2. Future: Antiproliferative agents to down-regulate inappropriate repair and proliferative response.

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XIII. ILD: REFERENCES 1. Gross, T.J. and Hunninghake, G.W., Idiopathic Pulmonary Fibrosis (Review). NEJM 345: 517-525, 2001.

Succinct focused review of idiopathic pulmonary fibrosis with excellent references.

2. Interstitial Lung Diseases of Unknown Cause: Disorders Characterized by Chronic Inflammation of the Lower Respiratory Tract. NEJM 310: 154- 166 and 310: 235-244.

An excellent comprehensive review of pathogenesis of ILD with emphasis on role of immune effector cells. In-depth comparison of IPF, sarcoidosis and Histiocytosis X.

3. Raghu, G., et al. A Placebo-Controlled Trial of Interferon Gamma-1b in Patients with Idiopathic Pulmonary Fibrosis. NEJM 350: 125-133,Syllabus 2004. First double-blind randomized trial of a potential treatment for IPF. No effect on progression-free survival but possible survival benefit.

4. Interstitial Lung Disease

eds. Schwarz, M.I. and King, T.E., Jr. (2003) Fourth Edition, Mosby, St. Louis MO Comprehensive recently updated textbook about multiple aspects of ILD. Excellent chapters on pathology(2010) by Colby, and IPF by King. 5. King, T.E., Clinical Advances in the Diagnosis and Therapy of the Interstitial Lung Diseases. Am J Resp Crit Care Med 172: 268-279, 2005.

State-of-the-art current review of interstitial lung disease which focuses on how to distinguish between different types of ILD, i.e. DIP, NSIP, BOOP, LIP. Superior references.

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Breathing In Unusual Environments - Stephen Ruoss, M.D. HHD221 Spring 2010 Page 211 Gas Exchange in Unusual Environments

Assigned Reading: West, Respiratory Physiology, Chapter 9.

A. Diving: HYPERBARIC environment B. High altitude: hypobaric environment

(remember: the FiO2 remains the same…) I. DIVING PHYSIOLOGY AND MEDICINE A. Diving Respiratory Physiology 1. The “rules” guiding pulmonary physiology under water (hyperbaric conditions): Syllabus

a. Alveolar gas equations: PAO2 =

[(PB – PH2O) x FiO2] – PACO2/R

b. Dalton’s law: Ptotal = sum of all partial pressures

(Ptot = P1 + P2 + P3) c. Boyle’s law: at a constant Tº,

P x V is constant, and/or, P1 x V1 = P2 x V2 2. Pressure conditions in diving (water is now the “environment”): (2010) a. In water, ambient pressure increases by 1 atm per 10 meters and b. By Boyle’s law, for a fixed amount of gas, volume will change inversely proportional to any pressure change: Year's

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1) Example 1, with comparison of diving methods, on descent to 30 meters:

c. So, for: fixed moles of gas: P = 4 x V = ¼ x Syllabus Fixed gas volume: P = 4 x V = 1 x B. Physiologic Consequences of Diving: 1. Descent barotrauma or “squeeze,” on breath-hold diving: a. Thorax squeeze: limited compression capacity of the human chest wall; on breath hold: (2010)Sea level 30 meters Pressure 1 atm 4 atm Lung vol. (@ TLC) 6 L 1.5 L 1) With the thorax compressed to its limit, any additional increase in depth/pressure forces blood into the thorax, with the risk of bleeding. b. Middle ear squeeze: 1) If pressure increases, without equilibration, options are: Year's i. Tympanic membrane rupture ii. Bleeding/edema c. Other sites for barotrauma risk: 1) Sinuses; GI tract; dental caries Last

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2. Ascent barotraumas, or the “seltzer” effect: a. Lung volume and pressure change on SCUBA ascent: Syllabus 1) Example 2, ascent from 30 meters, if breath- holding while SCUBA diving: 30 meters Sea level Pressure 4 atm 1 atm Lung vol. (% TLC) 100% 400% (!...this is the press./volume risk in ascent) b. Problems/consequences(2010) with ascent decompression: 1) Lung parenchymal rupture 2) Pneumothorax (esp. if there is airways obstruction, e.g., asthma) 3) Air embolism c. Decompression sickness (the “bends”): 1) On ascent and reduced pressure, dissolved tissue N2 moves into gas phase

2) Trapped N2 gas bubbles cause problems (joint Year's pain; capillary obstruction) 3) Long, deeper dives = increased risk 3. Diving reflex a. Diving (or cold water immersion) produces bradycardia, increased systemic pressure and decreased blood flow to extremities Last b. Effect is preservation of cardiac and brain perfusion

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c. Compromise is limited perfusion of muscles, but they can function by anaerobic metabolism for extended periods, and/or rely on O2 stored in myoglobin (esp. diving sea mammals) d. Diving reflex highly evolved in seals and whales; in humans, infants > adults

Syllabus

C. Medical problems with diving 1. Decompression sickness; the “bends” (see above) a. N is lipid(2010) soluble; high tissue solubility w/ high 2 pressure b. Brain, spinal cord, joints are sites for greatest sx, injury by gas phases N2 c. Symptoms: joint, skin, chest pain; paralysis d. Treatment: immediate recompression, then slow decompression

2. N2 narcosis:

a. Under high ambient press., increased N2 dissolved in Year'stissues, esp. lipid membranes b. Slowed neural conduction times; = anesthetic effects c. Lightheadedness, euphoria increase below 30 – 50m breathing air; coma by 100m d. He, and H, have less lipid solubility, and cause less neural effects; Last e. He-O2 mixture used for deep dives of >30m, with longer duration

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3. O2 toxicity:

a. O2 toxicity is function of partial pressure of O2, not simply the FiO2

b. Avoid pO2 > 0.5 atm; prefer < 0.3 atm

c. Very low O2 concentrations are used in diving at extreme depths to avoid high pO2; examples:

1) At 100m depth (= 10 atm), 0.5 atm of O2 would be achieved through breathing a mixture of gas with an FiO2 of: 0.5 atm/10 atm = 5% O2 (a marked contrast to the normal 21%)

2) At 200m depth, an FiO2 of only 1% O2 will produce a PAO2 of 159 D. Gas exchange problems in breath-holding diving 1. Physiologic considerations to recall: a. As ambient pressure increases, so does the partial pressure of any component gas (seeSyllabus Dalton’s law above); and b. Hyperventilation will decrease pCO2, and thus decrease ventilatory drive and increase breath-hold time; and c. Under non-hypoxic conditions, O2 transfer is not diffusion limited, so O2 (and CO2) will diffuse rapidly at the alveolar-capillary interface d. Example 3: breath-hold diving to 10 meter depth by an Ama diver(2010) 1) Start; hyperventilate at sea level:

Patm = 760 mmHg

PAO2 = 120 mmHg (16% O2)

PACO2 = 29 mmHg (4% C O2) 2) Arrival at 10 m (2 atm):

Patm = 2 x = 1520 mmHg

PAO2 = 240 mmHg (increased driving pressure)

PACO2 = 60 mmHg (increased driving Year's pressure) 3) Short duration at 10m:

Patm = 1520 mmHg

PAO2 = 149 mmHg (FAO2 = 10%)

(10% FAO2 would = PAO2 71 at sea level…)

PACO2 = 42 mmHg (3%) Last 4) W/ ascent to sea level: (w/ continued O2 use and CO2 production)

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Patm = 760 mmHg

PAO2 = 41 mmHg (5.4%) VERY marginal

PACO2 = 42 mmHg (5.4%) e. Therefore, the major hazard in breath-holding diving is the hypoxia produced during ascent, not while at depth. f. Risk is loss of consciousness on return to the surface, with subsequent drowning; accounts for thousands of diving fatalities/year. II. HIGH ALTITUDE PHYSIOLOGY AND MEDICINE: (HYPOBARIC ENVIRONMENT) A. Environmental constraints: hypobaric hypoxemia

1. The problems is NOT low FiO2 but rather low barometric pressure (PB) 2. Recall: Syllabus a. Alveolar gas equation:

PiO2 = (PB – PH2O) x FiO2

PAO2 = PiO2 – PACO2/R b. and is R is assumed = 0.8, then

PAO2 = PiO2 – PACO2 x 1.25

3. Thus as the barometric pressure falls, so falls the PiO2, and the PAO2; a. Representative pressures at various altitudes (at rest): (2010) Altitude (ft.) PB PiO2 PaO2 PaCO2 0 760 149 97 40 10,000 520 100 57 34 18,000 380 69 40 24 29,028 250 43 31 9 (w/ pH 7.60) Year's4. Note: Increasing altitude and hypoxia is associated with nonlinear relationship between pCO2 and pO2 (see figures below). This is the result of the ventilatory responses to altitude. Last

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B. Ventilatory Responses to altitude 1. Acute responses (minutes to hours):

a. Increased drive from peripheral (carotid body; O2 sensitive) and central (medulla; pH sensitive) stimuli: increased tidal volume, respiratory rate, minute ventilation. b. Improved(2010) pO2 due to increased ventilation and decreased pCO2 (as expected by the alveolar gas equation). c. Significant variability in ventilatory response between subjects; 1) Genetic 2) Associated with differing risks for medical consequences 2. Chronic (days to weeks): Year'sa. Further increase in ventilation, with fall in pCO2 and increase in pO2 b. Mechanism(s) not clear, but involve cooperative central and peripheral effects (? CNS cellular acidosis, and fall in intercellular HCO3) c. At extreme altitude, uncompensated respiratory alkalosis (pH > 7.5) Last d. As above, possible genetic factors, with marked variability between persons.

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Figure 1. The Rahn-Otis diagram with recent data from extreme high altitude. Point A is averageSyllabus alveolar gasses in un-acclimatized subjects (1-hour exposure) to 3800 m. Point B is after acclimatization in 3800 m. (Adapted from Rahn H. Otis AB: Man’s respiratory response during and after acclimatization to high altitude. Am J Physiol 157: 445, 1949; with permission). 3. High altitude natives and respiratory responses: a. Increased lung volumes (TLC, VC, FRC) b. Resting ventilation increased over adapted lowland natives (2010) c. NL rate, but increased tidal volume d. Increased diffusing capacity (due to increased lung vol. and alveolar area) C. Hematologic and Volume Responses to Altitude: 1. Increased hematocrit: increased erythropoietin release a. Hot increases to 60%; plateau by 6-8 weeks 2. Decreased plasma volume; also increases HCT Year'sa. ? cellular hypoxia and vascular leak? b. Contributes to hyperviscosity problems D. Hemodynamic Responses to Altitude: 1. Early increase in sympathetic tone/output (probably due to hypoxia): a. Increased BP, pulse, C.O., metabolic rate Last b. Parameters normalized by 2 weeks

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2. Chronic hemodynamic changes at altitude: a. Decreased stroke volume, C.O., with higher HR for given exercise rate than at sea level b. Increasingly severe limitation in maximum work capacity (VO2 and C.O.) w/ greater altitudes (see figures below)

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c. Exercise is associated with marked and increasing arterial Hgb desaturation as altitude increases (see figure below). (2010)

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d. At the summit of Mt. Everest, maximum work is reduced to < 20% of sea level capacity; in figure above14% O2 at 6300m is equivalent to summit of Everest. Last 1) (Note: 300 kgm/min = 50 watts = 12 ml O2/kg/min = moderate walk on flat ground)

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E. Oxygen Loading and Transport at High Altitude

1. Reduced difference between arterial and venous pO2, but O2 delivery is normal due to:

a. Higher O2 content of blood given the higher HCT/Hgb, and

b. Unloading easier on steep portion of the O2-Hgb curve

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2. Oxyhemoglobin dissociation curve is altered by respiratory and metabolic conditions: a. 2.3-DPG, produced from carbohydrate metabolism, shifts the O2-Hgb curve to the right; right shift also produced by fever, acidosis.

b. Alkalosis, including respiratory alkalosis, shifts the O2- Hgb curve(2010) to the left.

c. At extreme altitude, the observed shift in the O2-Hgb curve is to the left (see figure), due to the marked and uncompensated respiratory alkalosis at extreme altitudes (see sections A and B above).

d. Result of left shift in O2-Hgb curve is better O2-loading in marginal physiology conditions (see figure). Year's

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Syllabus F. Medical Problems at High Altitude 1. Periodic breathing; central apnea: Recurrent cycling of hyperventilation and hypoventilation/apnea a. Common above 10-12,000 ft., and almost universal at extreme altitudes b. Produces worsened to profound hypoxia; increased periodic breathing activity in REM sleep c. Treatment:(2010) acetazolamide (stimulation of ventilatory drive) d. Mechanism(s): 1) cellular hypoxia; exaggerated responses to both hypoxic (increased ventilation) and hypocapnic (apnea) stimuli:

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2. Acute Mountain Sickness (AMS) a. Sx: headache, malaise, insomnia, weakness, nausea/emesis; onset within hours of ascent b. Probably mediated by tissue hypoxia/edema c. Process on a continuum with more severe cellular injury events (HACE and HAPE below) d. Persons with poor ventilatory responses to hypoxia are at greater risk for developing AMS (and HAPE, HACE); (see figure below)

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e. Prevention: slow ascent; acetazolamide or steroids f. Treatment:(2010) descent; acetazolamide or steroids 3. High Altitude Cerebral Edema (HACE) a. Probable common cause for process with mild (AMS) to severe (HACE) presentation b. Headaches, confusion, ataxia, emesis, coma c. Rx as above; also pressure chamber (Gamow bag) if available 4. High Altitude Pulmonary Edema (HAPE) a. Rapid ascent, exercise, and brisk hypoxic pulmonary Year'svasoconstriction response are risk factors; increased risk for recurrence in those with prior HAPE b. Pulm. HTN, with increased vascular shear forces, as well as hypoxic endothelial injury, are suspects in cause of HAPE

c. Management: O2 supplement, descent or pressure bag, and vasodilator therapy (nifedipine, nitric oxide Last are proven Rx)

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5. Chronic Mountain Sickness a. Chronic pulmonary HTN, R ventricular hypertrophy and overload, with decompensation of cardiac function (cor pulmonale) b. Sx: malaise, poor exercises tolerance, chronic lower extremity edema, hyperviscosity due to high HCT (to as high as 80%) c. Rx: lower altitude; reversible in early phases

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Last Chronic Interstitial Lung Disease/ Pneumoconioses - Andrew Connolly, M.D., Ph.D. HHD221 Spring 2010 Page 225 Interstitial Lung Diseases

I. INTERSTITIAL LUNG DISEASES (ILD) OVERVIEW A. Clinical Features of ILD: 1. A diffuse, chronic disease of pulmonary connective tissue. 2. Restrictive; with decreased lung volume, compliance, and diffusion. 3. Comprises 15% of non-infectious lung disease seen by pulmonologists 4. May also cause pulmonary HTN B. Most Common Etiologies of ILD: 1. Environmental Agents: 25% 2. Sarcoid: 20% 3. Idiopathic: 15% Syllabus 4. Collagen Vascular Disease: 10% 5. (SLE, RA, PSS) C. ILD pathogenesis: 1. Chronic lung injury or multiple acute lung injuries 2. Smoldering response to alveolitis 3. Accumulation of fibrosis and inflammatory infiltrate (Fibrosing alveolitis)(2010)

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D. Possible Pathogenesis of ILD: “Fibrosing Alveolitis”

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E. Major Pathologic Categories of ILD (Robbins): 1. Fibrosing a. Idiopathic(2010) pulmonary fibrosis b. Cryptogenic organizing pneumonia c. Collagen vascular diseases d. Pneumoconiosis e. Drug reactions f. Radiation pneumonitis 2. Granulomatous a. Sarcoidosis b. Hypersensitivity pneumonitis Year's3. Cellular (Macrophage; Smoking-Related) a. Desquamative interstitial pneumonia b. Respiratory bronchiolitis-associated ILD 4. Eosinophilic

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II. CLASSIFICATION OF ILD (AKA DIFFUSE PARENCHYMAL LUNG DISEASE)

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A. DIAGNOSIS OF IPF w/o SURGICAL LUNG BIOPSY Last 1. Major Criteria (Must Have All Four) a. Exclusion of other known causes of ILD

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b. Restrictive PFT c. Bibasilar reticular abnormalities on HRCT d. Transbronchial lung biopsy or BAL showing no features to support an alternative diagnosis 2. Minor Criteria (Must Have Three of Four) a. Age > 50 yr b. Insidious onset of otherwise unexplained dyspnea on exertion c. Duration of illness > 3 mo d. Bibasilar, inspiratory crackles B. American Thoracic Society / European Respiratory Society Classification of Idiopathic Interstitial Clin-Rad-Path Dx Histologic Patterns Idiopathic pulmonary fibrosis UIP Syllabus Nonspecific interstitial pneumonia NSIP Respiratory bronchiolitis-ILD Respiratory bronchiolitis Desquamative interstitial pneumonia DIP Lymphoid interstitial pneumonia LIP

Acute interstitial pneumonia Diffuse alveolar damage Cryptogenic organizing pneumonia Organizing pneumonia III. IDIOPATHIC PULMONARY FIBROSIS(2010) A. Overview 1. “Usual Interstitial Pneumonia” histology 2. Insidious onset 3. Inexorable progression 4. Poor response to steroid therapy 5. => Is it an really inflammatory etiology 6. 70 % mortality at 5 years B. Year'sHistologic Features of Idiopathic Pulmonary Fibrosis 1. Key Histologic Features (those of UIP) a. Areas of dense fibrosis (old lesions) b. Fibroblastic foci (new lesions) typically at the edges of scars c. Patchy lung involvement Last d. Frequent subpleural and paraseptal distribution

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2. Pertinent Negative Findings a. Lack of active lesions of other interstitial diseases (i.e., sarcoidosis or Langerhans' cell histiocytosis) b. Lack of marked interstitial chronic inflammation c. Lack of granulomas d. Lack of substantial inorganic dust deposits, i.e., asbestos bodies (except for carbon black pigment) e. Lack of marked eosinophilia C. Causes of UIP Histology 1. IPF: 50 % 2. Collagen Vascular Disease: 20 % 3. Pneumoconiosis: 20 % 4. Radiation-associated: 5 % 5. Drugs: 1% 6. Post-viral: ? Syllabus IV. DESQUAMATIVE INTERSTITIAL PNEUMONIA A. Highly Cellular Lesion 1. Interstitial chronic inflammatory cell infiltrate 2. Large numbers of intra-alveolar histiocytes B. More uniform involvement of the lung C. Fibrosis is less conspicuous D. Mortality rate: 25 % at (2010)12 years E. Good response to steroid therapy F. No common associations with other diseases V. NONSPECIFIC INTERSTITIAL PNEUMONIA (NSIP) A. Recent addition to classification of IIP B. Two “variants”: 1. Cellular Year's2. Fibrotic C. This variant is reported to have a better prognosis than UIP VI. SMOKER’S-ASSOCIATED RESPIRATORY BRONCHIOLITIS A. Bronchiolocentric inflammation with B. DIP-like interstitial inflammation LastC. Only seen in heavy cigarette abusers

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D. Resolves with smoking cessation VII. PULMONARY LANGERHANS CELL HISTIOCYTOSIS A. It most commonly is isolated to the lung B. Strongly associated with heavy cigarette abuse C. CXR: 1. Reticulonodular infiltrates with cystic change 2. Predominantly bilateral upper lobe disease D. Good Prognosis E. Only a small number of patients progress to respiratory failure VIII. LYMPHOID INTERSTITIAL PNEUMONIA (LIP) A. Most of original cases are low grade lymphomas in the lung B. True LIP is rare and usually associated with : Syllabus 1. Immune deficient states 2. HIV infection in children 3. Collagen vascular disease (esp. Sjogren’s) 4. Rare idiopathic cases (women 40-60) IX. ORGANIZING PNEUMONIA (OP) A. Subacute onset of symptoms B. Associations: 1. Post-Infectious (2010) 2. Toxic fume inhalation 3. Collagen-Vascular Disease 4. GVHD/Rejection 5. Drug-associated 6. Idiopathic = Cryptogenic Organizing Pneumonia C. Good response to steroid therapy D. Fibrosis mostly in airspaces and small airways E. Year's Septae are not very thick X. HONEYCOMB LUNG (END-STAGE PULMONARY FIBROSIS) A. The normal lung is restructured into abnormal spaces lined by thick fibrous walls. B. Resembles a bee’s honeycomb on gross examination LastC. Signs and symptoms depend on the amount of honeycomb change

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D. Terminal course complicated by hypoxia and cor pulmonale E. Risk of Progression of ILD to Honeycomb Lung 1. High a. UIP b. LAM 2. Variable a. Pneumoconiosis b. Drug/toxic c. Radiation d. Hypersensitivity e. Collagen-Vascular 3. Low a. Sarcoidosis b. Langerhans cell granulomatosis Syllabus c. DIP d. Cellular NSIP XI. PNEUMOCONIOSES A. Definition: Lung disease associated with the inhalation and retention of industrial dusts B. Factors: 1. Size and Shape of Particles 2. Chemical Nature(2010) of Particles 3. Concentration of Particles 4. Duration of Exposure C. Particle Size 1. Optimal size: 0.1 – 5 microns 2. Larger: Deposited in the Upper Airway 3. Smaller: Easily cleared from the lung 4. Exception: Asbestos (javelin-like) D. Year'sChemical Nature 1. Non-fibrogenic: a. Carbon b. Iron c. Tin Last d. Graphite

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2. Fibrogenic: a. Silica b. Asbestos c. Beryllium d. Coal 3. Carcinogenic: a. Asbestos b. Radioactive Dusts E. Examples 1. Non-Fibrogenic a. Carbon (Anthracosis) in urban dwellers b. Tin 1). CXR in a Tin Worker 2). No Clinical or Functional AbnormalitiesSyllabus 2. Fibrogenic a. Silica Dust 1). Accumulation of dust particles along lymphatics 2). Egg shell-like calcification of hilar lymph nodes 3). Interstitial fibrosis (Usually takes decades) 4). Nodular/conglomerate fibrosis 5). Small birefringent crystalline needles b. Coal Dust(2010) (sometimes with Silica) c. 1). Exposure: i. Fluorescent light bulb makers ii. Nuclear industry 2). Acute Form: i. Resembles Allergic Alveolitis ii. Good prognosis if recognized Year's3). Chronic Form: i. Mimics sarcoidosis perfectly ii. Poor prognosis d. Asbestos 1). The Magic Mineral i. Greeks: 430BC incombustible lamp Last wicks

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ii. Romans: Cremation clothes to conserve ashes iii. Charlemagne: Fire cleaning of asbestos tablecloth 2). The Lethal Dust i. 1 AD Rome: Pliny the elder described lung disease in asbestos workers ii. 1900 England: First autopsy report describing pulmonary fibrosis in a textile worker iii. 1914 England: Asbestosis added to list of occupational diseases iv. 1935 UK/USA: Association of lung cancer and asbestosis v. 1960 S. Africa: Association of mesothelioma and asbestosisSyllabus 3). Asbestos-induced Lung Disease i. Progressive Pulmonary Fibrosis ii. Recurrent iii. Hyaline Pleural Plaques iv. Mesothelioma v. Bronchogenic Carcinoma F. ASBESTOSIS 1. Definition: Asbestos-(2010)induced pulmonary fibrosis 2. CXR: Interstitial Fibrosis (esp. lower lobes) 3. Latency: 10-20 years 4. CXR IN ASBESTOSIS

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G. ASBESTOS-ASSOCIATED 1. Forms a. PLEURAL EFFUSIONS b. HYALINE PLEURAL PLAQUES c. DIFFUSE PLEURAL FIBROSIS d. MALIGNANT MESOTHELIOMA 2. Asbestos-associated Pleural Effusion a. Effusions occur as early as 10 y after 1st exposure (mean 26 y) b. Effusion is an exudate which is frequently bloody c. Biopsy shows non-specific inflammation and fibrosis d. Asbestos bodies are not identifiable e. Condition resolves spontaneously but may recur f. Condition may be complicated by: 1). Diffuse Pleural Thickening Syllabus 2). Mesothelioma 3. HYALINE PLEURAL PLAQUES a. Prevalence of plaques increases with increased exposure to Asbestos b. Rarely seen in patients under the age of 40 (10-20 year latency) c. These do not cause any impairment of lung function/symptoms d. Pleural plaques(2010) are not precursors of malignant change 4. Asbestos-associated Diffuse Pleural Fibrosis a. Diffuse pleural thickening extending over variable proportions of the lung/thoracic cavity b. Usually starts at bases and is bilateral c. Usually follows episodes of acute d. Patients complain of dyspnea +/- Pleuritic pain e. Restrictive PFT pattern Year's5. MALIGNANT MESOTHELIOMA a. Usually an asbestos-related disease b. Dose-related but no threshold level c. Latency: 15-60 years; average 30-40 years d. Highly Malignant, locally aggressive Last 6. ASBESTOS AND BRONCHOGENIC CARCINOMA a. All types of bronchogenic carcinoma occur

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b. Risk is dose related; no threshold level c. Risk is synergistic with smoking e. Asbestosis (i.e., fibrotic lung disease) is not required f. Long latency period, earliest cases 5 years

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PULMONARY VASCULAR DISEASES: Pulmonary Edema, Pulmonary Embolism, and Pulmonary Hypertension

Assigned Readings: West, Respiratory Physiology, Chapter 4; West, Pulmonary Physiology and Pathophysiology, Chapter 6, 7.

I. PULMONARY CIRCULATION Swan Ganz Pulmonary Artery catheter allows measurements of the right atrial pressure, right ventricular pressure, pulmonary artery pressure, pulmonary capillary wedge pressure (equal to the left atrial pressure), and the mixed venous oxygen saturation. Cardiac output can be determined by thermodilution or by the Fick method (utilizing oxygen Syllabussaturations).

(2010)

II. PULMONARYYear's EDEMA A. Case Presentation: 58 M smoker presents with anginal chest pain. Vital signs reveal relative hypotension, tachycardia and decreased oxygen saturation on room air. Exam reveals bibasilar moist rales, and tachycardia with S3 gallop. EKG reveals anterior Q-waves. Chest radiograph reveals interstitial pulmonary edema, in a perihilar Last bat-wing presentation. Kerley B septal lines are present consistent with interstitial edema.

B. Pulmonary edema represents the leak of plasma fluid out of the pulmonary capillaries into the interstitium and subsequently the alveolar spaces. This can develop when the hydrostatic forces exceed the colloid osmotic pressure. Interstitial edema can worsen the collapse of pulmonary capillaries. Drowned alveoli are incapable of gas exchange, and serve to worsen ventilation- perfusion matching. C. Causes of increased capillary hydrostatic pressure include: myocardial infarction, mitral valve stenosis, fluid overload, pulmonary veno-occlusive disease. D. Causes of increased pulmonary capillary permeability include: inhaled or circulating toxins, sepsis, radiation or oxygen toxicity or ARDS. E. Causes of decreased lymphatic drainage include: increased central venous pressure, obstruction of lymphatics due to lymphangitic carcinomatosis. Syllabus F. Causes of decreased colloid osmotic pressure include: hypoalbuminemia, starvation, renal disease (nephritic syndrome). G. Uncertain etiologies: High altitude pulmonary edema, neurogenic pulmonary edema, over-inflation. (2010)

Year's III. PULMONARY EMBOLISM A. Case Presentation: 19 F athlete with exertional dyspnea, palpitation and near syncope. Medications: Oral contraceptives. Exam Lungs clear, Heart with loud, split S2 and 2/6 systolic murmur. LastB. Diagnostic evaluation revealed pulmonary hypertension (RVSP 70 mmHg), no intracardiac shunting.

C. Ventilation perfusion lung scan showed multiple mismatched perfusion defects high probability for pulmonary embolism. D. 90% of pulmonary emboli originate in the deep veins of the legs. Deep venous thrombosis and pulmonary embolism represent a continuum of the same disease. E. Risk factors for venous thromboembolism are summarized in Virchow’s Triad: Stasis: Immobility, bed rest, anesthesia, congestive heart failure, cor pulmonale, prior venous thrombosis. F. Hypercoagulability: Malignancy, anticardiolipin antibody, nephritic syndrome, essential thrombocytosis, estrogen therapy, Protein C and S deficiencies, Antithrombin III deficiency. G. Vessel wall injury: Trauma, surgery H. Pulmonary emboli can lead to pulmonary infarction I. Diagnostic modalities: Spiral CT-angiogram revealsSyllabus filling defects within pulmonary arteries J. Leiden thrombophilia study: Factor V Leiden heterozygote condition predisposes to clot formation, risk increased with oral contraceptives K. Pulmonary Hypertension Large vessel, chronic thromboembolic pulmonary hypertension. Proximal clots, may be amenable to thromboendarterectomy L. Small vessel obliterative pulmonary hypertension, PPH Involves smooth muscle(2010) proliferation, increased neointimal formation, vascular occlusion M. Consequences of pulmonary vascular occlusion are increased afterload to the right ventricle, leading to congestive heart failure IV. MANAGEMENT OF PPH A. Manage the right ventricle congestive heart failure Fluid restriction and diuretics Digoxin for increased inotropy B. Year's Anticoagulation, to diminish in situ thrombosis C. Manage the vascular occlusion Intravenous prostacyclin (Flolan). A vasodilator, and antiproliferative D. Subcutaneous Remodulin Calcium channel antagonists – to decrease vasoconstriction and proliferation Endothelin receptor antagonists – to suppress ET-receptor Last signaling

E. Novel anti-proliferatives – statins F. Surface Tension Contributes to Lung Compliance Alveolar membrane represents a large water-air interface. Surface tension arises due to the intermolecular attraction of water molecules, tends to collapse alveoli. G. Lungs filled with saline are easier to inflate than lungs filled with air because the air-water interface leads to surface tension. This surface tension contributes 2/3 of the work of inflating lung. H. Surface tension increases in smaller alveoli, promoting their collapse (atelectasis) Laplace equation: P = 2T / r Atelectasis is prevented because lung surfactant lowers the surface tension more in small alveoli. I. Surfactant Lowers Surface Tension and Stabilizes Alveoli Pulmonary surfactant is rich in lipid, dipalmitoylphosphatidylcholine (DPPC). Syllabus J. Surfactant proteins, B, C, A and D that confer organization on the lipids Surface tension of pure water is 72 dynes/cm Surface tension of water + detergent is lower, but still constant at different areas Lung surfactant demonstrates lower surface tension at small areas than large areas K. At low surface areas, some of the surfactant molecules are squeezed out of the monolayer and form micelles. On expansion, the micelles reinsert molecules into the surface monolayer. (2010)

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L. Surfactant is synthesized by Type II alveolar epithelial cells Lamellar inclusion bodies are rich in surfactant. Surfactant helps to prevent pulmonary edema, by decreasing the interstitial pressure that tends to “pull” fluid from the capillaries. M. Neonatal Respiratory Distress Syndrome / Hyaline Membrane Disease Surfactant synthesis occurs late in gestation, around 34 weeks (term pregnancy is 40 weeks) Failure of proper lung maturation is a major cause of death in newborns Premature birth and diabetes during pregnancy interfere with normal lung maturation Immature lungs at birth, lacking surfactant: 1. Greatly increased work of breathing 2. Pulmonary edema 3. Atelectasis N. Effective treatment is instillation of lung surfactant purified from calves. Syllabus REVIEW QUESTIONS 1) A premature infant is born without any surfactant. What is the ratio of the pressure inside an alveolus with diameter 0.2 mm to the pressure inside an alveolus with diameter 0.3 mm? A. 1.5 B. 0.67 C. 3 D. 1.3 (2010) E. 2.7 2) Which of the following statements is FALSE? A. A large bubble lined with water has a smaller pressure than a small bubble lined with water B. A large bubble lined with water has the same surface tension as a smaller bubble lined with water C. A large bubble lined with surfactant has a smaller surface tension Year'sthan a smaller bubble lined with surfactant D. A bubble lined with surfactant has a smaller surface tension than a bubble of the same size lined with water 2) C 1) A Answers:

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Last Occupational Lung Disease - Ware Kuschner, M.D. HHD221 Spring 2010 Page 243 Occupational Lung Disease

Assigned Reading: West, Pulmonary Physiology and Pathophysiology, Chapter 8.

LEARNING OBJECTIVES 1. To understand clinical features of occupational lung disease 2. To understand the basic elements of obtaining an occupational history and making a diagnosis of occupational lung disease 3. To understand how to prevent and manage occupational lung disease I. OCCUPATIONAL LUNG DISEASES, GENERAL PRINCIPLES: A. Occupational lung diseases result from inhalation of airborne toxins: vapors, gases, dusts, and fumes. Syllabus B. Occupational lung diseases are preventable through: 1. Job change 2. Personal respiratory protection 3. Engineering controls 4. Product substitution C. Occupational lung diseases have an improved prognosis with early detection and intervention. D. Avoidance measures are(2010) the cornerstone of treatment. II. MOST OCCUPATIONAL LUNG DISEASES FALL INTO ONE OF FOUR GROUPS: A. Asthma B. Pneumoconiosis (dust-related diseases) C. Hypersensitivity pneumonitis D. Irritant reactions III. WHENYear's SHOULD I CONSIDER AN OCCUPATIONAL ETIOLOGY IN THE PATIENT WITH RESPIRATORY DISEASE? AN OCCUPATIONAL ETIOLOGY SHOULD BE CONSIDERED IN ANY WORKER WITH: Adult onset asthma Interstitial lung disease A. Work-related Asthma Last 1. 10% - 15% of asthma in adults is attributable to occupational factors.

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2. Asthma is a clinical diagnosis that should be suspected whenever a worker complains of: a. episodic cough b. wheeze c. breathlessness d. chest tightness 3. Asthma affects the airways while sparing the lung parenchyma. Approximately 70% of asthmatics have a normal chest radiograph, even during an attack. Workers who have respiratory complaints and a normal chest x-ray should be evaluated for work-related asthma. 4. Airflow obstruction on spirometry that reverses after administration of a bronchodilator confirms the diagnosis of asthma. 5. Temporal relatedness to the workplace or identification of a workplace agent known to cause asthma establishesSyllabus the diagnosis of work-related asthma. B. Interstitial lung disease 1. The worker who presents with chronic, diffuse, bilateral interstitial infiltrates on a chest radiograph should be evaluated for interstitial lung disease caused by airborne toxins. 2. Interstitial lung diseases caused by occupational airborne toxins include: a. pneumoconioses:(2010) caused by inorganic materials such as coal dust, asbestos, and silica b. hypersensitivity pneumonitis: caused by organic materials such as fungi, plant, and animal proteins 3. Common features of interstitial lung disease are: a. dry cough b. dyspnea with exertion c. rales on auscultation d. reduced lung volumes IV. A LIMITEDYear's OCCUPATIONAL HISTORY CAN BE TAKEN IN TWO MINUTES A. Four occupational history questions provide very useful surveillance information in the evaluation of a worker with respiratory disease: 1. "What kind of work do you do? Please be as specific as possible and tell me exactly what you do at work." Last 2. "Do you think your medical problems are related to your work?"

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3. "Do your symptoms get better when you are away from work, such as during weekends or vacations?" 4. "Are you now, or have you ever been exposed to vapors, gases, dusts, or fumes?" B. Follow-up questions should focus on gaining as much detail as possible about the type, duration, and intensity of exposure and risk reduction practices such as the use of personal respirators. V. A DIAGNOSIS OF WORK-RELATED ASTHMA IS ESTABLISHED BY HISTORICAL AND PHYSIOLOGICAL EVIDENCE THAT SHOWS AN ASSOCIATION BETWEEN ASTHMA AND WORKPLACE EXPOSURES. A. Asthma caused by a workplace exposure is called occupational asthma. Asthma that pre-dated the workplace exposure, but is aggravated by an exposure (e.g. dust or cold air) in the workplace is called work-aggravated asthma. Together, these presentations of asthma are termed “work-related asthma”. Syllabus B. An occupational factor should be suspected in each of the following settings: 1. all cases of adult-onset asthma; 2. whenever the worker claims a link between work and symptoms; 3. when there is a history of asthma onset or deterioration after a job change; 4. when there is a history of occupational exposure to vapors, gases, dusts, and fumes; 5. in workers who (2010)are advised to use personal respirators on the job. C. Work-relatedness is strongly supported by the following evidence: 1. symptoms improve during vacations and weekends away from work 2. symptoms are worse at the end of the workweek 3. lung function studies show deterioration in airflow within 8 hours of the end of the workday and essentially normal Year'sairflow during long periods away from work. D. Hundreds of occupational agents have been reported to cause asthma and even more may aggravate pre-existing asthma. Examples include: 1. vegetable dusts 2. flours Last 3. animal dander 4. diisocyanates (plastics, varnishes)

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5. anhydrides (epoxy resins), 6. plicatic acid (western red cedar) E. Material Safety Data Sheets (MSDS) provide specific information about hazardous chemicals in the workplace. The Occupational Safety and Health Administration requires employers to maintain MSDSs and make them available to workers and physicians. The MSDS is a useful source of information about specific exposures that may cause or trigger asthma. Specific chemicals may sensitize the worker and then trigger asthma attacks. Common exposures such as nuisance dusts and cold air may also aggravate preexisting asthma. F. Management of work-related asthma first requires protection of the worker from the suspected toxic exposure(s). 1. Remove worker from exposure setting 2. Implementation of engineering controls to reduce ambient air concentration of offending agent Syllabus 3. Personal respiratory protection (e.g., respirators) 4. Beyond avoidance measures, management of work-related asthma is identical to non-occupational asthma and should include the use of bronchodilators and glucocorticoids VI. THE PNEUMOCONIOSES ARE A GROUP OF INTERSTITIAL LUNG DISEASES CHARACTERIZED BY PULMONARY FIBROSIS. DIAGNOSIS IS USUALLY MADE BY A POSITIVE EXPOSURE HISTORY AND TYPICAL RADIOGRAPHIC FINDINGS. TISSUE BIOPSY IS NOT REQUIRED (2010)TO ESTABLISH A DIAGNOSIS. A. Pneumoconiosis is the non-neoplastic granulomatous and fibrotic response of the lungs to inhaled inorganic materials such as minerals. 3 classic types of pneumoconiosis are: 1. asbestosis 2. 3. coal workers pneumoconiosis B. The term "asbestosis" specifically refers to the diffuse pulmonary Year'sfibrosis that results from asbestos exposure. C. The presence of five easily recognized findings makes the diagnosis: 1. typical radiographic findings; 2. history of probable exposure to asbestos; 3. appropriate latency (~ 20 years) from initial exposure to Last disease; 4. a restrictive pattern on lung function tests;

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5. inspiratory crackles on physical examination. D. Typical radiographic findings are: reticular and linear interstitial opacities that tend to predominate at the bases; reduced lung volume; and multi-focal pleural thickening with calcified and non- calcified pleural plaques. The pleural findings provide strong circumstantial evidence that the parenchymal fibrosis is due to asbestos exposure. A CT scan is more sensitive than chest radiography for detecting parenchymal or pleural disease. E. A history of probable exposure to asbestos can be based on the patient's job description or on a patient's report of past exposure. High risk occupations include: automobile repair (especially brake work); boilermakers; construction workers; demolition workers; navy yard workers, ship builders, and pipe-fitters. F. Pulmonary function tests in asbestosis should show a restrictive pattern including a reduced forced vital capacity and a reduced total lung capacity. The diffusing capacity should also beSyllabus reduced. G. Silicosis is diffuse lung disease caused by inhalation of crystalline silica and is the most common pneumoconiosis in the United States. Workers at risk are miners, ceramic workers, tunnel drillers, quarry workers and stone carvers. Characteristic radiographic findings of the most common type, chronic simple silicosis, include scattered small nodules (less than 1cm) that tend to involve the upper lung regions. Other radiographic findings include calcification of the hilar lymph nodes in an "egg shell" pattern. H. Chronic simple silicosis usually takes 10 years or more to develop after exposure to quartz.(2010) Two details are especially important: 1) chronic simple silicosis typically produces few, if any, symptoms and lung function is relatively preserved; indeed, the diagnosis may be made incidentally by chest radiography alone. 2) there is a significantly increased risk of tuberculosis among persons with silicosis. The small nodules may coalesce into larger patchy areas of fibrosis called conglomerate masses that may result in respiratory symptoms and impairment. This form of silica related lung disease is known as complicated silicosis. I. Coal workers' pneumoconiosis is a form of diffuse lung disease that Year'sresults from inhalation of coal dust for 20 years or more. Radiographic abnormalities include scattered small nodules predominantly in the upper lung zones of essentially no clinical significance and progressive massive fibrosis which can be lethal. Coal workers' pneumoconiosis is endemic in areas where coal workers are concentrated, including Kentucky, West Virginia and Last Pennsylvania, but uncommonly seen in other parts of the country.

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J. In sum, the pneumoconioses are diagnosed by a history of probable exposure to the appropriate inorganic material, a picture of diffuse parenchymal lung disease on chest radiographs with characteristic features of a pneumoconiosis, and an appropriate exposure-response interval. Additionally, the findings of a restrictive ventilatory defect on pulmonary function tests and inspiratory crackles on the physical examination support a pneumoconiosis diagnosis. No special workplace studies or biopsies are necessary. No specific treatment exists for the pneumoconioses. Removal from the offending exposure is the sole appropriate management option. VII. HYPERSENSITIVITY PNEUMONITIS IS A FORM OF DIFFUSE LUNG DISEASE CAUSED BY ORGANIC RESPIRATORY EXPOSURES. A. Hypersensitivity pneumonitis is an immune mediated (allergic) form of parenchymal lung disease caused by inhalation of organic dusts. The acute form is characterized by self-limited episodesSyllabus of fever, cough, and dyspnea occurring 4 - 6 hours after exposure. The chronic form is characterized by cough, dyspnea, and weight loss also resulting from organic particle inhalation, over months to years. B. Workers exposed to mold, mildew, and organic particles are at risk for developing hypersensitivity pneumonitis. Animal proteins, such as bird antigens (pet birds), and microorganisms (bacteria and fungi) that contaminate plant material such as wood chips or hay are among the more commonly reported causes of hypersensitivity pneumonitis. Features of the acute variant include flu-like symptoms (, myalgias, and cough, and), shortness of breath, and recurrent episodes(2010) of diffuse pneumonia. C. Recurrent exposure to organic antigens results in recurrent illness. The chest radiograph and chest CT scan may only show patchy ground glass opacities while more severe disease or recurrent episodes may result in scattered centrilobular nodules with patchy ill-defined consolidation or ground glass opacities. Lung biopsy will typically show noncaseating granulomas. Treatment is removal from the suspected exposure. D. Chronic hypersensitivity pneumonitis develops over years. In Year'scontrast with acute hypersensitivit y pneumonitis, it is insidious in onset and may result in pulmonary fibrosis, as well as noncaseating granulomas. On chest radiographs, upper lobe scarring, honeycombing, and atelectasis can mimic granulomatous disease. Diagnosis may be suggested by the history. Lung biopsy can be Last helpful.

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E. Corticosteroids may be useful for acute disease. The role of corticosteroids in chronic disease is less clear. In both acute and chronic disease, identification and avoidance of the offending organic exposure is the most important aspect of management. VIII. OCCUPATIONAL IRRITANT EXPOSURES CAN CAUSE ACUTE RESPIRATORY TRACT IRRITATION THAT MAY DEVELOP EITHER INSTANTANEOUSLY OR OVER HOURS. CHRONIC EXPOSURE TO LESS TOXIC IRRITANTS MAY CAUSE CHRONIC INFLAMMATION OF THE AIRWAYS. A. Overwhelming toxic inhalant exposures may result in severe respiratory symptoms such as burning, irritation, , and acute lung injury. Catastrophic exposures are healthcare emergencies typically managed, initially, by first responders and emergency department physicians. B. Ammonia and chlorine are common irritant gases that cause respiratory morbidity. Exposure to chlorine and ammoniaSyllabus may occur in the setting of an industrial accident as well as in the household. These gases are water soluble and consequently interact with the mucous membranes and upper respiratory tract very readily. As a consequence, these irritants have good warning properties. That is, they produce symptoms that immediately involve the eyes, nose, and respiratory tract, usually prompting the victim to flee the exposure setting if possible. Typical respiratory tract symptoms include cough, chest pain, and shortness of breath. Chlorine exposure may occur in water purification, plastics and chemical industries. Ammonia is used in the production of fertilizers. (2010) C. Gases that are poorly soluble in water are not immediately irritating and consequently do not have good warning properties. Common examples of water insoluble irritant gases include the oxides of nitrogen which may be encountered in silos, and fertilizer manufacturing, and phosgene gas which may be encountered in the production of plastics and in welding. These gases can produce lower respiratory tract disease including acute lung injury and hypoxia with scattered opacities on chest x-ray. The onset of Year'ssymptoms may be delayed for several hours after an exposure. Care is supportive. Long term sequelae include bronchiolitis obliterans, a condition characterized by inflammation and scarring of the airways and obstructive lung disease. Last

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D. Chronic bronchitis is a clinical disorder characterized by excessive mucous production, manifested by chronic or recurrent productive cough on most days for a minimum of three months each year for at least two successive years. Most cases of chronic bronchitis are attributable to either primary or secondary cigarette smoke exposure. However, chronic exposure to a spectrum of dusts and irritant gases can also cause chronic bronchitis. Workers at risk include those involved in operations where sustained exposure to irritant inhalants (i.e. gases, dusts, and fumes) occurs. Moderate to high dose exposures may occur in industries such as mining, agriculture, processing of grains and feeds, and the cotton and textile industries. Persons with chronic bronchitis have inflamed airways which are typically hyperreactive and prone to bronchospasm. Accordingly, many patients with chronic bronchitis will benefit from treatment with asthma medications. TAKE HOME POINTS: Syllabus 1. Occupational lung diseases share the common feature of being preventable 2. A history of exposure to a toxic particle, fiber, or gas is essential to making a diagnosis of an occupational lung disease 3. The presence of diffuse lung disease (i.e., interstitial lung disease) on a radiograph, or the diagnosis of adult-onset asthma, should lead to an exploration for an occupational etiologic factor(s) 4. The major occupational lung diseases fall into one of four categories: (2010)  Asthma  Pneumoconioses  Hypersensitivity pneumonitis  Acute irritant reactions 5. Treatment is predicated on eliminating exposure to the offending exposure

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I. EPIDEMIOLOGY A. 1 million deaths per year worldwide B. 161,840 estimated deaths in 2008 in the US C. More than the deaths due to breast (40,000), colorectal (50,000) and prostate cancer (30,000) combined D. Cigarette smoking responsible for about 87% of lung cancer, including 90% of the cases in men and 79% of the cases in women E. Lifetime risk in nonsmokers is <1%, c/w about 15% in heavy smokers (40 million US smokers in 2005; 90 million current and former smokers in 2005) F. Cases become apparent in mid-40’s, peak in mid-70’sSyllabus G. Cessation of smoking reduces risk by year 5, and at year 15 reduces the risk by 80-90% H. Passive smoking also associated with lung cancer, with about a 24- 80% increase in risk, depending on intensity of exposure I. Radon, asbestos, arsenic, ionizing radiation, nickel, formaldehyde, vinyl chloride also associated J. First degree relatives of lung cancer patients have a 1.5 to 5 fold risk of lung Ca, even when adjusting for the above risk factors K. Oncogenic viruses not (2010)identified yet, though human papilloma virus is suspect and there is a sheep virus that does cause lung cancer II. WORLDWIDE CIGARETTE SMOKING

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III. 10-YEAR RISK OF LUNG CANCER

Approximate 10-Year Risk of Developing Lung Cancer *+ Duration of smoking 25 yrs. 40 yrs. 50 yrs. Age Quit Smoking Quit Smoking Quit Smoking 1 pack per day smokers 55 <1 1 3 5 NA NA 65 <1 2 4 7 7 10 75 1 2 5 8 8 11

2 pack per day smokers 55 <1 2 4 7 NA SyllabusNA 65 1 3 6 9 10 14 75 2 3 7 10 11 15

*Estimated risk of developing lung cancer is expressed as percentage value. These tables assume that people who have quit smoking will continue to abstain for next 10 years and those who are still smoking will keep smoking the same amount for the next 10 years. For individuals with occupational asbestos exposure, the risks should be multiplied by 1.24. There was relative paucity of events observed among individuals in(2010) this study outside the given age ranges (i.e., younger than age 55, older than age 85), making prediction outside the given age range potentially unreliable. NA: data not available. +Reproduction with permission from: Bach, PB, Katten, MW, Thornquist, MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst 2003, 95:470. Copyright © 2003 Oxford University Press. IV. SMOKING CESSATION AND PREVENTION A. Approximately 450,000 deaths from all causes annually from Year'ssmoking B. Life expectancy of a heavy smoker at age 25 is 25% shorter than nonsmoker C. After one year of cessation, CHD mortality is reduced by one-half D. Physician counseling and nicotine replacement therapy each Last double cessation rate

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V. NO EFFECTIVE SCREENING TEST FOR LUNG CANCER Guidelines for Lung Cancer Screening Organization Recommendation Year International Association for the Recommended that individuals should only 2006 Study of Lung Cancer be screened with low-dose CT in the context of well-designed clinical trials US Preventive Services Task Evidence is insufficient to recommend for 2004 Force or against screening asymptomatic persons for lung cancer with either low dose computerized tomography, chest x-ray, sputum cytology, or a combination of these tests. American College of Chest Recommended that individuals should only 2003 Physicians be screened with low-dose CT in the context of well-designed clinicalSyllabus trials American Cancer Society Recommends against routine screening of 2002 asymptomatic persons American Academy of Family Recommends against the use of chest x- 1997 Physicians ray and/or sputum cytology in asymptomatic persons Canadian Task Force on the Recommends against the use of chest x- 1994 Periodic Health Examination ray or sputum cytology in asymptomatic persons American College of Radiology Recommends(2010) against the use of chest x- 1993 ray in asymptomatic persons American College of Physicians Recommends against the use of chest x- 1991 ray in asymptomatic persons American Thoracic Society Recommends against mass lung cancer screening programs except as part of well- designed, controlled clinical trials

VI. CT SCREENING FOR LUNG CANCER A. Year's In the 1960s and 1970s, large randomized trials conducted both in the U.S. and Europe that randomized volunteers to chest x-rays or a control arm were unable to demonstrate a lung cancer mortality reduction. 1. After the National Cancer Act in 1971, there was renewed interest in lung cancer screening with chest radiographs and Last sputum cytology.

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2. Three NCI sponsored, randomized trials were conducted at the Johns Hopkins Medical Institutions, the Memorial Sloan- Kettering Cancer Center, and the Mayo Clinic. 3. In the Hopkins and Memorial trials the study population was offered yearly chest radiography plus sputum cytology every 4 months. The control population was offered yearly chest radiography only. In these trials the addition of sputum cytology appeared to confer no lung cancer mortality rate advantage. 4. Although these studies both found a higher incidence of resectable disease in the screened population, none of these experiences showed a lung cancer mortality reduction with screening. 5. Again, though these studies found higher 5-year survival rates in the screened groups, an equal number of patients in both groups eventually died from their disease. Syllabus B. NCI and Mayo Clinic following 1500 asymptomatic patients over age 50 with >20 pack-yr. smoking history with CXR 1. After 3 yrs., 2800 non-calcified nodules found in 1049 patients 2. NSCLC identified in 35 patients, 21 of whom had stage 1A disease 3. 10 patients underwent thoracotomy for benign disease 4. For former smokers, the estimated cost per yr. of quality- adjusted life would(2010) be in excess of $500,000 C. The i-ELCAP study screened 31,567 patients between 1993 and 2005 (median, 2001) (most high-risk , some in Japan non-smoker). 1. 27,456 repeat annual screenings 1994 - 2005 (median, 2002) 2. 13% (4186 of 31,567) baseline CT and 5% (1460 of 27,456) f/up CT required immediate further workup. 3. Biopsy of a pulmonary nodule 535 participants - malignant disease in 492 (479 lung cancer, 13 other malignancy), Year'sbenign in 43. 4. Estimated 10-year lung-cancer–specific survival rate was 80% (95% CI, 74 to 85), 88% (95% CI 84-91%) for stage I 5. Significant controversy about the study due to publication of 10 year survival with < 10 year median f/up, and funding from tobacco industry was initially not disclosed Last

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VII. NATIONAL LUNG SCREENING TRIAL A NCI enrolled 50,000 current or former smokers in a trial comparing CT and CXR screening B. Powered to detect a 20% reduction in lung cancer mortality C. Accrual complete, results in 2011 D. More information at www.cancer.gov/nlst VIII. PRESENTATION OF LUNG CANCER Clinical features at presentation: Anorexia/malaise 55-88% Supraclavicular nodes 26-42% Chest pain 20-33% Pleural effusion 12-33% Syllabus Hemoptysis 8-61% Cough 6-31% Neurological symptoms 4-21% Hepatomegaly 3-20%

IX. PULMONARY NODULES A. With increasing sensitivity of imaging modalities, pulmonary nodules are increasingly(2010) detected- in up to 2/3 of the population! B. Factors that favor malignancy: 1. Smoking, advanced age, spiculated margins, lack of calcification, growth C. No growth of nodules within 2 years usually signifies benignity D. Alternative etiologies: Quiescent fungal (cocci, histoplasmosis, cryptococcus), mycobacterial or viral (varicella) infections, healed granulomas, hamartoma E. Year'sDiagnostic options for identified nodules: 1. Watchful waiting over 2 years 2. Fine needle aspiration under CT guidance (80-90% sensitive, depending on size) 3. Immediate resection 4. FDG-PET imaging (only useful if nodule >7mm) LastF. Patient preference very important in choosing among nearly equivalent options

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1. Physician preference frequently determinative X. DIAGNOSIS: TISSUE IS THE ISSUE

History/Physical Exam

Chest X-ray, routine labs

Chest CT (include liver and adrenals

Bronchoscopy (central), CT or US guided

Biopsy (peripheral), Thoracentesis, or

Sputum Cytology (rarely) Syllabus

XI. LUNG CANCER HISTOPATHOLOGY A. Adenocarcinoma is the most common form (~40%) 1. Least associated with smoking and most common form in nonsmokers 2. Peripheral 75% of the time 3. Variable prognosis 4. Bronchioloalveolar(2010) cell type distinct in biology and pattern of spread XII. SQUAMOUS CELL CARCINOMA A. Second most common form; most common in smokers B. Central in distribution (60-80%), may cavitate C. Diagnosis predicated on keratin formation, intercellular desmosomes D. Better prognosis than adenocarcinoma in early stage, fewer Year'ssystemic treatment options XIII. LARGE CELL CARCINOMA A. Neuroendocrine differentiation B. Prognosis more closely resembles aggressive adenocarcinoma LastC. Frequently shows necrosis grossly

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XIV. SMALL CELL CARCINOMA (SCLC) A. Accounts for ~15% of lung Ca types B. Highly associated with cigarette smoking C. Metastasizes early and is very rarely amenable to surgical resection D. Treated with combination chemotherapy- if confined to thorax, curable in ~25% of cases with chemotherapy/radiation XV. NEUROENDOCRINE CARCINOMA A. Neuroendocrine tumors show submicroscopic cytoplasmic dense core (neuroendocrine) granules and can synthesize neuropeptides B. Carcinoids are composed of bland cells with finely dispersed chromatin – spectrum from typical carcinoid to SCLC C. Are relatively low grade tumors, and metastasize slowly, with favorable prognosis even with involvementSyllabus D. Frequently present centrally in young women XVI. SURGICAL RESECTION A. The primary cure for non-small cell (NSC) lung cancer is surgical resection but only with disease confined to the lung/lymph nodes. High relapse rates. B. Operative mortality of thoracotomy is about 2-3%, so selecting patients for resection and potential cure is a major responsibility C. In the past operations sometimes(2010) resulted in incomplete resection, frequently because of inadequate preoperative staging- less so with PET D. Clinical staging of tumors is assessed by the 1997 international lung cancer TNM staging system, updated 2009 XVII. PHYSIOLOGIC EVALUATION A. To determine operability in patients with potentially resectable disease B. Year's Pulmonary function tests C. Quantitative perfusion scan D. Cardiopulmonary exercise test for patients with borderline pulmonary function E. Non-invasive assessment of myocardial perfusion, if clinically Last indicated

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XVIII. LUNG CANCER STAGING A. Chest CT B. Mediastinoscopy or other lymph node biopsy if nodes enlarged C. FDG-PET scan may identify occult mediastinal or distant metastasis D. CT or MRI brain if clinically indicated (all but peripheral stage I) E. Biopsy confirmation of positive findings on imaging tests mandatory unless there is overwhelming evidence of metastasis XIX. PET SCANNING A. Fluorine-18 bound to a D-glucose analog (FDG) and picked up by metabolically active tissues, including tumors B. Several thousand ring detectors in a $1.8m scanner detect intracellular accumulation of FDG Syllabus C. Spatial resolution about 5 to 7 mm D. Roughly 95% sensitive and 75% specific 1. Less metabolically active tumors, like bronchioloalveolar cell, not detected XX. INTERNATIONAL LUNG CANCER STAGING SYSTEM (1997, UPDATED 2009) A. T: Tumor size and level of invasion of adjacent structures B. N: Presence or absence(2010) of nodal spread and site of nodal spread C. M: Presence or absence of distant metastases D. Clinical or Pathologic stage determined by combination of T, N and M status – most critical component of prognosis XXI. TNM STAGING A. IA: T1N0M0 B. IB: T2N0M0 C. Year'sIIA: T1N1M0 D. IIB: T2N1M0, T3N0M0 E. IIIA: T1-3 N2M0, T3N1M0 F. IIIB: T4 Any N M0, Any T N3 M0 LastG. IV: Any T Any N M1

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XXII. INTERNATIONAL STAGING SYSTEM FOR LUNG CANCER CHART (1997) International Staging System for Lung Cancer, 1997 Revision + Primary Tumor (T) T1 – Tumor < 3 cm diameter without invasion more proximal than lobar bronchus T2 – Tumor > 3 cm diameter OR Tumor of any size with any of the following: Invades visceral pleura Atelectasis of less than entire lung Proximal extent at least 2 cm from carina T3 – Tumor of any size with any of the following: Invasion of chest wall Syllabus Involvement of diaphragm, mediastinal pleura, or pericardium Atelectasis involving entire lung Proximal extent with any of the following T4 – Tumor of any size with any of the following: Invasion of mediastinum Invasion of heart or great vessels Invasion of trachea or(2010) esophagus Invasion of vertebral body or carina Presence of malignant pleural or pericardial effusion Satellite tumor nodule(s) within same lobe as primary tumor Nodal involvement (N) NO – No regional node involvement N1 – Metastasis to ipsilateral hilar and/or ipsilateral peribronchial nodesYear's N2 – Metastasis to ipsilateral mediastinal and/or subcarinal nodes N3 – Metastasis to contralateral mediastinal or hilar nodes OR ipsilateral or contralateral scalene or supraclavicular nodes Metastasis (M) Last M0 – Distant metastasis absent M1 – Distant metastasis present (including metastatic tumor

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nodules in a different lobe from the primary tumor) Stage groupings of TNM subsets Stage IA T1 N0 M0 Stage IIIA T3 N1 M0 IB T2 N0 M0 T1 -3 N2 M0 Stage IIA T2 N1 M0 Stage IIIB Any T N3 M0 IIB T2 N1 M0 T4 Any N M0 T3 N0 M0 Stage IV Any T Any N M1

+Adapted from Mountain, CF, Chest 1997; 111:1710. Syllabus

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6TH EDITION T/M AND DESCRIPTOR PROPOSED T/M

T1 (≤ 2 CM) T1A

T1 (2 – 3 CM) T1B

T2 (≤ 5 CM) T2A

T2 (5 – 7 CM) T2B

T2 (> 7 CM) T3 T3 INVASION T3 Syllabus T4 (SAME LOBE NODULES) T3

T4 (EXTENSION) T4

M1 (IPSILATERAL LUNG) T4

T4 (PLEURAL DISSEMINATION) M1A M1 (CONTRALATERAL LUNG) (2010)M1A M1 (DISTANT) M1B

PROPOSED T/M STAGE BASED ON PROPOSED T/M DEFINITIONS Year'sN0 N1 N2 N3 IA IIA IIIA IIIB

T1A IA IIA IIIA IIIB

T2A IB IIA IIIA IIIB LastT2B IIA IIB IIIA IIIB

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T3 IIB IIIA III IIIB

T3 IIB IIIA IIIA IIIB

T3 IIB IIIA IIIA IIIB

T4 IIIA IIIA IIIB IIIB

T4 IIIA IIIA IIIB IIIB

M1A IV IV IV IV

M1A IV IV IV M1B IV IV SyllabusIV IV ADAPTED FROM GOLDSTRAW P ET AL. J THORAC ONCOL. 2007;2:706-714

XXIII. MEDIASTINAL ADENOPATHY

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XXIV. SURVIVAL BY CLINICAL OR PATHOLOGIC STAGE

Syllabus

XXV. SURVIVAL IN SMALL CELL CARCINOMA

(2010)

Year's XXVI. PROGNOSTIC FACTORS BESIDES STAGE A. More differentiated tumors do better B. Lymphatic or blood vessel invasion pathologically is ominous C. Never smokers do better LastD. Women survive longer, regardless of stage or therapy

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XXVII TREATMENT OF NSCLC A. Stage I – Surgical resection with cure rates of 60-80% 1. Radiation therapy (stereotactic) an option for patients unfit for surgery, other ablation strategies under investigation 2. Controversy about adjuvant (post-operative) chemotherapy in IB B. Stage II – Surgical resection with cure rates of 50-70% 1. Adjuvant chemotherapy (or neoadjuvant (pre-operative)) with 3 months of combination treatment (cisplatin based) can improve cure rates 5-15% 2. Adjuvant radiation therapy not usually recommended C. Stage III – Controversy over best therapy with cure rates about 30% 1. Approaches include Chemotherapy +/- Radiation +/- Surgical resection Syllabus 2. Multidisciplinary discussion critical (medical oncology, radiation oncology, surgical oncology) D. Stage IV - (metastatic) – no cure, median survival about 1 year 1. Some long term survivors (5 years + ) with newer therapies 2. Chemotherapy doubles median survival, improves quality of life 3. Gradual progress with newer chemotherapy drugs 4. Newer agents target(2010) angiogenesis (VEGF) and the Epidermal Growth Factor (EGF) pathway 5. Steps in personalizing therapy being made XXVIII. TREATMENT OF SMALL CELL LUNG CANCER (SCLC) A. In limited stage SCLC (can encompass all in a radiation field), overall response rate of 80-90% with combined chemotherapy/radiation; complete remission in 50-60%, cure of 15-20% due to high relapse rate. B. In extensive stage SCLC, overall response rate of 60-80%, with Year'scomplete remission in 15-20%, almost all relapse with lower responses with second line therapy, median survival about 1 year C. Prophylactic brain radiation offered to all SCLC patients Last

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XXIX. THE CHALLENGE OF LUNG CANCER A. Overall 5 year survival remains ~15% B. Minimal funding for lung cancer research historically and currently C. Gradual improvements in surgical techniques, radiation techniques, chemotherapy and other systemic treatment D. Currently the best approach is prevention, prevention, prevention

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Last Lung Lab 2 - Faculty HHD221 Spring 2010 Page 267 Lung Lab 2

CASE 4 A 61-year-old woman complains to you of a persistent, non-productive cough. She feels "tired and run down" all the time. She finds herself short-of-breath when climbing stairs. She is afebrile, and her CBC is normal. Her CXR shows interstitial markings in both lung fields. She recently retired from her 30-year career as a Chemistry teacher at the local high school, and she has never smoked. QUESTIONS: 1. What is your differential diagnosis at this point in the history?

Syllabus

2. Is this disease acute or chronic? How might you clarify or confirm your impression?

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On further questioning, the patient reports that she had previous bouts of pneumonia spanning a period of 3 years. Review of these CXRs show interstitial infiltrates that have progressed. She also reports that she has given up playing tennis because it was too tiring. A CT scan is done [See CWP lab materials LungLab2_Case4_CT1, and _CT2] 3. How does this additional information narrow your differential diagnosis?

4. What will you do next to evaluate this patient?

Syllabus

5. What specific morphologic features on lung biopsy might help you narrow your differential?

(2010)

Examine glass slide # 140 6. Describe your findings compared to normal lung histology: Year's

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CASE 5 A 56-year-old man is brought into the Emergency Room in a somnolent condition. He appears thin and undernourished. Vital signs include: BP 90/60, P120, RR 22, and Temperature 38.0. The patient was found in a city park and the ambulance driver suspects that he may be a homeless person. At the time you see the patient, he is unable to give a coherent history.

PE: There is a slight odor of alcohol on the breath of the patient. There is dullness to percussion over the right upper lung fields, rhonchi in same area.

LAB: CBC: Hgb 9.0, HCT 30%, MCV 120, WBC 14,400 (44% PMNs, 4% bands, 32% lymphs, 4% eos, and 16% monos). CXR: [See CWP LungLab2_Case5_CXR1] Syllabus QUESTIONS: 1. What is your single most likely diagnosis?

2. Examine slide #18 from your Pathology(2010) slide set. Describe your findings.

3. What is your anatomic diagnosis?

Year's

4. What is the pathophysiology of this disease? Last

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You are asked to consult on an AIDS patient with respiratory distress, who has the process shown in the provided CXR [See CXR in CWP LungLab2_Case5_CXR2] and in your glass slide #24. 5. Describe your findings from Slide 24:

6. What is your anatomic diagnosis? Syllabus

7. How does the pathophysiology of this disease differ from that in slide #18?

(2010)

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CASE 6 A 61 year old man presents with dyspnea, cough, fatigue, and a weight loss of 15 pounds over 6 months. Recently he has become confused and disoriented. He has an 80 pack-year history of cigarette smoking.

PE: Decreased breath sounds in the right lung.

QUESTIONS: 1. What is your differential diagnosis at this point?

Syllabus Laboratory Finding: Marked hyponatremia

Radiology: [See original CXR and Chest CT scan in CWP LungLab2_Case6_CXR and _CT]

(2010) 2. What is your differential diagnosis now?

3. Look at the Slide #131. Does this confirm your impression? How is the processYear's spreading?

4. How do you explain this patient’s confusion and disorientation?

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5. Is this process amenable to a surgical cure? Why?

6. Where are common secondary (distant) sites for this process? [See CWP LungLab2_Case6_Gross]

7. How do the other major histologic variants of tumor behave differently?

Syllabus

8. In a patient with a similar process how might you explain: a. Weakness and hypokalemia?

b. Proximal muscle weakness,(2010) diplopia, and bilateral ptosis?

c. Unilateral ptosis, miosis, and anhidrosis?

Year's

d. Hoarseness?

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I. CLINICOPATHOLOGIC FEATURES OF CANCER A. Cancer diagnosis B. Predicting cancer behavior = guiding cancer therapy II. FEATURES TO SUGGEST THE PRESENCE OF CANCER A. Mass noted on exam or imaging studies

Syllabus

(2010)

B. Impingement of adjacent structures C. Functional activity (eg hormone synthesis) D. Bleeding E. Year'sSecondary infections F. Rupture or infarction G. Cachexia H. Paraneoplastic syndromes Last

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III. INITIATION OF CANCER EVALUATION/DIAGNOSIS History

Physical Exam

Imaging Studies Lab tests

Biopsy

A. Methods of biopsying tissue 1. Excisional biopsy Syllabus

2. Incisional biopsy(2010) 3. Punch biopsy

Year's

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4. Fine needle aspiration

Syllabus 5. Core needle biopsy

6. Endoscopic biopsy (2010)

Year's

7. Curettage B. Why not assume everything is cancer? 1. Clinically observed mass Last a. Infection (new or old) b. Benign growth

Clinical Features Of Tumors - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 276

2. Clinical symptoms a. Chronic inflammation b. Chronic bleeding IV. DIAGNOSIS OF CANCER AND DETERMINATION OF PROGNOSIS A. Major Determinants of Prognosis 1. Site of Origin

Syllabus

Basal cell carcinoma Pancreatic carcinoma a. Early versus late detection b. Ease of surgical excision c. Biological nature of tumors 2. Cancer Type a. Neoplasm – any growth due to a single clone b. Tumor – a mass, not necessarily a growth or even due to cell(2010) proliferation c. Cancer – a malignant neoplasm 3. Cancer grade 4. Cancer stage B. Trends of Malignant 1. Metastasize Year's

Last

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2. Invade local structure C. Trends of Benign versus Malignant Benign Malignant Syllabus Circumscribed Infiltrative borders Homogenous Necrosis Cells resemble normal counterparts Nuclear atypia High mitotic index D. Benign (2010)

Year's Leiomyoma (uterus) Thyroid adenoma Last

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Thyroid Adenoma E. Malignant Syllabus

Colonic adenocarcinoma Pleomorphic sarcoma (2010)

Breast carcinoma V. BEFORE THE MASS A. Carcinoma in situ Year'sThe tumor cells are still confined to the site where they originated and they have neither invaded neighboring tissues nor metastasized afar. B. Dysplasia Last Disorderly proliferation of cells; a premalignant condition.

Clinical Features Of Tumors - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 279

C. Metaplasia The occurrence of one cell type in place of another; often a response to injury.

Syllabus

VI. MANAGERIAL NEOPLASM CATEGORY A. Clinically benign 1. Local excision is always curative 2. Metastasis never occurs B. Recurrences do occur but are not destructive 1. Metastasis never(2010) occurs C. Clinically malignant 1. Local recurrence common 2. Metastasis occurs 3. Metastasis assumed to be present at time of diagnosis D. Clinically intermediate 1. Local recurrence common and may be destructive a. Metastasis never occurs Year's2. Local recurrence common a. Metastasis very rare, unless tumor “dedifferentiates” 3. Local recurrence common a. Metastasis can rarely occur without dedifferentiation E. Cancer types Different behaviors and different therapies Last 1. Carcinoma

Clinical Features Of Tumors - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 280

Cancer of epithelium

2. Sarcoma Cancer of mesenchymal connective tissue Syllabus

3. Leukemia/lymphoma Cancer of hematopoietic cells (2010)

Year's VII. GRADING AND STAGING OF TUMORS A. Grade Grade reflects the degree of differentiation of the tumor cells (i.e. describes the degree to which the tumor cells resemble normal Last cells of the same tissue type) and often requires assessment of: 1. architecture of the neoplasm

Clinical Features Of Tumors - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 281

2. nuclear features 3. mitotic activity 4. cytoplasmic differentiation

Low grade adenocarcinoma High grade adenocarcinoma B. Stage Syllabus Stage describes the extent of spread of the cancer and helps determine the managerial category C. Local invasion 1. Capsule formation 2. Infiltrative local invasion 3. Expansile mass – easily movable, well- defined cleavage plane 4. Perineural invasion(2010)

D. Metastasis 1. Seeding of body cavities and surfaces 2. Lymphatic spread 3. Hematogenous Year'sspread

Last

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Colonic adenocarcinoma metastatic Carcinomatosis of abdominal wall to liver

VIII. STAGING CRITERIA A. For most cancers, the stage is based on 3 main factors: 1. The size of the primary (original tumor) and Syllabuswhether the tumor has grown into nearby structures.

(2010)

2. Lymph node involvement by cancer

Year's

Last

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3. Metastasis to distant body sites

B. Primary tumor (T) Syllabus

(2010)

C. Year's Regional lymph nodes (N)

Last

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D. Distant metastases (M) Syllabus

E. Stage grouping

(2010)

Year's

Last

Clinical Features Of Tumors - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 285

F. Non small cell lung cancer survival by stage

G. Treatment options: Stage I Lung NSCLC Syllabus 1. Surgery a. Wedge resection b. Segmental resection c. Lobectomy 2. External radiation therapy 3. Surgery followed by chemotherapy 4. Clinical trial 5. Watchful waiting(2010) 6. External radiation therapy for palliation 7. Chemotherapy 8. Clinical trial IX. LABORATORY DIAGNOSIS OF CANCER A. Prognostic/Predictive markers 1. Diagnostic marker AnalyteYear's to provide pathologist with additional data for diagnosis 2. Prognostic marker Marker independent of clinicopathologic features to indicate natural outcome of neoplasm 3. Therapeutic (predictive) marker Marker independent of clinicopathologic features to indicate response to Last therapy B. Histology and cytology

Clinical Features Of Tumors - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 286

C. Immunohistochemistry 1. Immunohistochemistry to determine origin of tumor

2. Immunohistochemistry to determine presence of therapy targets Syllabus

Estrogen Receptor HER2/neu

D. FISH (2010) 1. FISH to determine presence of pathognomonic translocation

Year's

Last

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2. FISH to determine presence of HER2 amplicon

E. PCR F. DNA sequencing G. Flow cytometry H. Tumor markers I. Serum markers Syllabus Examples: 1. Prostatic specific antigen 2. Alpha fetoprotein 3. CA125 J. Gene expression arrays (2010)

Year's

Last

Syllabus

(2010)

Year's

Last Human Cancer Biology - Joseph Lipsick, M.D., Ph.D. HHD221 Spring 2010 Page 289 BASICS OF CANCER BIOLOGY

LEARNING OBJECTIVES: A. Impact of cancer on human population B. Classification of human cancer C. Cancer arises from a single cell D. Causes of human cancer E. Mutagens are carcinogens I. IMPACT OF CANCER ON THE HUMAN POPULATION A. Leading Causes of Death in U.S. Syllabus

(2010)

B. Change in Causes of Death

Year's

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C. Invasive Cancer versus Age

Syllabus D. How Many Events to Cause Cancer?

(2010)

Year's

Last

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E. Cancers by Type in U.S.

Syllabus

from American Cancer Society

F. Cancer Incidence Rates* for Men, 1975-2002 (2010)

Year's

Last

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G. Cancer Death Rates in U.S. by Gender and Site

Syllabus from American Cancer Society

H. Lung Cancer and Smoking in US

(2010)

Year's

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I. Cancer Death Rates*, by Race and Ethnicity, US,1998-2002

Syllabus J. Mammogram Prevalence Women 40 and Older, US, 1991-2004

(2010)

Year's

Last

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K. Fecal Occult Blood Test Prevalence Adults 50 Years and Older, US, 1997-2004

Syllabus II. CLASSIFICATION OF HUMAN CANCER A. Diagnosis of Neoplasia

(2010)

B. The Vocabulary Hyperplasia – increased number of cells Year'sHypertrophy – increased size of cells Dysplasia – disorderly proliferation Neoplasia – abnormal new growth Anaplasia – lack of differentiation Tumor – originally meant any swelling, but now equated with neoplasia Last Metastasis –growth at a distant site

Human Cancer Biology - Joseph Lipsick, M.D., Ph.D. HHD221 Spring 2010 Page 295

C. Colonic Polyps

from Rubin and Farber, Pathology D. Histology of Colonic Polyps Syllabus

from Kinzler and Vogelstein, Cell 1996 E. Colon Cancer (2010)

Year's from WebPath

Last

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F. Classification of Neoplasms Benign Tumor (-oma) Adenoma (“adeno-” means gland-like) Fibroma Lipoma (“lipo-” means fat)

Malignant Cancer (carcinoma or sarcoma) Adenocarcinoma Fibrosarcoma (“sar-” means fleshy) Liposarcoma

Leukemia and Lymphoma

G. Carcinoma vs Sarcoma Syllabus

(2010)

H. Types of Epithelia

Year's

Last from Junqueira, et al., Basic Histology

Human Cancer Biology - Joseph Lipsick, M.D., Ph.D. HHD221 Spring 2010 Page 297

I. Epithelial Origin of Glands

Syllabus

from Poirier and Dumas, Review of Medical Histology

J. The Prognosis (2010)

Year's

“It’s tough to make predictions, especially about the future.” Last

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K. Neoplasms BENIGN MALIGNANT NON-INVASIVE INVASIVE / METASTATIC ~well-defined borders ~irregular borders ~well differentiated ~poorly differentiated ~regular nuclei ~irregular, larger nuclei ~rare mitoses ~more frequent and/ or abnormal mitoses

L. Growth Fraction and Doubling Time Syllabus

(2010)

M. Predictors of Behavior Year'sGrade – How bad do the cells look?

Stage – Where has the cancer spread? Tumor Nodes (Lymph) Metastases Last

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N. Metastasis

Seeding body cavities Lymphatic drainage to lymph nodes Hematogenous via blood vessels

O. Staging Colon Cancer

Syllabus

from Rubin and Farber, Pathology III. CANCER ARISES FROM A SINGLE(2010) CELL

Year's

1858 – Rudolf Virchow proposes that “omnis cellula e cellula”. All cells come from cells. Metastatic cancer cells resemble the primary. Last All cells of a cancer come from a single cell.

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A. Cancer Arises from a Single Cell Cancers are usually clonal in origin. X-inactivation studies in human cancer Transformation observed in cell culture.

B. Tumor Clonality by X-Inactivation

Syllabus

C. Tumor Clonality as a Diagnostic Immunoglobulin and TCR genes rearrange Rearrangements are unique in each cell Rearrangements display allelic exclusion

D. Clonality of Lymphoid Proliferation(2010) Cell Type Benign Malignant B Lymphocyte Ig Light Chain Ig Kappa or Lambda Only Heterogeneity Plasma Cells Heterogeneous Ig Monoclonal Ig Spike Electrophoresis T Lymphocyte Heterogeneous Variable Homogeneous Variable Regions Regions E. Year's Cancer: Selection for Single-Cell Survival in a Multi-Cellular Organism Cells must make critical decisions: Stem cell renewal Differentiation Growth vs quiescence Cell death Last Things can go wrong at all of these levels.

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IV. KNOWN CAUSES OF HUMAN CANCER Chemical Exposure Tobacco smoke Environmental (PCBs) Occupational (coal tar, asbestos) Diet (aflatoxin) Radiation (UV, ionizing) Infection Viruses (EBV, HepB, HPV) Bacteria (Helicobacter) Inherited familial cancer syndromes (very rare)

A. Enough S’nuff – The Sot Weed Factor Syllabus

(2010)

1761 – Sir John Hill notes that snuff causes nasal cancer Nature or "nurture"?

Year's

Last

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B. Human Migration and Cancer

Syllabus

from Rubin and Farber, Pathology C. Same Virus, Different Outcomes (2010)

Year's

Last

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D. Estimates of Avoidable Cancer Deaths

Peto, 2001 Syllabus V. MUTAGENS ARE CARCINOGENS A. Coal Tar is a Carcinogen -- Observation

(2010)

1775 – Percival Pott discovers “occupational cancer” of scrotum in chimney sweeps and in hands of gardeners who spread coal tar Year's

Last

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B. Coal Tar is a Carcinogen -- Experiment

1891 -- Katsusabura Yamagiwa shows that coal tar causes skin cancer when painted on rabbits’ ears.

C. Radiation Causes Cancer Syllabus

(2010)

1908 – Clunet shows that X-rays cause cancer in animals.

D. X-Rays Are Mutagens Year's

Last

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E. Carcinogens Are Mutagens X-rays are carcinogenic X-rays cause mutations Therefore, carcinogens are mutagens? Puzzle: Ames test for mutagens in Salmonella scores some by not all carcinogens

F. Modified Ames Test for Carcinogens

Syllabus

G. Mutagens are Carcinogens(2010)

Year's

Last

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H. What About Hormones?

SUMMARY Syllabus A. Cancer is a leading cause of death in US. B. Studies of human migration imply environmental causes of common cancers. C. Smoking, radiation, occupational hazards, and some infections cause cancer. D. Grading and staging predict the behavior of cancers. E. Cancer arises from a single cell (clonal). F. Mutagens are carcinogens.(2010)

Year's

Last

Molecular Basis Of Cancer 1 - Michael Cleary, M.D. HHD221 Spring 2010 Page 307 Molecular Basis of Cancer I

Recommended reading: “Pathologic Basis of Disease”, 8th edition, Chapter 6.

ESSENTIAL CONCEPTS 1. Cancers display six hallmark features as a consequence of acquired mutations, which are facilitated by relative deficiencies in the repair and sensing of DNA damage.

2. Mutations of cellular oncogenes cause self-sufficiency of growth signals, which normally comprise a myriad of pathways initiating at the cell membrane and ultimately impinging on the nuclear cell cycle machinery.

3. Loss of tumor suppressor gene function results in the insensitivity to growth-inhibitory signals. Syllabus 4. The RB pathway is critical for cellular growth control and disrupted by a variety of mechanisms in virtually all cancer cells.

5. TP53 is a guardian of the genome and of the tissue that orchestrates graded responses of senescence, cell cycle arrest or apoptosis.

6. Telomere biology plays both protective and enabling roles in cancer pathogenesis. (2010)

Year's

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I. HALLMARK FEATURES OF CANCER CELLS A. Cancer: basic principles 1. Non-lethal genetic damage is critical. 2. Enabled by defects in sensing and repair of DNA damage. 3. Multistep process at phenotypic and genetic levels. 4. Arises from tissue-specific stem cells and progenitors. B. Six hallmark features of cancer cells

Syllabus

C. Important terminology (2010) 1. Proto-oncogenes Normal cellular genes that can be converted into oncogenes by mutation or over-expression. 2. Oncogenes Mutated cellular genes (or viral genes) whose products (onco-proteins) promote the development of cancer. 3. Tumor suppressor genes Cellular genes whose products normally suppress the Year'sformation of cancer. II. ONCOGENES AND GROWTH CONTROL A. Self-sufficiency in growth signals The run away car analogy “The accelerator is stuck on” LastB. Control of cell proliferation

Molecular Basis Of Cancer 1 - Michael Cleary, M.D. HHD221 Spring 2010 Page 309

Syllabus C. Growth factors, receptors and their targeted therapies: 1. Growth factors Autocrine production of growth factor to which cancer is responsive (e.g. PDGF secretion by glioblastomas). 2. Growth factor receptors Over-expression of receptor confers hyper-response to normal growth factor levels. a. EGF receptor (ERBB1) in various carcinomas (e.g. lung, colon).(2010) b. HER2 (ERBB2) in breast carcinomas. 3. Targeted therapies Erbitux (anti-EGFR antibody) (Imclone) Herceptin (anti-HER2 antibody) (Genentech) D. Signal-transducing proteins RAS--most common oncogene abnormality. Year'sIntrinsic GTPase activity abrogated by point mutations.

Last

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E. Nuclear transcription factors MYC--most commonly involved (translocations, amplifications) Regulates cell cycle control genes among many others.

F. Deregulated gene expression following promoter/enhancer substitution Syllabus

(2010)

G. Cyclins & cyclin-dependent kinases Ultimate goal of growth-promoting signals = entry of cells into the cell cycle. 1. Cell cycle goals: Year's

Last

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2. CDKs drive the cell cycle a. Cyclin-Dependent Kinases Phosphorylate key targets. Inactive forms expressed constitutively. b. Cyclins Cyclic production & degradation activates CDKs.

Syllabus

3. The cell cycle: a relay race of CDKs & cyclins (2010)

Year's

Last

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4. CDK inhibitors: brakes on the cell cycle

Syllabus H. Growth and anti-growth signaling

(2010)

Year's

III. TUMOR SUPPRESSOR GENES A. Insensitivity to growth-inhibitory signals Last “The brake is broken”

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1. Retinoblastoma 40% heritable Autosomal dominant trait Recessive mechanism Leukocoria (cat’s eye reflex)

B. Retinoblastoma genetics Syllabus

C. The Rb pathway (2010) Proliferative signals Cyclin D CDK4 P Year'spRB S phase E2F entry

Last

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D. Disruption of the Rb pathway in most human cancers Syllabus

(2010) 1. RB loss a. Retinoblastomas--100% b. Breast, small cell lung & bladder carcinomas 2. Cyclin D over-expression a. Malignant lymphoma b. Breast, esophageal & liver cancers 3. CDK4 over-expression a. Amplifications in melanomas, sarcomas & Year'sglioblastomas 4. INK4A loss a. Melanoma-prone kindreds--25% b. Pancreatic carcinoma--75% c. Glioblastomas--40-70% d. Esophageal, non-small cell lung & bladder Last carcinomas

Molecular Basis Of Cancer 1 - Michael Cleary, M.D. HHD221 Spring 2010 Page 315

E. TP53: guardian of the genome and the tissue 1. p53 acts as a cellular stress sensor

Syllabus

2. Guardian of the genome

(2010)

Year's

Last

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3. The pathway of p53-induced G1 arrest

Syllabus 4. p53 serves as an inducer of apoptosis “Guardian of the tissue”

(2010)

A fail-safe mechanism against “inappropriate” proliferation Year's

Last

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5. Two pathways lead to p53 activation and are disrupted by mutations in cancer cells.

F. Many tumor suppressors identified in familial syndromesSyllabus play a role in sporadic cancer Gene Familial syndrome Sporadic cancers RB Familial retinoblastoma lung, prostate, bladder P53 Li-Fraumeni many: colon, lung, etc. WT1 Wilms tumor nephroblastoma NF1 Neurofibromatosis type 1 neuroblastoma NF2 Neurofibromatosis type 2 schwannomas, meningiomas VHL Von-Hippel Lindau(2010) renal cell carcinoma APC Familial adenomatous colon cancer polyposis INK4a Familial melanoma melanoma, pancreatic PTC Gorlin syndrome basal cell carcinoma, medulloblastoma PTEN Cowden disease glioblastoma, prostate, breast BRCA1 Familial breast cancer breast cancer BRCA2 Familial breast cancer under investigation Year's G. Tumor suppressor genes – two functional categories: 1. Caretakers Do not directly promote growth of tumors. Inactivation leads to genetic instability and increased mutation rate. 2. Gatekeepers Last Directly regulate the growth of tumors by inhibiting their growth or promoting their death.

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IV. PROGRAMMED CELL DEATH & CANCER A. Evading apoptosis “The ignition is locked on” B. Necrosis versus apoptosis

Syllabus

C. Tumor cells evade cell death by various mechanisms

(2010)

Year's

V. CELLULAR IMMORTALITY A. Limitless replicative potential Last “The gear can’t be disengaged”

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B. Telomere biology contributes to genome stability and cellular immortality C. Normal human cells have a limited proliferative lifespan

Syllabus

D. Telomeres are simple repeats

1. Caps at chromosome ends that prevent loss of genomic sequence during(2010) replication. 2. Simple tandem repeats of G-rich sequence TTAGGG (in humans) 3. 5’ end replication problem leads to telomere attrition (approx. 100 bp per cell division). E. The end-replication problem Year's

Last

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F. Telomerase

1. Specialized reverse transcriptase that maintains telomere length by adding new repeats. 2. Loss of expression limits replicative capacity, but also prevents outgrowth of transformed cells. G. The telomere hypothesis of cancer Syllabus

(2010)

1. Telomere shortening activates responses that prevent cancer formation. 2. Senescence and crisis responses suppress tumor formation. 3. Telomerase reactivation is a rate-limiting step in human Year'stumorigenesis. 4. Aspiring cancer cells must negotiate these responses while transitioning from a telomerase- state to a telomerase+ state. Last

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H. Double-edged sword of telomere-division limitation

I. Telomere uncapping activates a DNA damage responseSyllabus

(2010)

Year's

Last

Syllabus

(2010)

Year's

Last Molecular Basis Of Cancer 2 - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 323 Molecular Basis of Cancer Part 2

I. HALLMARKS OF CANCER: √ √ √

Syllabus

Genomic instability Figure 1. Weinberg & Hanahan 2000. Weinberg & Hanahan described six hallmarks of cancer. This section focuses on angiogenesis, invasion & metastasis, and a seventh hallmark, genomic instability. (2010) II. SUSTAINED ANGIOGENESIS A. Tumors cannot enlarge beyond 1-2 mm in diameter unless vascularized. 1. Limit of diffusion of oxygen and nutrients from blood vessels B. Neovascularization provides oxygen and nutrients, growth factors from endothelial cells, and a route for metastasis. III. NEOVASCULARIZATIONYear's A. Recruitment of endothelial cell precursors or sprouting of existing capillaries. Last

Molecular Basis Of Cancer 2 - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 324

Figure 2. RobbinsSyllabus and Cotran B. Similar to physiologic angiogenesis, but tumor blood vessels are tortuous, irregularly shaped and leaky. IV. TUMOR ANGIOGENESIS Tumors produce several angiogenic factors. Two important factors are Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Tumor growth beyond 1-2 mm is dependent on angiogenic switch, tilting balance in favor of angiogenesis factors. A. Tumor-associated angiogenic factors are produced by tumor cells or from inflammatory cells(2010) (e.g., macrophages) that infiltrate tumors 1. VEGF, bFGF B. “Angiogenic switch” (Folkman & Hanahan) 1. Hypoxia, p53 mutation, ↓ thrombospondin-1, ↑ HIF1 and VEGF V. ANTI-ANGIOGENESIS FACTORS Tumors also induce anti-angiogenesis factors. Several are proteolytic cleavageYear's products of larger proteins. Inhibitors of angiogenesis are a new promising class of cancer therapeutics. A. Thrombospondin-1 B. Proteolytic cleavage products 1. Angiostatin (plasminogen) Last 2. Endostatin, tumstatin (collagens)

Molecular Basis Of Cancer 2 - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 325

C. Therapeutics (Judah Folkman) 1. Endostatin 2. Anti-VEGF and VEGF-R2 antibodies 3. Small molecule inhibitors of VEGF-R2

Syllabus

Figure 3. After 12 days endostatin therapy (Boehm, Nature, 1997 ). VI. ANTI-ANGIOGENESIS THERAPY

(2010)

P<0.001

Figure 4. Hurwitz, NEJM, 2004 A. Bevacizumab (Avastin®), anti-VEGF antibody, prolongs survival in Year'smetastatic colorectal cancer B. Few side effects VII. TISSUE INVASION A. The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. LastB. Next to metastasis, invasiveness is the most reliable feature that differentiates malignant from benign tumors.

Molecular Basis Of Cancer 2 - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 326

Benign breast tumor Malignant breast tumor Figure 5. Robbins and Cotran VIII. INVASION OF EXTRACELLULAR MATRIX A. Detachment ("loosening up") of the tumor cells from each other 1. Down-regulated expression of E-cadherin (which mediates homotypic adhesions in epithelial tissue) Syllabus B. Attachment to matrix components 1. Altered expression of integrins C. Degradation of ECM 1. Matrix metalloproteinases (infiltrating macrophages); therapeutic role of MMP inhibitors 2. Release of growth, angiogenic and chemotactic factors from ECM D. Migration of tumor cells(2010) IX. EPITHELIAL-MESENCHYMAL TRANSITION A. Reminiscent of EMT, a process occurring during tissue patterning in normal embryologic development. Year's

Last

Molecular Basis Of Cancer 2 - Robert West, M.D., Ph.D. HHD221 Spring 2010 Page 327

B. Drivers and Mediators of EMT

Syllabus

Figure 7. Massague, 2004. Molecular pathways of EMT. Convergence on repression of E-cadherin expression. X. METASTASIS Metastasis marks a tumor as malignant because benign neoplasms do not metastasize. With few exceptio(2010)ns, all cancers can metastasize. Metastatic spread strongly reduces the possibility of cure; hence, short of prevention of cancer, no achievement would confer greater benefit on patients than methods to block distant spread.

A. Pathways of Spread 1. Seeding of body cavities and surfaces a. e.g. ovarian cancer seeding peritoneal cavity 2. Lymphatic spread Year'sa. Pattern of lymph node involvement follows natural routes of lymphatic drainage, e.g. breast cancer to axillary lymph nodes. b. Biopsy of sentinel nodes 3. Hematogenous spread a. In venous spread, the liver (portal drainage) and lungs Last (caval drainage) are most often involved

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Metastasis to liver

Figure 8. Robbins and Cotran. B. Metastatic Cascade 1. Metastasis is an inefficient process Syllabus

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(Robbins, p. 311). C. Sites of Metastasis Different tumor types have different preferred sites of metastasis. 1. Anatomic drainage Year's2. Adhesion to organ-specific endothelial surface molecules 3. Chemokines (normal roles in leukocyte trafficking) a. Some breast cancer cells express CXCR4 and CCR7, receptors for chemokines expressed by lymph nodes and lung 4. “Seed and soil” hypothesis; organ microenvironment Last (Stephen Paget; 1889)

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D. Genetics of Metastasis In early studies in mice, different tumor cell clones have different propensities to metastasize, suggesting metastasis genes. Yet few have been identified.

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Figure 10. Fidler, 2003, Nat Rev Cancer. Metastasis genes? A new model of metastasis? (2010)

E. Metastasis Signature in Primary Tumor In microarray studies, gene-expression signature distinguishes primary and metastatic cancers. But, some primary tumors have metastatic signature, which is predictive of unfavorable outcome. Year'sSuggests metastatic propensity encoded in bulk of tumor cells, not rare cell. Last

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17-gene signature predicts outcome Syllabus

Ramaswamy, 2003, Nat Genet.

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F. Stromal contribution Metastatic signature includes stromal genes. Underscores contribution of stroma to tumor progression. Table 1 – The 17-gene signature associated with metastasis Gene Gene name GenBank ID Up-regulated in metastases: SNRPF Small nuclear ribonucleoprotein F AI032612 EIF4EL3 Elongation initiation factor 4E-like 3 AF038957 HNRPAB Heterogeneous nuclear ribonucleoprotein M65028 A/B DHPS Deoxyhypusine synthase U79262 PTTG1 Securin AA203476 COL1A1 Type 1 collagen, α1 SyllabusY15915 COL1A2 Type 1 collagen, α2 J03464 LMNB1 Lamin B1 L37747 Down-regulated in metastases: ACTG2 Actin, γ2 D00654 MYLK Myosin light chain kinase U48959 MYH11 Myosin, heavy chain 11 AF001548 CNN1 Calponin 1(2010) D17408 HLA-DPB1 MHC Class II, DPβ1 M83664 RUNX1 Runt-related transcription factor 1 D43969 MT3 Metallothionein 3 S72043 NR4A1 Nuclear hormone receptor TR3 L13740 RBM5 RNA binding motif 5 AF091263 Ramaswamy,Year's 2003, NAT Genet.

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XI. ROLE OF STROMAL MICROENVIRONMENT Carcinoma-associated fibroblasts (CAF), but not normal-associated fibroblasts (NAF), when combined with immortalized but non-tumorigenic prostate epithelial cells (BPH-1) give rise to tumors in athymic mice.

XII. CARCINOGENESIS Syllabus A. Carcinogenesis is a multi-step process Evidence that cancer initiation requires mutation of multiple genes. 1. Epidemiology a. Cancer incidence increases exponentially with age 2. Experimental models of chemical carcinogenesis a. Initiation and promotion 3. DNA transfection experiments a. Co-transformation with MYC and RAS b. Minimal set(2010) of genetic alterations: hTERT; RAS; SV40 T (Rb, p53, protein phosphatase 2A) (R. Weinberg) 4. Molecular genetic analysis of human tumors B. Colorectal Carcinogenesis Colorectal cancer has been a useful system to study stepwise progression. Year's

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Figure 14. Kinzler & Vogelstein. C. Multi-step Carcinogenesis “Menu” of multi-step carcinogenesis. Syllabus

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~4-8 alterations

Figure 15. Weinberg & Hanahan 2000. XIII. DNAYear's SEQUENCE CHANGES

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XIV. CHROMOSOME TRANSLOCATIONS

Over-expression of oncogene

Creation of oncogenicSyllabus fusion protein

XV. ANEUPLOIDY (2010)

A. Gain of oncogenes B. Loss of tumor suppressor genes Year's

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XVI. LOSS OF HETEROZYGOSITY (LOH)

Syllabus XVII. LOCALIZED AMPLIFICATION N-myc amplification in neuroblastoma linked to poor prognosis.

• N-myc amplification in (2010)neuroblastoma

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XVIII. EPIGENETIC CHANGES: ABERRANT DNA METHYLATION Epigenetic changes are heritable in the short term (i.e. maintained through cell division), but do not involve mutations in the DNA itself. Two main types are DNA methylation and histone modification (acetylation, methylation).

A. DNA is methylated on cytosine of CG dinucleotides B. Focal hyper-methylation within “CpG islands” inactivates tumor suppressor genes Syllabus

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Paradox: Mutation rate in normal cells is so low that if multiple mutations are required, cancer should never arise. Last

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XIX. INSTABILITY Hypothesis: An early mutation occurs in a mutator (caretaker) gene, thereby increasing rate of subsequent mutation in precancerous cells. A. Genomic Instability 1. “Caretaker genes”

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Figure 24. L. Loeb. B. Microsatellite Instability (MSI) 1. Hereditary nonpolyposis colorectal cancer; 15% of sporadic colon cancer 2. Defects in mismatch(2010) repair (MLH1, MSH2)

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MSI arises from defects in mismatch repair, causing genome-wide expansion/retraction of short simple nucleotide repeats (micro-satellites; seen in PCR assay). This results in frameshift mutations, which create premature termination and functional loss of tumor suppressor genes such as TGFbRII. C. Chromosome Instability (CIN) 1. Familial adenomatous polyposis syndrome (APC mutation); 85% of sporadic colorectal cancer 2. Defects in chromosome segregation, DNA double-strand break repair, telomeres

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Chromosome instability (CIN) is less well understood, but may arise from defects in chromosome segregation, DNA double strand break repair, or telomere function, and results in unbalanced translocations, and chromosome gains and losses(2010) (seen by spectral karyotyping), which e.g. can result in loss of tumor suppressor genes like p53 or APC.

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XX. TUMOR PROGRESSION AND HETEROGENEITY

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Figure 27. Robbins and Cotran. Genomic instability creates tumor heterogeneity, which with selective pressure facilitates tumor progression and drug resistance. Analogy with organismal evolution. (2010)

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Last Tumors Of The Lung - Charles Lombard, M.D. HHD221 Spring 2010 Page 341 TUMORS OF THE LUNG

ASSIGNED READING: Robbins pages 757-766

INTRODUCTION Although both benign and malignant lung tumors occur, most tumors of the lung are malignant. In the early 1900’s lung cancer was considered a rare tumor. However with widespread abuse of cigarette smoking, lung cancer has become the most common cause of death from neoplasms, both worldwide (921,000 in 1998) and in the USA (197,000 in 1999). In women, lung cancer death rates have (1985) surpassed the death rate from breast cancer. Although smoking is clearly the primary exogenous casual factor implicated in the overwhelming majority of cases of lung cancer, there is recent evidence suggesting some genetic predisposition to the development of the disease. Ability to metabolize carcinogenic substances varies and measurable differences in metabolismSyllabus that appear to correlate with susceptibility to lung cancer in smokers have been described.

We will examine only the most important and common tumors of the lung in this section.

I. CLASSIFICATION OF COMMON LUNG TUMORS A. BENIGN TUMORS 1. Hamartoma (2010) B. LOW GRADE MALIGNANCIES 1. Carcinoid C. BRONCHOGENIC CARCINOMAS 1. Squamous cell (epidermoid) carcinoma 2. Adenocarcinoma 3. Bronchoalveolar carcinoma 4. Large cell undifferentiated carcinoma Year's5. Small cell (oat cell) carcinoma D. METASTATIC NEOPLASMS II. EXPLANATORY NOTES A. HAMARTOMA 1. These lesions have a somewhat controversial histogenesis. For many years they have been regarded as localized Last development tissue abnormalities. However, it is clear that most are not congenital but rather, arise in adults. Some

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have postulated that they are unusual responses to injury. However, many now believe that these hamartomas are simply benign neoplasms. Regardless of their histogenesis, the term hamartoma is well ingrained in the literature and is unlikely to change. These lesions are grossly well circumscribed (1-3 cm diameter). Most are found in peripheral regions of the lung. Microscopically, hamartomas consist of an unorganized conglomeration of well- differentiated cartilage, connective tissue, and epithelium. The lesions are expansile but not invasive. They account for about 10% of solitary lung nodules. 2. There are a wide variety of other benign lung tumors, however, they are all rare: hemangiomas, chondromas, lipomas, and benign clear cell tumors to name a few. B. low grade malignant tumors 1. Carcinoid Syllabus This tumor is found most commonly in middle-aged people who are non-smokers. They usually arise in a central location (80%). Common symptoms at presentation include: cough, hemoptysis, and fever with post-obstructive pneumonia. These tumors only rarely produce the carcinoid syndrome (palpitations, tachycardia, flushing, and diarrhea) that is seen with intestinal carcinoid tumors. Although 5-10% of these tumors present with regional lymph node metastases, the survival with resection is excellent. These tumors are only rarely responsible for a patient's death. Histologically, these(2010) tumors have a variety of patterns with nests, ribbons, and cords of cells. Cytologically, they are uniform without appreciable mitotic activity. The most outstanding feature of these tumors is that the cells contain large numbers of neurosecretory granules. They can be identified by silver stains (argyrophil stain), immunoperoxidase stains (chromogranin A), and also by electron microscopy ("dense core granules"). They are highly vascular and frequently have a prominent endobronchial growth pattern. These features account for Year'sthe clinical features of hemoptysis and post-obstructive pneumonia. Rarely a carcinoid tumor shows atypical features: nuclear atypia, mitoses, and tissue necrosis. These tumors are more aggressive and are called atypical carcinoid tumors. The survival is poorer with a 5-year survival of about 50%. Unlike the usual carcinoid tumor these most frequently arise Last in smokers.

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2. Other Interesting but Rare Tumors Sclerosing hemangioma, oncocytoma, epithelioid hemangioendothelioma, cystic carcinoma, mucoepidermoid carcinoma, ... C. BRONCHOGENIC CARCINOMAS These have been traditionally lumped into two major groups for clinical purposes: Small cell undifferentiated carcinomas (oat cell carcinoma) and Non-small cell lung carcinomas (NSCLC i.e. squamous carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma). The presentation, clinical behavior, and response to therapy are very different between these two groups. Even among the NSCLCs there are some differences in presentation and clinical behavior. 1. Squamous Cell Carcinoma These account for about 33% of bronchogenic lung carcinomas and are far more common in menSyllabus than women (even among smokers). Most of these tumors arise from large bronchi and form large central masses. Consequently, they present with cough, hemoptysis and symptoms of post obstructive pneumonia. These tumors are the lung tumor most likely to cavitate and mimic a cavitating . Squamous carcinoma, particularly the well differentiated tumors, grow more slowly than other bronchogenic lung carcinomas. Despite regional spread to hilar and ipsilateral mediastinal lymph nodes, they can frequently be successfully resected.(2010) Recurrences, when they occur are more likely to be local (lung, mediastinum) than distant (bone, brain, other visceral organs). Poorly differentiated squamous cell carcinomas behave more aggressively and their clinical course is similar to that for adenocarcinoma and large cell undifferentiated carcinoma. The development of squamous cell carcinoma follows in a progressive manner from squamous metaplasia to dysplasia to carcinoma-in-situ to squamous carcinoma. The sequence is similar at other sites (uterine cervix, oral mucosa, and Year'sesophagus). The histologic features of squamous carcinoma include intercellular bridges between neoplastic cells and keratinization of neoplastic cells. These tumors frequently form "keratin pearls". Immunologic stains are helpful in the differential diagnosis of the different types of lung tumors and the differences are summarized in a table Last below.

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2. Adenocarcinoma This histologic type of lung cancer appears to be increasing in incidence, particularly in women. These tumors arise from bronchial lining cells. While some occur in a central location, most are situated in the periphery of the lung. The association with smoking is less strong than the association of smoking with the other bronchogenic carcinomas, however, there is a definite link. Of the lung cancers un- associated with cigarette smoking, adenocarcinomas are by far the predominant type. Because of their peripheral location, they may grow to a large size before becoming clinically apparent. They also frequently invade the pleura. These carcinomas as a group behave in a clinically more aggressive fashion than squamous carcinomas with earlier spread to lymph nodes (even tumors less than 3 cm dia. have a 50% likelihood of lymph node metastases), bone, brain and visceral organs. Clinical manifestationsSyllabus are frequently related to metastatic spread: CNS symptoms, bone pain, abnormal liver function tests. When treated tumor recurs, it most commonly recurs at a metastatic site. Histologically, adenocarcinomas are characterized by neoplastic cells which form glands and/or produce mucin (PAS or Mucicarmine positive). In general, adenocarcinoma-in-situ cannot be identified in the lung. Metastatic adenocarcinoma from extrapulmonary sites can mimic a primary adenocarcinoma of the lung. Histologically, there may be no features to separate these possibilities. However, there (2010)is an immunologic stain which is helpful in identifying pulmonary adenocarcinomas as being primary as opposed to metastatic. TTF-1 stains both pulmonary adenocarcinomas as well as thyroid tumors. As long as a metastatic thyroid carcinoma can be excluded (histology, thyroglobulin stains) a TTF-1 positive tumor is consistent with a lung primary. Multiple nodules of course favor metastatic disease. In some cases, one must rely on the clinician to clinically exclude extrapulmonary origins of the tumor. Year'sAdenocarcinoma of the lung with extensive pleural involvement can be difficult to distinguish from mesothelioma of the lung. The following studies are of some help: mucin stains (mesothelioma is negative on PAS and Mucicarmine stains), immunoperoxidase stains, and electron microscopy Last (EM).

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Many adenocarcinomas of the lung are associated with the scarring of the lung. For many years the concept that these tumors arose in previously scarred lung was popular. However, it is now known that the vast majority of these tumors do not arise in scarred lung, but rather undergo necrosis and scarring as the tumor grows. While true "scar carcinoma" do arise in previously scarred lung (old infarcts, old tuberculosis cavities, areas of honeycomb lung), it is clear that these cases account for a small minority of adenocarcinomas associated with scarring. 3. Bronchioloalveolar Carcinoma These tumors are thought to arise from cells of the peripheral airway of the lung and from alveolar lining cells. They are well-differentiated carcinomas with only a minimal amount of cytologic atypia. They have a characteristic growth pattern with spread of neoplastic cells along the preexisting lung structures particularly the alveolarSyllabus septae. Some of these tumors form distinctive papillary structures, others simply show atypical columnar cells lining alveoli. A third variety shows columnar cells with hypersecretion of mucin. This leads to consolidation of lung with mucinous secretions and these patients frequently have multifocal disease and present with dyspnea and cough productive of mucoid sputum. The clinical behavior of these tumors is quite diverse. Localized tumor nodules without spread to lymph nodes do very well with excision.(2010) If the tumor is multifocal (frequently involving both lungs) the tumors are unresectable and the prognosis is poor with patients succumbing to local complications of tumor growth in the lungs. Note: mucinous secreting bronchioloalveolar tumors are commonly multifocal. Distant spread of these tumors may occur but it is uncommon. Mucin secreting carcinomas of the pancreas, stomach and intestines when they metastasize to the lung may appear histologically identical to primary bronchioloalveolar adenocarcinomas. It is important to alert the clinician to this possibility when this pattern of tumor is Year'sencountered. 4. Large Cell Undifferentiated Carcinoma These tumors are sufficiently undifferentiated by light microscopy that one cannot reliably classify them as either adenocarcinomas or as squamous cell carcinomas. However, if one performs EM in most cases one can identify one of these two lines of differentiation. There is little Last impetus to do this in most cases as the tumors behave in an

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identical way regardless as to which line of differentiation they show by EM. In general, they present clinically and behave like poorly differentiated adenocarcinomas. They are usually peripheral and commonly present with distant metastases. 5. Small Cell Undifferentiated Carcinoma (Oat Cell Carcinoma) These tumors are virtually only found in smokers (usually quite heavy smokers). The tumors rise from undifferentiated multipotential bronchial lining cells and show prominent neuroendocrine features (simulating the Kulchitsky cell, a neuroendocrine cell of the normal bronchial mucosa). These tumors may show divergent lines of differentiation with areas of adenocarcinoma or of squamous carcinoma admixed with the neuroendocrine carcinoma. These features are found most frequently at the time of autopsy and some of the features may be related to treatment of these tumors. Clinically, most of these tumors present as centralSyllabus masses. They commonly have small parenchymal lesions and massive hilar and mediastinal lymph node metastases. At presentation, at least 2/3rds of patients have clinically detectable metastatic disease (bone, liver, adrenals, skin and brain), and for treatment purposes all patients are presumed to have at least subclinical spread of disease outside of the lung. For this reason this type of carcinoma (except in rare cases of peripheral oat cell carcinomas) is not considered to be a disease amenable to surgical therapy. Fortunately, this tumor is both highly radiosensitive and sensitive to multidrug(2010) chemotherapy. Untreated, virtually all patients are dead within 9 months. With treatment median survival is about 10 months, with 2 year survival less than 10%. 6. Histologically, the key features are: a. small cells with high N:C (nucleus: cytoplasm) ratio b. distributed hyperchromatic chromatin without nucleoli; c. high mitotic rate and d. abundant necrosis. These cells are fragile and on Year'shistologic sections the nuclear chromatin frequently appears as a dark blue smear, frequently around vessels. 7. Small cell undifferentiated carcinoma has been subdivided by pathologists (without much success or clinical significance). A major differential diagnosis is with lymphoma. The differential diagnosis is most clearly Last resolved by using keratin stains (oat cell + / lymphoma -) and common leukocyte antigen (oat cell - / lymphoma +). Some

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of the oat cell carcinomas are chromogranin positive and most can be demonstrated to have neurosecretory granules by EM (although they are generally scarce).

Differences Between Small Cell Undifferentiated Carcinoma (SCLC) and Non- Small Cell Lung Cancer (NSCLC)

SCLC NSCLC

Neuroendocrine differentiation Yes No Metastases at presentation Yes sometimes Surgically curable never sometimes Chemotherapy sensitive yes partialSyllabus Radiotherapy sensitive yes partial 5 year survival near zero 5 - 10%

Squamous Adenocarcinoma of Small Cell Mesothelioma Cell the lung Carcinoma Carcinoma Pankeratin + + + (dot-like) + CK 5/6 + neg.(2010) neg. + P 63 + neg. neg. neg. TTF-1 neg. + + neg. CEA +/- + +/- + Calretinin +/- neg. +/- + Synaptophysin/ neg. neg. + neg. Chromogranin Table of IPOXYear's staining results for tumors of the lung

8. Metastatic Tumor of the Lung Metastatic tumors are the most common tumor to involve the lungs. About 20-40% of malignant neoplasms will metastasize to the lungs by the time of the patient's demise. Last Most metastases are blood borne. Virtually any tumor can

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metastasize to the lung. In most cases metastases are multiple and bilateral. III. GENERAL NOTES REGARDING LUNG CANCER A. Spread of Tumor 1. Local Extension a. Pleura (common) b. Chest wall (rare) c. Esophagus and mediastinal structures, especially epidermoid and oat cell type d. Apical lesions [superior sulcus ("Pancoast") tumors] with invasion of chest wall, brachial plexus, ribs, vertebral bodies and sympathetic nerve chain resulting in Horner's syndrome (Pupillary constriction, anhidrosis, ptosis) 2. Lymphatics Syllabus a. Within lung to pleura with resulting effusion b. Bronchial and mediastinal lymph nodes 1) Pressure on and invasion of mediastinal vessels and nerves leading to vena cava syndrome, hoarseness (recurrent laryngeal nerve), paralysis of diaphragm (phrenic nerve) and (invasion of esophagus) 2) Node involvement in carinal angle at bifurcation of trachea may be demonstrated roentgenologically(2010) or by bronchoscopy or mediastinoscopy; evidence of inoperability 3) Scalene lymph node (palpable or non- palpable) c. Pericardium 1) Hemorrhagic effusion 2) Thickened parietal pericardium 3) Constriction (constrictive pericarditis) Year's3. Blood Borne Metastases a. Metastases are often the first evidence of a primary lung carcinoma (especially brain involvement). All patients with a suspected brain tumor should have chest films etc. to rule out a primary lung tumor. b. Other common sites of metastasis: liver, kidney, Last adrenals, bone and skin

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B. Methods Of Diagnosis 1. Sputum cytology (requires 3 specimens on consecutive days) a. Central lesions -- 80% positive results b. Peripheral lesions -- 40% positive results 2. Bronchoscopy and bronchial washing/brushing/biopsy a. Visualized (central) lesions -- 95% positive results b. Non visualized (peripheral) lesions -- 80% positive results 3. Fine needle aspiration biopsy of lung mass a. Varies from series but up to 95% positive results in carefully selected cases 4. All cytology cases carry a small but definite risk of a "false positive" result i.e. diagnosis of cancer when patient in fact has benign disease. The risk varies dependentSyllabus on the skill of the cytologist but reported false positive rates range from 1-4%. 5. Scalene/mediastinal lymph node biopsy a. In cases of suspected lung cancer a diagnosis of spread of the tumor outside the lung can be made by biopsying the lymph nodes in the prescalene fat pad, the cervical region or the mediastinum. By means of these procedures, positive nodes were found in over 60% of the patients with negative x-ray films of the mediastinum. If mediastinal exploration (mediastinoscopy)(2010) yields negative results, the tumor is resectable in approximately 90% of the cases. If a mediastinal, carinal or scalene lymph node is involved by cancer, the patient is considered to have an unresectable tumor at most institutions. 6. Open thoracotomy with frozen section diagnosis of lung mass IV. SOLITARY NODULE IN THE LUNG A. Year's Usually discovered on routine chest films B. Although in the past it was considered reasonable medical practice to observe solitary nodules for periods of time to see whether or not they were enlarging lesions, in today's practice it is best to definitively diagnose the lesion as soon as it is discovered. C. Differential diagnosis Last 1. Granulomas (healed tuberculosis, histoplasmosis, coccidioidomycosis, etc., often contains foci of calcification)

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2. Hamartoma 3. Tumor of lung (nearly all malignant): 13% in 35-39 year-old age group 75% in 70-79 year-old age group D. STAGING OF LUNG TUMORS Definitions T1, T2 primary tumor mass confined to lung T3 primary tumor with a) contiguous spread to chest wall, diaphragm, mediastinal pleura or b) to within 2 cm of carina T4 primary tumor with a) infiltration of mediastinum (heart, great vessels, esophagus) or b) presence of malignant pleura effusion. N0 No lymph node metastasis N1 Ipsilateral hilar lymph nodes Syllabus N2 Ipsilateral mediastinal lymph nodes or subcarinal nodes N3 Any more distal nodal metastases M0 No evidence of distant metastases M1 Distant metastases (brain, bone, skin, liver)

STAGES OF LUNG CANCER Stage T (2010)N M SURGERY I 1,2 and 0 0 yes II 1,2 and 1 0 yes IIIA 3 or 2 0 +/- IIIB any and 3 0 no IV any and any 1 no V. SYSTEMICYear's MANIFESTATIONS OF LUNG AND PLEURAL CANCER A. HORMONAL ABNORMALITlES: 1. Cushing's syndrome* Oat cell tumor/carcinoid 2. Inappropriate antidiuretic Oat cell tumor hormone secretion 3. Carcinoid syndrome Rarely carcinoid and oat cell tumor Last4. Hypercalcemia Squamous cell carcinoma

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5. Gonadotropin (HCG) Rare undifferentiated carcinomas containing large pleomorphic cells 6. Hypoglycemia Fibrous mesothelioma

Degenerative changes of the pituitary basophils, which produce ACTH ("Crooke's hyaline degeneration") and adrenocortical hyperplasia, are found in the majority of patients that die of oat cell carcinoma. Cushing's syndrome may even be associated with some of the carcinoid tumors. B. CONNECTIVE TISSUE ABNORMALITlES: 1. Pulmonary hypertrophic osteoarthropathy: Any malignant chest tumor. (May also be secondary to pulmonary inflammatory processes or bronchiectases. Sometimes found in association with cardiac, hepatic or gastrointestinal disorders!) Syllabus C. NEUROMYOPATHIC ABNORMALITlES: 1. Cerebellar cortical degeneration 2. Subacute spinocerebellar degeneration 3. Peripheral neuropathy 4. Myopathies 5. Mental aberration [sometimes caused by the increase in ACTH - corticosteroids (oat cell cancer) or hypercalcemia (epidermoid carcinoma)] D. VASCULAR AND HEMATOLOGIC(2010) ABNORMALITlES: 1. Carcinoid heart disease (endocardial fibrosis) 2. Venous thrombosis (mucin producing carcinomas) 3. Anemia 4. Leukemoid reaction E. DERMATOLOGIC ABNORMALITlES: 1. Dermatomyositis 2. Acanthosis nigricans Year's3. N.B. The incidence of pulmonary neoplasms is definitely related to general atmospheric, home and personal pollution: cigarette smoking (epidermoid and oat cell carcinoma), occupational pollutants (oat cell carcinoma, malignant mesothelioma), etc. Thus, it is now believed that the great majorities of lung tumors are an environmental disease and Last are preventable!

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Last Chest Imaging 3 - Ann Leung, M.D. HHD221 Spring 2010 Page 353 Chest Imaging 3

LEARNING OBJECTIVES 1. To review types and costs of imaging studies most commonly ordered to evaluate lung disease 2. To review anatomy of visualized intrathoracic structures 3. To distinguish between normal and abnormal findings 4. To illustrate characteristic appearances of common (and some uncommon) lung diseases.

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Last Anticancer Drugs 1 - James Whitlock, M.D. HHD221 Spring 2010 Page 355 Anticancer Drugs 1

Assigned Reading: Katzung, Ch. 55

LEARNING OBJECTIVES: 1. Understand the pharmacology (mechanisms of action, toxicities, resistance) of traditional (un-targeted) anti-cancer drugs that disrupt DNA synthesis, alter DNA structure, and change genome stability. 2. Understand the pharmacology (mechanisms of action, toxicities, resistance) of anti-cancer drugs that target pathways important for tumor growth regulation. 3. Understand the principles for using anti-cancer drugs in combination. TOPICS: Syllabus A. Principles of anti-cancer chemotherapy B. Targets for anticancer drugs C. Cell cycle specificity D. Drugs that act by damaging DNA E. Mechanisms of drug resistance F. Drug toxicities ) (2010)

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Last Neoplasia Lab - Faculty HHD221 Spring 2010 Page 357 NEOPLASIA LABORATORY This laboratory consists of three case presentations with microscopic slides and digital photographs. Gross pathology specimens will be presented by your lab instructors during lab. GOALS OF THIS LAB: 1. Know the histologic and gross features used to decide the presence or absence of tumor. 2. Be able to recognize the gross and microscopic appearance of metastatic tumor. 3. Appreciate the various levels at which malignancy is assessed: clinical, histologic, and cytologic. Consider the various ways that we use to assess the presence of tumor and diagnose it. 4. Understand the modes of tumor spread: direct extension,Syllabus hematogenous, and lymphatic. 5. Understand the basic nomenclature of neoplasia. Understand the guidelines used for neoplasia nomenclature, i.e. a malignant epithelial tumor is a carcinoma. What is the importance and function of naming lesions? 6. Begin each case by generating a broad differential diagnosis that includes as many possible diagnoses as you think appropriate, whether they are neoplastic or not. 7. Understand why staging and grading of tumors is important and how these particular lesions(2010) are staged.

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Neoplasia Lab - Faculty HHD221 Spring 2010 Page 358

CASE ONE A 64 year old bank vice-president with a past history (15 years earlier) of lumpectomy and radiation for breast cancer presents now with diarrhea for the past several months. Otherwise she feels fine and notes that she has been dieting successfully for the first time in her life with a weight loss from 167 to 149 lb. (height 5'2'') over a 12-week period. On a routine annual check-up 3-months earlier, she had occult blood in her stools, but did not respond to your notices that she should return for evaluation. Physical exam is unremarkable.

You arrange for the patient to have a barium enema the next day. The radiologist reports a mass in the transverse colon.

QUESTIONS 1. What is your clinical differential diagnosis at this point? Syllabus

You arrange for flexible colonoscopy and biopsy 3 days later. A large polypoid fungating lesion (3 cm apparent diameter) is seen in the transverse colon and biopsied(2010) (slide 5). A smaller (1 cm) polypoid lesion is also seen at the splenic flexure and is removed (slide 1). 2. Find slide 5 in your slide box. This is a section of colon that has been resected. Identify the normal portion of the colon and the abnormal area. What are the features that enable us to differentiate the two and make the correct diagnosis? What features differentiate this lesion from others that occur in the colon? What is your histopathologic diagnosis? Year's

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3. What clinical information do you want to know before proceeding to surgery? What is the purpose of obtaining this information?

You obtain a bone scan, liver scan, and chest x-rays. These are negative. You arrange for surgery, now 3 weeks after the initial patient presentation. The surgeon removes a 30 cm segment of colon and mesenterySyllabus surrounding the mass [see NeoplasiaLab_Case1a_Gross in CWP]. Why was the mesentery removed? Histologic sections demonstrate full thickness involvement of the bowel wall in the sections examined by the pathologist. Ten lymph nodes are recovered from the mesenteric fat and two contain carcinoma.

(2010) 4. What are the modes of tumor spread within the bowel and its associated tissues? How else can this lesion spread?

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5. What is the final clinicopathologic stage of this tumor in both the Dukes' system and the TNM system?

6. What is the histologic grade (well-, moderately- or poorly-differentiated) of this tumor (slide 5)? Does this influence prognosis of this tumor? Syllabus

7. Are the entities in Slides 5 and 1 related? Is slide 1 an example of hyperplasia, hypertrophy or neoplasia? [See NeoplasiaLab_Case1b_Gross(2010) for specimen similar to Slide 1]

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Neoplasia Lab - Faculty HHD221 Spring 2010 Page 361

CASE TWO A 21 year old young man experiences right knee pain while doing weight- lifting exercises. X-rays show a radiolucent area in the metaphyseal area of the distal femur with cortical destruction and radiodense material extending into the soft tissue laterally [See provided X-ray and CWP NeoplasiaLab_Case2]. The radiologist indicates that this is likely to be a malignant tumor. You schedule the patient for biopsy.

1. What is your differential Diagnosis? Why is it important to develop a differential diagnosis prior to biopsy?

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2. Examine slide 79 (from a ); what is your morphologic Dx?

3. What are the clinical, radiologic,(2010) and histologic features that allow you to make this diagnosis? Within which broad class of neoplasm is this lesion placed? What type of clinical behavior typifies this lesion?

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Neoplasia Lab - Faculty HHD221 Spring 2010 Page 362

CASE THREE A 22 year old first year female medical student presents with lower abdominal discomfort noticed over the last few months. Physical examination reveals a palpable left lower quadrant (LLQ) mass.

1. What is your differential diagnosis? What diagnostic studies would you choose to proceed with first in order to narrow your diagnosis?

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Studies reveal an 8 cm mass at the position of the left ovary. The lesion is surgically excised (slide 74) [See NeoplasiaLab_Case3_Gross in CWP for a memorable photo].

2. What tissues form the constituent elements of this lesion? What is your pathologic diagnosis? Year's

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Neoplasia Lab - Faculty HHD221 Spring 2010 Page 363

3. How are these lesions classified and what is their clinical behavior?

4. In what locations can these lesions occur? Syllabus

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Last Anticancer Drugs 2 - James Whitlock, M.D. HHD221 Spring 2010 Page 365 Anticancer Drugs 2

Assigned Reading: Katzung, Ch. 55

LEARNING OBJECTIVES: 1. Understand the pharmacology (mechanisms of action, toxicities, resistance) of traditional (un-targeted) anti-cancer drugs that disrupt DNA synthesis, alter DNA structure, and change genome stability. 2. Understand the pharmacology (mechanisms of action, toxicities, resistance) of anti-cancer drugs that target pathways important for tumor growth regulation. 3. Understand the principles for using anti-cancer drugs in combination. TOPICS: Syllabus A. Antimetabolites B. Plant alkaloids C. Hormonal agents D. Targeted drugs E. Combination chemotherapy

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Last Mammalian Lung Development – Mark Krasnow, Ph.D. HHD221 Spring 2010 Page 367 Mammalian Lung Development

No lecture notes – please attend lecture.

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