PFTs, ABGs, and RF in Obstructive and Restrictive Pulmonary Diseases

The major reason why I decided to write this essay was to show you how arterial blood gases and pulmonary function tests can help you in diagnosis and differential diagnosis of respiratory failure, obstructive and restrictive lung diseases.
This not a repetition of Drs Bellot and Jacobus’ lectures in Diseases of Respiratory System, this a comprehensive look on the problem, where I purposefully omitted some details; please excuse me if you find the omissions relevant or significant for the topic covered.
As you have learnt, the majority of pulmonary diseases, according to their major pathophysiologic mechanisms, can be divide two broad categories: obstructive and restrictive. I will start with definitions and major conceptual issues and then we proceed to lab findings.

Obstructive Lung Diseases
Obstructive diseases are characterized by reduction in ventilation due to increased airflow resistance as a result of
o Blockage of airways by mucus plugs (bronchial asthma and chronic bronchitis)
o Narrowing of airway lumina by hypertrophied and/or inflamed mucosa (chronic bronchitis)
o Bronchoconstriction (bronchial asthma)
o Loss of elastic recoil and impairment of expiratory flow (emphysema)
     -If you are interested in this mechanism look for a “equal pressure point” concept
Another component of respiration, perfusion, is less affected by obstructive lung diseases (except emphysema, which, by definition, is characterized by reduction in pulmonary vasculature).

How an increased resistance affects lung volumes?
1) Residual volume (RV) increases
     -RV – lung volume at the end of maximal exhalation
2) Vital capacity (VC) decreases
     -VC – volume that can be exhaled after a maximal inhalation
3) Total lung capacity (TLC) increases too because TLC = RV + VC, and an increase in RV is more that a decrease in VC
4) Forced vital capacity (FVC) moderately decreases because of increased airway resistance
     -FVC – volume that can be forcefully exhaled (during 5 sec) after a maximal inhalation. NB: understand the difference in TLC and FVC, which change in opposite directions
5) Forced expiratory volume in 1 sec (FEV1) significantly decreases because forceful expiration induced airflow turbulence with substantial reduction in flow rate
     -FEV1 – volume which is exhaled during the first second of FVC measurement
6) FEV1) / FVC ratio decreases [see explanation in 4) and 5)]

How an increased resistance affects ABGs?
Increased resistance to airflow leads to air retention in the lower airways with low PAO2 and high PACO2 (“A” – alveolar). Similar changes can be detected in the arterial blood: decreased PaO2 and increased PaCO2 (hypoxemia and hypercapnia).

How respiratory failure develops in patients with obstructive lung diseases?
At early stages of obstructive lung diseases, high concentration of carbon dioxide activates respiratory center that changes the pattern of breathing and maintains near- normal level of blood gases. With time and increased work of breathing, hypoxemia and hypercapnia rise and reach the levels of PaO2 < 60 mm Hg and PaCO2 > 50 mm, the condition is known as hypercapnic respiratory failure. High PaCO2 level lowers pH (respiratory acidosis) and activates bicarbonates retention by the renal tubules (metabolic compensation).

Restrictive Lung Diseases
This group is quite heterogeneous and is characterized by abnormalities in alveolocapillary interface, such as:
• Edema (pulmonary edema)
• Inflammation (pneumonia, ARDS, aspiration of gastric content)
• Fibrosis (idiopathic pulmonary fibrosis, pneumoconioses, sarcoidosis, etc)
Accumulation of pathologic substances in the pulmonary interstitium leads to an increase in lung elastic recoil, reduction in lung compliance, compression of microvasculature and inhibition of gas diffusion through the air-blood barrier. In such settings, perfusion is affected the most. Ventilation is reduced too, but not so severe as in obstructive lung diseases, and usually allows tachypnea to compensate blood gases abnormalities.

How lung volumes are changed in restrictive lung diseases?
1) Residual volume (RV) decreases due to an increased elastic recoil
2) Total lung capacity (TLC) decreases because of low RV and low VC (reduced compliance)
3) Forced vital capacity (FVC) moderately decreases because of extensive parenchymal fibrosis and preserved airway conductivity
4) Forced expiratory volume in 1 sec (FEV1) slightly-moderately decreases (similar to FVC)
5) FEV1 / FVC ratio remains normal or slightly increases [see explanation in 3) and 4)]
Therefore, TLC and FEV1/FVC are widely used in clinical practice for differentiation of obstructive and restrictive lung diseases.

ABGs in patients with restrictive lung diseases
Severe inhibition of perfusion along with relatively spared ventilation lead to severe hypoxemia. In such settings, tachypnea becomes a leading compensatory mechanism and a reason of PaCO2 reduction (hypocapnia).

Respiratory failure in patients with restrictive lung diseases
If hypoxemia falls below 60 mm Hg, respiratory failure ensues. But contrary to obstructive diseases, in restrictive diseases hypoxia is not associated with raise in carbon dioxide. In such patients hypocapnia and respiratory alkalosis usually persists, therefore the condition is named hypoxic respiratory failure. If respiratory failure worsens, concentration of carbon dioxide can turn from low to high. Hypercapnia in patients with restrictive lung disease is a grave sign implying an inability to maintain adequate alveolar ventilation.

I hope you found my explanations useful.

Good luck,

Dr. Y.

Asbestos, Mesothelioma and Lung Cancer

A very interesting question about asbestos-related malignancies was raised today at PACE session. The question was: what is more common asbestos-associated tumor, mesothelioma or bronchogenic carcinoma.

The fact that asbestos exposure tremendously increases risk of mesothelioma is well known and I am not going to discuss it here. But relationship between asbestosis and lung cancer is still obscure, because tobacco smoking masks the influence of asbestos fibers on neoplastic transformation within the bronchial linings. The freshest text in my specialty, Rubin’s Pathology (5th Ed, 2008) states “an association between cancer of the lungs and asbestos exposure is clearly established in smokers. A slight increase in the prevalence of lung cancer has been reported in nonsmokers exposed to asbestos, but small amount of cases renders an association questionable” (P.168).

We can find a reasonable amount of publication browsing the Web. A reputed site, which I trust, “Health and Safety Executive” from the UK contains statistics data about mortality from asbestos-related malignancies; the data indicate that less amount of people die of asbestos-related lung cancer than of mesothelioma (at least not more) http://www.hse.gov.uk/statistics/causdis/asbfaq.htm#mesothelioma..

I hope I answered the question.

Dr. Y.

Is Emphysema a COPD?

I apologize for a long silence; a promised essay about respiratory failure is coming soon, I am just trying to bring my thoughts about it together and meanwhile I discovered a quite intriguing (for medical students) question: why emphysema belongs to a group of chronic obstructive pulmonary diseases? Where is the obstruction? That is the question. Do you have any ideas?

Dr. Y.

Heart Failure, Part 5. Mechanisms, Compensatory Mechanisms and Their Adverse Effects

When I finished writing this part, I found it too long, but I decided to post it anyway: on Tuesday and Thursday Semester 4 students will have PACE sessions and after that they will definitely loose any interest in Cardiovascular Pathology. So, before that happened, please read the last part of Heart Failure.

There are three primary physiologic mechanisms that regulate stroke volume: preload, afterload and contractility, which have been (thoroughly?) explained in the previous posts. We have learnt that cardiac failure, as an inability of the heart to maintain stroke volume, can develop either through reduced preload, or increased afterload, or impaired contractility. Each of these factors has its own causes, ways of development, and mechanisms of compensation. It is important to understand that both physiologic mechanisms of heart activity and compensatory mechanisms have their own limits, which, if overwhelmed, may produce adverse effects on cardiac function and structure. Let’s talk again about preload, afterload and contractility but now in terms of heart failure development and compensation.

Preload. Reduced preload of the ventricles (e.g., mitral stenosis, hypertophic or restrictive cardiomyopathy) will automatically lead to decreased stroke volume and subsequently, to ventricular failure. Few physiologic mechanisms can compensate this phenomenon:
1) When the ventricles cannot accommodate all required blood, it will stay in the atria with their distension (preload increase) and activation of Frank Starling mechanism.
   a. We always keep in mind limitations of Frank-Starling mechanisms: after a certain point, an increase in EDV will lead to a fall in SV.
2) Sympathetic activation will enhance force of atrial contraction and tone of venous compartment of systemic circulation with augmented venous return to the heart (=increased preload)
   a. An increment in sympathetic tone will induce a considerable amount of adverse effects:
      i. Increased heart rate that is not always good, e.g., tachycardia will reduce preload
      ii. Calcium influx with possible arrhythmia and ischemia
      iii. Too much venous return will overwhelm the pulmonary circuit with possible development of pulmonary edema
      iv. A raise in arteriolar resistance will increase afterload and ca cause multisystem organ ischemia
3) Activation of renin-angiotensin system as well as synthesis and secretion of antidiuretic hormone with water and salt retention count for a great deal in cases of cardiac failure caused by hypovolemia
   a. Adverse effects of renin and ADH surplus:
      i. An excess in EDV – a fall in SV (see above)
      ii. Activation of myocardial fibrosis
      iii. An increase in arteriolar tone with elevation in afterload

Afterload. Increased afterload is always bad: pressure or volume overload, or thinning of the heart wall always have unfavorable effects on cardiac function. Pressure and volume overload induce the following compensatory mechanisms:
1) An increase in preload
   a. See the adverse effects of preload above
2) Myocardial hypertrophy with augemented force of contraction and reduction of overall afterload (see LaPlace law)
   a. Adverse effects of myocardial hypertrophy:
      i. Growth of cardimyocytes is always accompanied by production of extracellular matrix with subsequent myocardiosclerosis
      ii. Inadequate growth of blood vessels with diminished oxygen and nutrient supply
      iii. Changed geometry of cardimyocytes: larger diameter – less surface/volume ratio with insufficient metabolite transport through the sarcolemma.
3) Release of natriuretic peptides with reduction in arteriolar tone and volume of circulating blood (inhibition of sodium reabsorption).

Contractility. Impaired contractility often becomes a cause of heart failure, for example in patients with acute MI or chronic ischemic heart disease. Affected contractility can be partially compensated by
1) An increase in preload
2) Activation of adrenergic nervous system
3) Medications, e.g., beta-adrenoceptor agonists or phosphodiesterase inhibitors.
Adverse effects of too high preload and activated sympathetic nervous system have been covered above. About side effects of the mentioned drugs, please refer to Dr. Babbini’s lectures.

With this post I finish my talk about heart failure and I truly hope that my work helped you a little to understand this pathology. Going through my posts you had chances to appreciate this problem in all its complexity, and I believed it would influence in good way your approach in diagnosis and management of heart failure, a very serious medical problem in the modern world.

Very soon I will start to work on respiratory failure, I guess, I have a few words to say about it.

Good luck,

Dr. Y.

Squatting in TOF, an Answer to Nathan's Question

Hi Everybody,
Nathan asked me so intersting question, that I decided to post it:” Dr. Yakubovskyy, I was wondering if you could elaborate on why the squatting position is common in pts with Tetrology of Fallot. The only explanation I have found is that it presumably lessens the right to left shunt. I've tried to dig deep into my physio knowledge to explain it but can't come up with an answer that is satisfying. Thanks”.
The answer: As you know, TOF is a relatively common and very serious congenital heart defect. The major problem in patients with TOF is severe cyanosis (hypoxemia) associated with right ventricular outflow tract obstruction (RVOTO) and reduction in pulmonary blood flow. Squatting is a mechanism that helps patients to cope with an acute attack of cyanosis. There are not very many recent publications, which shed light on the protective mechanisms of squatting in the patients with TOF; the last one appeared in 2002 with the major postulated mechanism as the reduction of amount of deoxygenated blood entering the systemic circulation through VSD. Besides that, there are few more possible protective mechanisms, which deserve to be mentioned here. To save space I combined all known (for me) effects of squatting in the patients with TOF and presented in the diagram below. Enjoy.

Dr. Y.

Heart Failure, Part 4. Contractility

Contractility (syn.: inotropy) is a unique feature of cardiac muscle that provide cardiomyocytes with ability to generate force, which is independent of preload and afterload. In addition to force, contractility also influences velocity of sarcomere shortening during the phase of isovolumetric contraction. An increase in generated force and velocity of cardiomyocyte shortening will enhance the ejection velocity and, correspondingly, ejection fraction and stroke volume (with concomitant reduction in end systolic and end diastolic volume).

Factors enhancing contractility

• Sympathetic stimulation
• Catecholamines
• Inotropic drugs (see below)

Factors inhibiting contractility

• Physiologic
• Vagal (parasympathetic) stimulation
• Pathologic
• Advanced heart failure (unknown mechanism)
• Acute MI
• Chronic ischemic heart disease

Inotropic drugs

• Drugs used for cardiac failure treatment
• Beta-adrenoceptor agonists (dopamine, dobutamine, etc)
• + peripheral vasodilation with resoration of end-organ perfusion and reduction of afterload
• Phosphodiesterase inhibitors (milrinone)
• + veno and arterial vasodilation with a decrease in preload and afterload
• Digoxin
• Caffeine
• Theophylline

To be continued

Heart Failure, Part 3. Afterload

Afterload can be defined as stress (or tension, T) that cardiac wall experiences during systolic ejection. According to LaPlace law, wall tension is directly proportional to intrachamber pressure (P) and radius (r) and inversely proportional to wall thickness (h): T=PXr/2h.Therefore, changes in chamber pressure, volume and/or wall thickness will affect afterload and, correspondingly, stroke volume.

Factors influencing pressure (P)

• Blood pressure. Intrachamber (left/right ventricular) pressure during systolic ejection is very close to the pressure in the aorta or pulmonary trunk. That means, in cases of systemic or pulmonary hypertension, elevation in ventricular pressure will automatically increase afterload. And visa versa, reduction in blood pressure will reduce afterload. 
• Valvular stenosis interferes with chamber empting and causes accumulation of blood with subsequent increase in pressure (and volume)
• Congenital heart defects. E.g., atrial and ventricular septal defects, and patent ductus arteriosus increase pressure (and volume) load on the right chambers  

Factors influencing radius (r)

• Valvular insufficiency leads to reverse blood flow with an increase in chamber volume 
• Dilated cardiomyopathy 
• Valvular stenosis (see above) 
• Congenital heart defects (see above)

Factors influencing wall thickness (h)

• Myocardial hypertrophy with an increase in sarcomere mass and reduction of wall stress 
• Physiologic myocardial hypertrophy seen in athletes
• Pathologic myocardial hypertrophy as a compensatory process in patients with cardiovascular diseases, e.g., systemic hypertension
• Ventricular aneurysm, e.g., in old MI, with sclerosis and thinning of the wall
• Advanced heart failure with volume overload (thinning of the myocardial wall)  

How afterload affects stroke volume? An increase in afterload (P, r, or h) reduces velocity of cardiomyocyte shortening. Because of short period of systolic ejection (0.2 sec), stressed cardiac muscle does do not have enough time to contract properly and to expel blood from the ventricle. Therefore stroke volume goes down. At the same time, accumulation of blood within the chambers will increase end systolic volume and, subsequently, end diastolic volume (or preload). Elevation of end diastolic volume will activate Frank-Starling mechanism, which partially compensate a reduction in stroke volume induced by afterload increase.

Amendment: Pharmacologic correction of afterload

• Vasodilators: reduction of blood pressure with subsequent afterload decrease
  
• Beta-blockers
  
• ACEI/ARBs
  
• Nitrites: potent venodilators, used in acute heart failure (e.g., pulmonary edema) to reduce preload
  
• Human BNP analogs: vasodilatory and diuretic effects
  
• Diuretics: reduction of volume of circulating blood and blood pressure with subsequent diminishing in afterload
• + preload reduction

To be continued

Heart Failure, Part 2. Preload

A major function of the heart – pumping blood in the aorta and truncus pulmonalis – can be evaluated by measurement of cardiac output (CO), and it can be done in different ways (discussion of methods of CO calculation is beyond the scope of Pathology). For us, it is enough to understand that CO directly depends on stroke volume (SV) and heart rate (HR). There is another integrated indicator of cardiac function: cardiac index, which is more reflective toward an individual patient and, therefore, more preferable in the clinical settings.

There are three, well known from the course of physiology, primary mechnasims that regulate stroke volume: preload, afterload and contractility.

Preload corresponds to diastolic filling of the chambers and stretching of the cardiac wall. The key factor that affects preload is central venous pressure, which goes up with sympathetic vasoconstriction. According to famous Frank-Starling law, as more stretched the myocardium is, as higher stroke volume will be. In this situation we can find stronger contraction of cardiomyocytes. (Do not confuse stronger contraction with enhanced contractility because, according to definitions, contractility corresponds to changes in the force generated by the myocardium at the non-changing diastolic filling).

Impaired preload. When a chamber cannot accommodate the required amount of blood, stroke volume and cardiac output will decline and, subsequently, heart failure will follow. There are few mechanisms of preload impairment reduction):
- Decreased myocardial compliance (insufficient myocardial relaxation) seen in

   • Ventricular hypertrophy (left or right), because hypertrophied myocardium fails to relax properly during diastole

   • Hypertrophic and restrictive cardiomyopathy due to hypertrophy and sclerosis of the myocardium
- Obstruction of a chamber inflow
   • Valvular stenosis, e.g., mitral stenosis that leads to preload reduction of the left ventricle

- Compression of the heart within the pericardic sac (cardiac tamponade)

   • Pronounced hydropericardium or exudative pericarditis
   • Acute MI with ventricular wall rupture
- Decreased venous blood pressure, usually associated with hypovolemia
- Impaired atrial contraction in atrial fibrillation

Limitations of Frank-Starling law. In the chart below you can see how end diastolic volume affects stroke volume. In healthy people (blue line), EDV increase leads to gradual elevation of SV, which reach plateau at EDV ≈ 200 ml. In patients with heart failure (pink line), we see similar dynamics, but after certain point (EDV ≈ 200 ml) SV goes down (= further EDV increase will reduce SV). Interpretation of these findings will lead us to the conclusion that in patients with an advanced heart failure, when diastolic filling is significantly elevated, Frank-Starling law does not work, and less amount of blood will be pumped out.

To be continued tomorrow

TO THE FOLLOWERS

My dearest Followers!
May I ask you to show your photos? It will help me to communicate with you.
Sincerely,
Dr. Y.

Heart Failure, Part 1. Introduction

There are not so many topics in Pathology, which are easier to explain and learn than heart failure. I have been working in many countries and everywhere students were able to recognize a pitting edema and nutmeg liver. On the other hand, there are not so many topics, which are more difficult than heart failure.

Confusions begin with nomenclature: the condition can be called “heart failure”, “congestive heart failure”, or “cardiac failure”; we can use all these terms as synonyms.

Also there is no complete agreement how to define cardiac failure:

A good definition we can find in Harrison’s Online: “Heart failure (HF) is a clinical syndrome that occurs in patients who, because of an inherited or acquired abnormality of cardiac structure and/or function, develop a constellation of clinical symptoms (dyspnea and fatigue) and signs (edema and rales) that lead to frequent hospitalizations, a poor quality of life, and a shortened life expectancy”. (http://www.accessmedicine.com/ content.aspx?aID=2902063&searchStr=congestive+heart+failure). A pathologist can find this definition purely clinical, which does not disclose the leading pathophysiologic features.

According to Robbins Basic Pathology “Congestive heart failure is a multisystem derangement that occurs when the heart is no longer able to eject the blood delivered to it by venous system”. (7th Ed., P.362). A little bit confusing and, inter alia, incomplete definition, because, so-called compensatory phase of cardiac failure is not mentioned there.

If you open Rubin’s Pathology, you will need to read whole page (431, 5th Ed.) to understand what heart failure is.

The best definition, in my opinion, is given in my favorite text Robbins and Cotran Pathologic Basic of Disease: “In heart failure … the heart is unable to pump blood at the rate commensurate with the requirements of the metabolizing tissues or it can do so only at an elevated filling pressure” (7th Ed. P.560). This definition (pretty similar to that given in your handouts) covers the condition, when the heart is overloaded, but still is to maintain cardiac output.

To be continued tomorrow

Autopsy: Secrets & Mysteries Revealed by Dr. Jeffery Nine

Few days ago Dr. Jeffery Nine, a Medical Examiner and Associate Professor of Pathology from University of New Mexico, visited Dominica Campus and gave a presentation "Autopsy: Secrets & Mysteries Revealed by Dr. Jeffery Nine". I really enjoyed it, it is always nice to see a professional talking about his professional stuff. Possibly, you will be able to attend a postmortem examination this semester, and before that I advise you to watch Dr. Nine's presentation and to have an idea what is going on in the Autopsy Room. Here is the link: http://exmediasite.rossmed.edu.dm/exmediasitedm/Viewer/?peid=7c773eabcf6d48529c0d3491a7c9026e
Usually elements of Forensic Pathology are taught within Environmental Pathology, but sometimes this subject is not covered at all. If you questions about either Forensics or Dr. Nine's presentation, please go ahead.
M.Y.

TO SEMESTER 4 STUDENTS: CARDIOVASCULAR PATHOLOGY

Dear All,
One week ago, with Diseases of the Heart and Blood Vessels you started a new semester. There is no need to emphasize the significance, social and economic impact of those disorders. Luckily, the proper pathologic processes which affect Cardiovascular System are not very complicated; many pathologists, including me, believe that within the course of Systemic Pathology, diseases of the heart and blood vessels is the easiest part to learn and to deal with. Nevertheless, in my opinion there are few topics, which usually create difficulties for learners and therefore deserve special attention:
1) Heart failure, especially its pathogenesis
2) Differential diagnosis of vasculitides
3) Cardiomyopathies
4) Congenital heart diseases
If you have any problems with those topics or with any topic from Diseases of the Circulatory System, you can ask my right here. If necessary, next week we can organize a session, like “Pitfalls in Cardiovascular Pathology”, where we can go through the pathologies you choose.
Sincerely,
Michael Yakubovskyy, MD

A MESSAGE TO THE STUDENTS

Dear All,

There is the XXI century outside, the century which began with triumph of information technologies in all areas of human activities including medical education. Staying with Ross over the past four years I have been a witness of implementation of the mediasite, audience-response system, virtual microscopy, podcasting, televideoconferencing, etc. I believe the time has come to move further and start to implement Web 2.0 technology in our mutual teaching-learning process.

This is not an attempt to create an additional spot for spoon feeding or lecturing. Using interactive technology I will try to help you to develop your clinical reasoning, to step further from blind memorization of isolated chunks of information, and also to create a clear understanding of diseases despite all their complexity. I would also like to show you that medicine and pathology, in particular, still are more an art than a science where everything can be measured, calculated, and unscrambled. It was always like that, and I think the situation won’t change very soon.

As we are not limited here to the Learning Objectives, we can go beyond the traditional courses of Pathology 1 and 2, discuss issues raised in Cases of the Week, at Pathology Club meetings, your PBL session, etc.

Your posts will be the best evidence that you appreciate my attempts to built bridges between you and me.

Cheers,

Michael Yakubovskyy, MD

Your Teacher of Pathology