Case Learning Objectives:

1. Describe normal V/Q matching and regional variations within the lungs
2. Describe pathological causes of V/Q mismatch
3. Describe what constitutes the A-a gradient, a normal A-a gradient and the significance of a widened A-a gradient

Q1. 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.

Thinking broadly, when a patient presents with dyspnea, chest pain and tachypnea, the different diagnoses under consideration should include both cardiac and pulmonary origins. The table below contains five potential diagnoses, some of their expected signs and symptoms, and how the case patient's history and medical tests align with these parameters.

When reviewing the chart above, dyspnea means difficult, labored or uncomfortable breathing. Tachypnea means abnormally rapid breathing. Hemopytsis means coughing up blood.

Sources: (Papadakis & McPhee, 2015; Bolooki & Askari, 2010; Mortelli & Manning, 2002; Cayley, 2005)

Q2. 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)

As highlighted by the table above, many of the clinical findings and exam results support a diagnosis of pulmonary embolism (PE) and eliminate other potential choices. The rationale for this differential diagnosis is outlined below. Four of the five diagnoses can be ruled out based on the following observations.

• Myocardial Infarction (MI). The diagnosis of myocardial infarction is associated with hyperlipidemia, chest pain, dyspnea and tachypnea. All of these signs were present in the case patient. Hyperlipidemia is an important risk factor for coronary heart disease. The case patient was taking Atorvastatin to lower her cholesterol and reduce this risk factor. With an MI, the provider would expect to see elevated troponin levels over time. Troponins are regulatory proteins of cardiac and smooth muscle and are released after heart muscle is damaged. The case patient had troponin levels below the cutoff for cardiac injury (<0.01ng/mL). Further, in a MI, radiating chest pain is often observed. Pain did not radiate in this patient. Finally, MI from right-sided heart failure often presents with an increase in jugular venous distention (JVD) resulting from elevated blood pressure in the jugular vein (jugular venous pressure). JVD was not present in this patient.
• Pericarditis. Pericarditis is swelling and inflammation of the pericardium. It is characterized by chest pain that is worse when lying flat. It is associated with dyspnea/tachypnea, couph, night sweats and fever (Spangler, 2015). All of these symptoms are present in the case patient. However, with pericarditis, the ECG will reveal serial changes in the ST-segment of the ECG. These are not observed in the case patient. 
• Pneumonia. Fungal pneumonia can present with an increased temperature, tachycardia, tachypnea, and respiratory distress (Romeo, 2014). While these are present in the patient, there is no evidence of pulmonary consolidation or rales (abnormal rattling sound when breathing).The acute onset of the symptoms also make this diagnosis less likely. 
• Acute Respiratory Distress Syndrome (ARDS). ARDS is associatd with diffuse alveolar damage and lung capillary injury and defined by the acute onset of severe hypoxemia and bilateral pulmonary infiltrates (Eloise, 2015). This syndrome results from an inciting event including trauma, pneumonia, sepsis, and many other causes. While the initial clinical presentation of ARDS parallels that of the case patient, the radiography of this patient did not reveal bilateral inflitrates, which normally will have a patchy peripheral distribution. Further, the hypoxemia associated with ARDS is refractory to supplemental oxygen, unlike the case patient whose O2 concentration increased with O2 (Eloise, 2015).

Given these eliminations, the diagnosis of pulmonary embolism is specifically supported by:

• Definition. Pulmonary embolism is a blockage of one of the pulmonary arteries of the lung.
• Clinical Findings. Observe acute chest pain, dyspnea, tachypnea, hemopytsis
• History of Deep Vein Thrombosis (DVT). DVT is a significant risk factor for the development of PE and part of the Wells criteria described in answer 5 below. Deep vein thrombi/blood clots can cause PE when the clot breaks off and travels throug the heart to the pulmonary arteries where it causes an obstruction (Goldhaber & Bounameaux, 2012).
• Results of the D-Dimer blood test. D-Dimer is a fibrin degradation product that is elevated in the blood after a blood clot has been degraded. The normal threshold is between 300-500ng/mL. Our patient has a D-Dimer vale of 2000ng/mL indicative of blood clot degradation.
• Pulmonary Review. Wheezing was heard in the lower lung fields on the left. The wheezing could result from pulmonary bronchoconstriction from the presence of a pulmonary emboli (Windebank et al., 1973).
• V/Q results. Demonstrate a V/Q mismatch indicative of PE. A normal V/Q scan would elimate PE.
• ECG Results. The ECG results reveal sinus tachycardia. Tachycardia is observed in 70% of patients with a PE (Papadakis & McPhee, 2015). Besides tachycardia, the ECG results are normal. This is an important finding and helps eliminate a diagnoses of myocardial infarction. 
• Past Medical History. Hyperlipidemia is also associated with increased incidence of deep vein thrombosis (DVT). Hyperlipidemia decreases fibrinolysis (break down of clots) leading to larger clot size. This is because it increases the level of a blood plasminogen activator (enzyme that degrades fibrin clots) inhbitor (Diaz et al., 2012).
• Past Medical History. The case patient also has a history of asthma and takes albuterol-PRN to address this problem. Recent research has shown that asthma, an inflammatory disorder, can increase the risk for pulmonary embolism. Additionaly oral corticosteroid use may also further increase this risk (Majoor et al., 2013).
• Medications. The case patient takes daily oral contraceptive pills. Estrogen/progesteron oral contraceptives are a risk factor for spontaneous thrombosis (Westgate & Fitzgerald, 2005). Estrogen/progesterone birth control can have these effects because they increase plasma fibrinogen and the activity of coagulation factors (factors VII and X). Further, they can decrease antithrombn III, an important inhibitor of coagulation. Additionally, they can also increase platelet activity (Freedman & Loscalzo, 2015). All of these effects can promote thrombus formation. 

Sources: (Goldhaber & Bounameaux, 2012; Diaz et al, 2012; Eloise, 2015; Freedman & Loscalzo, 2015; Majoor et al., 2013; Papadakis & McPhee, 2015; Romeo, 2014; Spangler, 2015; Windebank et al., 1973)

Q3. Given your top diagnosis what specific tests do you need to run in order to confirm it?

The following flowchart highlights the specific tests that should be considered to confirm the diagnosis of PE. The D-Dimer tests was already conducted, revealing elevated levels of D-Dimer. Given this information, the next test would by CT angiography. As described below, the V/Q scan can also help determine if PE can be excluded.

Source: (Pignone, Nicoll, & McPhee, 2012)

Computed tomography (CT) angiography will help visualize the flow of blood through arteries and veins of the lung and the rest of the body. It is performed by injection of an iodine-rich contrast agent injection. A CT scan is performed as the contrast agent flows throughout the body to identify areas of impaired blood flow. The CT angiography can confirm the presense of a pulmonary embolism by identifying full or partial arterial occlusion (Wittram et al., 2004).

Q4: Results of a VQ Scan are shown below. Elaborate on the following:

• Ventilation/Perfusion Ratio (V/Q Ratio). This is the ratio of pulmonary ventilation (V) to pulmonary blood flow (perfusion) (Q). This ratio is very important to understand the appropriate exchage of O2 and CO2 between the blood and the air. The normal V/Q ratio of the total lung is approximatley 0.8, indicating near equal ventilation and perfusion. The value of 0.8 results from normal ventilation of 4L/min divided by normal perfusion/cardiact output of 5L/min.
• However, the V/Q ratio is NOT uniform across the lung when standing or sitting up. Due to the effect of gravity, there is more perfusion at the base of the upright lung than at the apex. We can better understand perfusion to the lung, by looking at the West Zones from figure 12 in Lecture 6: Pulmonary Blood Flow. This figure demonstrates that that there are three zones of blood flow in the lung and blood flow is determined by the transcapillary pressure gradient. The transcapillary pressure gradient (PTCap) is the difference in pressure between the pulmonary artery and the alveoli. The figure highlights that blood flow is strongest at the base of the upright lung, where the PTCAP is highest.

• Using figure 16 from Lecture 6: Pulmonary Blood Flow, we see how this increased pulmonary blood flow contributes to regional variations in the V/Q ratio-where there is a lower V/Q ratio on the bottom and a higher V/Q ratio on the top of the lung. This makes sense, because Q, the denominator, is smaller on the top of the lung, then the bottom. Therefore, these two figures help visualize how there is normally some degree of V/Q mismatch in the lungs.

• Hypoxic Vasocontriction. The body has certain mechanisms to maintain the V/Q ratio. One of these mechanisms is hypoxic vasoconstriction. This vasoconstriction is triggered by hypoxemia, low oxygen levels. When the V/Q ratio is low (resulting from under/poor ventilation or increased blood flow rate to a specific area), vessels can constrict to decrease perfusion and redirect/shunt blood to other areas. Decreasing the perfusion to the affected/damaged area, normalizes the V/Q ratio and increases the total area of the lung that is involved in gas exchange.
• V/Q Defect. While there is normally a mismatch across the lung, different pathologies can cause significant inequalities in the V/Q ratio that can lead to hypoxemia (low concentration of O2 in the blood) and other severe consequences associated with morbidity and mortality.
• V/Q Defect in PE. A pulmonary embolism can alter the V/Q ratio in multiple ways. First, it creates an abnormally high V/Q ratio at the site of embolism because perfussion to that area is so small due to the emboli blocking flow (Q). V/Q at this location approaches infinity. The area blocked by the embolism creates physiologic alveolar dead space that can no longer exchange O2 and CO2. However, this creates a decreased/lower V/Q ratio in the surrounding alveoli because of the redirected blood flow to these areas (Q increases). This results in increased perfusion and decreased ventilation. Because of this phenomenon, administration of 100% O2 improves the condition by increasing regional ventilation and restabilizing the V/Q ratio.
• The V/Q scan and findings for the case patient are outlined below. 

• Additional Clinical Test to Identify Pathological Distrubance. Hypoxemia (low concentration of O2 in the blood), as present in this case, can result when there is a mismatch between ventilation and perfusion. To determine if oxygen is being transfered properly, providers can look at the A-a gradient calculation. This compares how effectively O2 moves from the alveoli (A) to the pulmonary (a) blood and is measured as the PO2 difference. An A-a gradient greater than 10 mmHg indicates a problem with gas exchange/transfer.

Q5: Given the positive diagnosis, what additional tests might be indicated for this patient?

• Given the diagnosis of pulmonary embolism (PE), it is important to investigate the patient’s history of deep vein thrombosis (DVT). It is anticipated this is where the embolus originated. The Wells Criteria table below is a clinical evaluation tool to help determine both the likelihood of PE and DVT. Based on the review of systems, DVT is expected to be linked to the pulmonary embolism because of the patient’s past history of DVT, the 4cm swelling on the left leg, and the calf tenderness. The higher D-Dimer value is also indicative of DVT. Finally, the long duration of the patient’s flight with no movement (14 hours), is a significant risk factor for DVT.

• To confirm suspicions of DVT, a venous compression ultrasound (CUS) of the lower extremities can be used to identify the blood clot.  Benefits of ultrasound include that it is noninvasive, it does not require radiation, and the measuring instrument can be portable. It also has high specificity and sensitivity in symptomatic patients (like our case). Clots are identified using this technique because they cannot be compressed. 

Q6: What do we do following the diagnosis? What is the mainstay treatment for PE? What is the evidence for newer treatment modalities?

• With a diagnosis of PE and DVT, immediate initiation of therapeutic anticoagulation treatment is recommended by the American College of Chest Physicians in order to reduce mortality rates (Guyatt et al., 2012). For PE, low-molecular weight heparin (LMWH) or fondaparinux are recommended over unfractionated or subcutaneous heparin. A vitamin K antagonist is also recommended alongside warfarin to block the clotting actions of vitamin K.
• Heparin is an anticoagulant that activates antithrombin which, in turn, inhibits clotting enzymes including thrombin and factor Xa (Weitz, 2015).
• Anticoagulats do not remove the clot. They function by stopping the further growth/formation of clots.  Current anticoagulant treatment still allows for recurrence of DVT/PE. Further, to monitor/prevent major bleeding risk, close laboratory monitoring  across time is important to ensure appropriate dosage.
• The EINSTEIN program conducted three randomized trials of a new drug rivaroxaban for the treatment of both acute and continued DVT and PE (Agnelli et al., 2010). Rivaroxaban is an orally active, direct factor Xa inhibitor. Factor Xa is important in the blood clotting cascade (see figure below). In the study, this drug was compared in efficacy and safety to LMWH + Vit K antagonist. It was found to be as effective as standard therapy (with an accepatable risk of bleeding). Further, it reduced the reoccurance rate of DVT/PE by 82% as compared to placebo. These findings support the use of this single-drug therapy in outpatient management of DVT (Agnelli et al., 2010).
• It is also important to review the patients use of oral contraceptives and consider alternative birth control methods/dosages, given her history of DVT and recent PE.
• Further, given the patient's occupation and long travel times, it is important to review the importance of moving on long airplane trips to increase blood flow and assess how often she should be flying.

Source: (Guyatt et al., 2012)

Citations:

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