Case Study Number 3:

Learning Objectives

Describe normal VQ matching and regional variations within the lungs

Describe pathological causes of VQ mismatch

Describe what constitutes the A-a gradient, a normal A-a gradient and the significance of a widened A-a gradient.

Chief Complaint: “I can’t breath”

HPI: Pt is a 35-year-old female with a past medical history significant for hyperlipidemia and asthma that presents to the emergency department with chief complaint of acute onset dyspnea. The pt states that she is a business executive who travels between Chicago and Tokyo every week. For the last 2 weeks she has been battling a productive cough, runny nose, with night sweats but had no fever. She had been taking over the counter cold medication to deal with these symptoms and they had provided her some relief. She had also been short of breath and had used her albuterol inhaler, which had provided symptomatic relief. However, today she returned from Tokyo on a 14-hour flight. She didn’t get up the entire flight because of her cold but did notice some swelling in her left leg during the flight. While collecting her baggage she developed sudden onset 8/10 chest pain worse with deep inspiration, coughing up blood, dyspnea, and tachypnea. She attempted to use her albuterol inhaler but this provided no relief. An ambulance was called and brought to the ED. She required 3L of O2 in transport and could not lie flat. The pt denies any radiating chest pain, nausea, vomiting, or diarrhea.

Review of Systems: (Italics indicates positive)

General: No Fevers, Chills, Night sweats, no weight loss

HEENT: No headaches, tinnitus, vision changes, dysphagia

Respiratory: Dyspnea, Cough, hemoptysis

Cardiac: Chest pain, Racing heart, Orthopnea, Leg swelling

GI: No nausea, vomiting, diarrhea, constipation, blood in stool

GU: No changes in urinary frequency, urgency, hesitancy, burning,

Neuro: no weakness, tingling, burning sensation

Past Medical Hx:

Hyperlipidemia

Asthma

Deep Vein Thrombosis-(2010)

Past Surgical History

No pertinent history

Medications

Atorvastatin-20mg daily

Albuterol-PRN

Oral Contraceptive Pills-once daily

Physical Exam:

Vitals: BP 145/ 90  P 115 R 25 Temp 100.0 O2 sat 96% on 3L O2

Wt: 55 Kg Ht:165cm BMI: 20

Appearance: Appears her stated age, in moderate respiratory and painful distress

HEENT: EOMI, conjunctiva are pink with no evidence of jaundice, hearing grossly intact, missing left lateral incisor

Pulm: vesicular breath sounds on the right, diffuse wheezing in the lower lung fields on the left

Cardio: No JVD. No tenderness to palpation. No chest wall deformities. Tachycardic, normal rhythm, normal S1 and S2 no murmurs, rubs or gallops.

Abdomen: bowel sounds heard but hypoactive after 2 mins in each quadrant. Abdomen is soft, not distended, not tender to touch. No guarding or rebound tenderness.  

Extremities: Peripheral pulses intact and symmetric bilaterally. Swelling and calf tenderness to palpation 4cm on the left leg, right leg not swollen or tender

Neurologic: Pt is awake, alert and oriented x 3, no focal deficits noted.

MSK: Pt 5/5 muscle strength in all 4 extremities and 5/5 grip strength.

Labs:  

WBC 12.1x10^3/uL, RBC 5.19x10^6/uL, Hgb 13.5 g/dl, HCT 43%, MCV 82.9

Na: 137 mEq/mL, Cl 94 mEq/mL, HCO3- 22mmol/L, BUN 8.6 mg/dL, Cr .9 mg/dL, Glucose: 126 mg/dL Tbil .6, AST 19, ALT 15, AlkPhos 67, Total Protein 7.6, Albumin 4.4

D-Dimer: 2000 ng/mL

Troponin I: <0.01 ng/mL

Procalcitonin: <0.05mcg/L

Chest X-ray: Radiologists impression “Normal chest x-ray, no acute findings”

Chest X-

ray div

 EKG:  Cardiologists interpretation “Sinus tachycardia otherwise normal ECG”

EKG div

Question 1. Given the pt’s history and physical exam list your differential diagnosis including at least 5 possible diagnoses. (Remember the differential diagnosis should be broad and really just include causes that could account for the relevant symptoms) Essentially what could account for acute onset dyspnea, chest pain, and tachypnea.

Answer 1:

Differential Diagnosis for dyspnea and chest pain:  Highest acuity to least…

Myocardial Infarction (MI):

• Patient specific symptoms and risks: Hyperlipidemia, 35 years of age on birth control, high stress job with lots of travel, episodes of diaphoresis
• Helpful information to be obtained that was not provided in case: Illicit drug use (cocaine, marijuana), smoking history, alcohol consumption, caffeine/coffee consumption, over the counter diet pills
• Clinical presentation of MI in young women is very diverse (30-54 years of age): Report of pain or discomfort in chest (including pressure and heaviness), arms/hands, back, jaw, shoulders/shoulder blades, neck, legs and throat. General symptoms reported: shortness of breath/dyspnea, fatigue/exhausted, indigestion/heartburn, nausea/vomiting, anxiety/anxious/stress/emotional, sweating diaphoresis, hot/flushed, dizziness/lightheadedness/fainting, weakness, headache, loss of motor function, palpitations/heart racing.[1]

Pulmonary Embolism (PE):

• Patient specific symptoms and risks: symptoms of active DVT (Left lower extremity swelling and pain), history of DVT, 35 years of age on oral contraceptives (smoking history not provided), prolonged immobilization (14 hour flights bi weekly and not getting up at all during the most recent flight back), coughing up blood
• Clinical presentation of PE: ranges from zero symptoms to symptoms of shock. Commonly present with dyspnea followed by pleuritic pain, cough, symptoms of deep venous thrombosis (unilateral or bilateral edema, pain, and warmth) and hemoptysis (rare).

Pneumonia:

• Patient specific symptoms and risk: productive cough, runny nose, coughing up blood (tuberculosis?), night sweats (tuberculosis?), fatigue and malaise from cold (potentially poor oral intake? Decreased plasma protein level?), international travel, large periods of time breathing recycled airplane air, dyspnea and tachypnea
• Clinical presentation of community acquired pneumonia: most common are cough, fever, pleuritic chest pain, dyspnea, and sputum production (mucopurulent sputum associated with bacterial pathogen, Scant-watery sputum associated with atypical pathogen). Gastrointestinal symptoms (nausea, vomiting, diarrhea) and mental status changes. Chest pain occurs in 30 percent of cases, chills in 40 to 50 percent, and rigors in 15 percent. Commonly found on physical exam are fever, tachypnea, tachycardia, and audible crackles. 

Congestive Heart Failure (CHF):

• Patient specific symptoms and risk: shortness of breath, swelling in left lower extremity
• Clinical presentation: shortness of breath secondary to pulmonary edema, peripheral edema

Pericarditis:

• Patient specific symptoms and risk: orthopnea
• Clinical presentation of pericarditis: pleuritic chest pain that increases with inspiration or when reclining and is relieved by leaning forward, pericardial friction rub, EKG changes - diffuse ST segment elevation and PR interval depression with T wave inversion

Question 2. Now given the clinical presentation, physical exam and labs What is your top diagnosis? (Use your differential and think through what data lead you to believe your top diagnosis is correct and go against the others)

Answer 2.

All cardiac diagnosis (MI, pericarditis, CHF) ruled out because:

• Normal EKG, only tachycardia
• Normal electrolyte levels on basic metabolic panel (chloride was only slightly low)
• Normal troponin level – would be elevated above 0.01 and trend up over time with repeated test to indicate MI
• CXR normal, no signs of enlarged heart or pulmonary edema
• Heart sounds normal (S1, S2 present and no murmurs, rubs or gallops appreciated)
• Lower extremity swelling is unilateral – CHF patients would have equal systemic vascular congestion/edema

Pneumonia is ruled out because:

• CXR was clear, no areas of opacities, atelectasis, or pleural effusion that would contribute to a pneumonia diagnosis.
• Elevated white blood count can be explained by recent cold and/or stress.
• The low procalcitonin lab indicates that there is not a bacterial infection taking place.
• Pulmonary embolism is the most likely diagnosis. Because:

The patient has all of the criteria to meet wells clinical prediction rule for PE except malignancy. [5]

• Clinical signs of DVT (asymmetric leg swelling, palpable calf pain)
• Diagnosis of PE is more likely than an alternative diagnosis
• Heart rate greater than 100 beats per minute
• Previous diagnosis of DVT or PE
• Bed rest immobilization or surgery within the past four weeks
• Hemoptysis
• Malignancy within the past six months

Patient’s clinical data that supports PE diangosis:

• Current swelling and calf tenderness to palpation 4cm on left leg
• PE is more likely than other diagnosis in differential
• Patient is in sinus tachycardia with a heart rate of 115
•  Patient did not move for 14 hours just prior to the onset of her symptoms.
• She is reporting bloody sputum with coughing
• D-Dimers are the degradation product of cross-linked fibrin and a value greater than 500 usually indicates high suspicion of a PE or a DVT. The patient has D-Dimer level of 2000.

Question 3. Given your top diagnosis what specific tests do you need to run in order to confirm it?

Answer 3.

To make a definitive diagnosis of PE you do one of the following tests:

Computed tomography pulmonary angiogram (CTPA). This is probably the most commonly used test since it is very fast (Can be done in less than 5 minutes) and is readily available at most hospitals. The draw back to this exam is that the contrast used in this test is very nephrotoxic and should not be used for pregnant women or people with poor kidney function. [5]
Ventilation-perfusion scanning (V/Q scan).  This test scans for abnormal blood flow through the lungs after a radioactive tracer has been injected and you breathe a radioactive gas.  The draw back to this exam is that it takes longer than a CTPA (approximately 30 minutes) and you have to be supine for a long period, which exacerbates the orthopnea. One of the benefits of this test is that the radiopharmaceuticals do not impact the kidneys. [5]
Pulmonary Angiogram. A large bore catheter is inserted in the arm or groin and contrast is injected.  This contrast is also nephrotoxic.  The advantage of this exam is there is potential for clot removal as well as diagnosis.  The draw back to this test is that it is not readily available at all hospitals, it is invasive, expensive, and the contrast is nephrotoxic. [5]
Magnetic resonance imaging (MRI). This test may be used to view clots in the deep veins and lungs.  This test is very expensive and requires you to be supine and in a tube.  This is not ideal for people that are claustrophobic. [5]

Question 4. Results of a VQ Scan are shown below. Before interpreting the results below please elaborate on the following:

Question 4A. What is the ventilation perfusion ratio (V/Q ratio)? (Include a short discussion on hypoxic vasoconstriction)

Answer 4A.

           V represents the transport of gas from the environment to the alveoli for gas exchange (normally 4-6 L/min). Q represents the pulmonary blood flow to the alveolar capillaries.  The V/Q ratio tells you the amount of air and blood available to participate in the gas exchange at the alveolar sacs.  In a perfect system there would be just enough oxygen provided through ventilation to saturate the blood fully.  This concept is referred to as V/Q matching. The normal V/Q ratio is 0.8 – 1.2[6].

           Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to alveolar hypoxia (without hypercapnia) that distributes pulmonary capillary blood flow to alveolar areas of high oxygen partial pressure[7]. The proposed mechanism is related to oxygen gated potassium channels. The theory goes that when oxygen partial pressure falls is above 100 mmHg at the alveolar sac that oxygen acts as a ligand for the potassium channel and allows potassium to leak out of the smooth muscle cell and hyperpolarize [8].  The hyperpolarized muscle does not contract and the overall effect is vasodilation.  However, if there is not enough oxygen, partial pressure falls below 100 mmHg then the potassium channels will close and the cell will reach its action potential.  Vasoconstriction and parallel shunting are the result.

Question 4B. What is a V/Q defect? Does a regional V/Q mismatch normally exist in the lungs? What does it tell you? What do you expect for this situation? (Include short discussion of west zones)

Answer 4B.

         A V/Q defect, also called V/Q mismatch, is when the ventilated alveoli are not close to the perfused capillaries, and this arrangement results in abnormal gas exchange.  The lungs have variations in the V/Q ratio throughout the different fields due to gravity; and, a very small-scale amount of V/Q mismatch does occur normally in the lungs, but larger scale mismatch is considered pathologic.  Low V/Q indicates inadequate ventilation (due to cessation of breathing, airway obstruction, etc.) and the result is intrapulmonary shunting (perfusion without ventilation). Infinite V/Q ratio occurs when there is a vascular obstruction and the subsequent Q = 0 [6].

An Alveolar - arterial (A-a) gradient is the discrepancy between the alveolar and arterial oxygen partial pressures (PAO2 -Pa O2). The normal range is 5 -15 and it develops due to regional V/Q mismatching, physiologic shunting, and diffusion limitations (a very small contribution).  The A-a gradient is useful in assess the integrity of the alveolar capillary unit. An abnormally increased A–a gradient suggests a defect in diffusion, V/Q (ventilation/perfusion ratio) mismatch, or right-to-left shunting (blood completely bypasses ventilated alveoli and cannot be oxygenated). You would see variation in the A-a gradient as you moved from the different west zones of the lungs. 

J.B. West was an author of a classic paper that used a dog to experimentally describe the distribution of blood flow in isolated upright lungs in relation to the vascular and alveolar pressures.  He ended up dividing the lung into four zones.  Gravity is the cause for the differences seen in the individual zones. Zone 1 occurs primarily at the apex of the lung or in patients on positive pressure ventilation.  The pressure in the alveolar sac (PA) is larger than that of the pulmonary arteriole (Pa) and the pulmonary venule (Pv).  The pressure difference causes the capillary to collapse and no gas exchange occurs.  In zone 2 the Pa >PA>Pv.  This zone is normally seen from the apex to the midlung.  The level of gas exchange that takes place in this zone is impacted by factors affecting pulmonary transmural pressure such as respiratory cycle, cardiac cycle, and cardiac output.  Zone 3 has the best ventilation and perfusion of all of the zones, the Pa>Pv>PA.   These conditions prevail in the middle to lower lung. The pulmonary transmural pressure is positive along the entire length of the vessel and maximal perfusion takes place.

Zone 4 has the same pressure distribution pattern as zone 3 and is seen at the extreme bases of the lungs.  However, it differs from zone 3 in that the extra alveolar vessels that feed the Pa are decreased in size due the anatomy of the lung and subsequent increased pressure of the pleural space.  The Q is smaller in zone 4 than in zone 3.  Zone 4 is at increased risk for developing pulmonary edema.

Question 4C.What is a V/Q scan? How is it performed?

Answer 4C.

            Ventilation–perfusion (VQ) scan is a nuclear medicine scan that uses radioactive material (radiopharmaceutical) to examine airflow (ventilation) and blood flow (perfusion) in the lungs. The aim of the scan is to look for evidence of any blood clot in the lungs, called pulmonary embolism (PE), though it can also show COPD, cancer, and other pulmonary disorders as well [10,11].

            Ventilation scans are performed to improve the low specificity of the perfusion scans. V/Q scans are preferable over pulmonary angiography for sensitive patients, such as children, pregnant women, and those with clear lungs on x-ray, due to the lower dose of radiation. Patients with contrast allergy and nephrotoxicity, as well as claustrophobia and obesity, also warrant the use of V/Q scanning for PE over CT angiography [10,11].

            The test is completed in two phases. The nuclear medicine technician has the patient breath in radiopharmaceutical agents through a nebulizer then takes a series of images with the gamma camera.  Phase 2 involves the patient getting a different type of radiopharmaceutical agent intravenously and taking another set of images with the gamma camera.  The patient is in a supine position for the images and the entire test lasts 30 minutes to 1 hour. This is significantly longer than the CT angiography series that can be completed within 5 minutes [10,11].  

Question 4D. How would O2 help this patient and how would it change the V/Q ratio?

Answer 4D.

            When a person has a PE the flow gets moved away from the area of obstruction and added to the flow of patent areas. This effectively increases Q of the perfused tissue and decreases the V/Q ratio of the functional tissue. Increasing the partial pressure of the inhaled gas by increasing the percent O2, on top of the hyperventilation that the patient is already exhibiting, would assist in decreasing your A-a gradient and increased your V/Q ratio.  This would facilitate a greater gas exchange at the alveoli/capillaries that are sill patent.

Question 4E. What is the interpretation of the scan below (Fig 1)? Match this up with the clinical findings.

Answer 4E.

The ventilation series shows decreased ventilation, lighter gray, in the left lung as compared with the right. This is in keeping with the localized diffuse wheezes heard in the left lower lung. The perfusion scan shows significant decrease in flow to the majority of the left lobe and to parts of the right anterior lobe.  This suggests that multiple emboli have reached the patient’s lungs.

The alveoli are able to sense a localized increase in the partial pressure of oxygen that is associated with a lack of gas exchange.  These alveoli will constrict to move air towards the alveoli that are still able to participate in gas exchange.   This phenomenon explains the audible wheezes heard in the left lung.

Question 5. Given the positive diagnosis and confirmation of your suspicions what additional tests might be indicated in this patient. Why is that important (Hint: Where did the embolus come from? There was a clinical finding and a major criterion of well’s score that would indicate further testing).

Answer 5.

The Patient had swelling and tenderness in the left lower leg that was suggestive of a DVT as well as a positive history of DVT.  That would be the likely source of her PE and a doppler ultrasound should be done to confirm the diagnosis.  A doppler ultrasound test uses reflected sound waves to determine whether a blood clot is present in the large veins of the legs. [5]

It is important to identify the source of the emboli so that steps can be taken to prevent further thrombi from embolizing to the lungs.  For example, if we can verify that the clot in her left lower leg is venous in nature we can take the patient to the operating room and place an inferior vena cava filter to prevent further emboli from reaching her lungs.

Question 6. What do we do now that we have the diagnosis? What is the mainstay treatment for a PE? Does this actually remove the clot? There are newer treatment modalities available what is the evidence for these? (Hint: Einstein PE trial)

Answer 6.

The main treatment for a PE is anticoagulation. Intravenous heparin is usually the anticoagulant of choice because it has a short half-life and is reversible.  Heparin does not impact the blood clots that already exist, but it does stop further clots from forming and arrests the existing clots growth.  If a DVT is identified then the recommendation is to get an inferior vena cava filter to prevent emboli from reaching the lungs. [13,14]

Pulmonary emboli can vary greatly in their severity. Below are two algorithms that assist with the evaluation and treatment course that is appropriate for the patient’s condition.  Essentially, the healthcare providers have to establish if a patient is hemodynamically stable or not.  When stable, people can be sent home on anticoagulation medications such as warfarin.  Since warfarin takes a few days to reach a therapeutic level daily PT/INRs have to be drawn during the early titration phase and the patient requires a combined anticoagulation therapy with either intravenous heparin(which would require them to stay in the hospital) or subcutaneous injections of lovenox(which is a low molecular weight heparin shot, no PTT monitoring required) until they reach therapeutic PT/INR on warfarin.  Treatment with warfarin requires regular PT/INR levels and close monitoring of vitamin K rich dietary consumption.  

A new medication on the market for outpatient anticoagulation therapy is called Xeralto.  It works by inhibiting platelet activation and fibrin clot formation via direct, selective and reversible inhibition of factor Xa in both the intrinsic and extrinsic coagulation pathways.  The advantage of this medication modality is that it does not require regular coagulation labs for treatment monitoring and does not restrict the dietary vitamin K intake. [12]

The patient in the case study is hemodynamically stable, BP is 145/90, but she is in moderate respiratory distress, respiratory rate 25 and oxygen saturation 96% on 3L O2.  If her condition worsens then her treatment team may consider giving her a thrombolytic agent such as tissue plasminogen activator or a more invasive intervention such as surgical or catheter embolectomy. [13,14]

References:

1. http://www.uptodate.com.proxy.cc.uic.edu/contents/coronary-heart-disease-and-myocardial-infarction-in-young-men-and-women?source=search_result&search=MI+differential+women&selectedTitle=1%7E150
2. http://circoutcomes.ahajournals.org/content/8/2_suppl_1/S31/T2.expansion.html
3. http://www.uptodate.com.proxy.cc.uic.edu/contents/overview-of-acute-pulmonary-embolism-in-adults?source=search_result&search=PE&selectedTitle=1%7E150
4. http://www.uptodate.com.proxy.cc.uic.edu/contents/diagnostic-approach-to-community-acquired-pneumonia-in-adults?source=search_result&search=pneumonia&selectedTitle=3%7E150#H2
5. http://www.aafp.org/afp/1998/0215/p711.html
6. Gould, E. (2007). Respiratory Physiology. In Deja Review: Physiology (2nd ed., pp. 91-122). McGraw-Hill.
7. Sommer, N., Dietrich, A., Schermuly, R., Ghofrani, H., Gudermann, T., Schulz, R., . . . Weissmann, N. (2008). Regulation of hypoxic pulmonary vasoconstriction: Basic mechanisms. European Respiratory Journal, 1639-1651.
8. Boron & Boulpaep, (2012). Medical Physiology (2nd ed.)
9. Costanzo, L. (2014). Physiology with Student Consult online access (5th ed.). Philadelphia Pa.: Saunders Elsevier.
10. http://www.insideradiology.com.au/pages/view.php?T_id=65#.VlDOOdCprzI
11. http://caa.medinuclear.com/site/1946caa_/Interpreting_VQ_scans3.pdf
12. http://www.nejm.org/doi/full/10.1056/NEJMoa1007903
13. http://www.uptodate.com.proxy.cc.uic.edu/contents/overview-of-the-treatment-prognosis-and-follow-up-of-acute-pulmonary-embolism-in-adults?source=see_link
http://www.uptodate.com.proxy.cc.uic.edu/contents/rivaroxaban-drug-information?source=search_result&search=xeralto&selectedTitle=1%7E103#F6724165
14. http://www.uptodate.com.proxy.cc.uic.edu/contents/image?imageKey=PULM%2F57249%7EPULM%2F99762&topicKey=PULM%2F8265&source=see_link&utdPopup=true