Learning Objectives

1. Describe normal VQ matching and regional variations within the lungs

The ventilation-perfusion ratio (V-Q ratio) is the ratio of alveolar ventilation to pulmonary blood flow. For our lungs to function efficiently, blood supply should match gas supply. Ideally this ratio should be one so that there is no wasted ventilation or perfusion. In a healthy individual, the VQ ratio is 0.8 because air ventilation is approximately 4 L/min and blood cardiac output is approximately 5 L/min, giving us a VQ ratio of 4/5 or 0.8.

Due to the effects of gravity, there will be changes in the hydrostatic pressure in the lung. The changes in trans-capillary pressure gradients across the length of the lung will cause regional variations in blood flow. At the apex of the lung, or zone 1, alveolar ventilation is higher than blood flow, therefore giving us the highest possible VQ ratio. At the base of the lung, or zone 3, blood flow is highest and therefore the VQ ratio is lowest. At the middle of the lung, or zone 2, the VQ ratio has intermediate values; this region generally shows pulsatile blood flow. Overall, at the base of the lung we have highest ventilation due to the more compliant alveoli and we also see the highest perfusion due to the highest trans capillary pressure.    

Figure 1 below shows that the regional differences in PO2 (40-150 mmHg) are much greater than the regional differences in PCO2 (0-45 mmHg). Source: Costanzo 5th edition. 

2. Describe pathological causes of VQ mismatch

A V/Q defect can be caused by ventilation of lung regions that are not perfused (dead space) or due to perfusion of lung regions that are not ventilated (shunt).

- A pulmonary embolism is when blood flow to a portion of the lung is occluded, therefore creating a dead space (Q=0), and thus causing wasted ventilation. No gas exchange is possible in dead space because there is no blood flow to receive oxygen from alveolar gas or add CO2 to alveolar gas. Therefore, V/Q = infinity

- A right-to-left anatomical shunt occurs when there is perfusion of lung regions that are not ventilated. An airway obstruction is not allowing the alveolar gas to exchange with the arterial blood supply. Because there is no ventilation, V/Q = 0. 

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

The A-a gradient measures the efficiency of the oxygen exchange between the lung alveoli and pulmonary capillaries. One can use this measure to determine whether the lungs are properly transferring oxygen into the blood. It is simply the difference in the alveolar and arterial partial pressures of oxygen. A normal A-a gradient should be approximately zero because oxygen should equilibrate across the alveolar-pulmonary capillary barrier, but it can range between 5-15 mmHg in healthy individuals and is easily calculated by computing (age +10)/4. An elevated A-a gradient is an indicator for improper gas exchange, for example in cases of hypoxemia, where the blood oxygen levels are lower than normal.

Causes for an elevated A-a gradient include:

- Interstitial lung disease

- Pneumonia

- Pulmonary vascular disease (shunt) i.e. a pulmonary emboli or pulmonary hypertension     

- V/Q mismatches of large vessels or emboli of small vessels

Clinical Case Questions:

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.

- Myocardial infarction (MI) : angina, dyspnea, tachypnea

- Acute Respiratory Distress Syndrome (ARDS) : dyspnea, tachypnea, tachycardia, cough and chest pain may also exist

- Pulmonary Embolism (PE) : Fever, Productive cough, Wheezing, Hemoptysis. The patient also has a history of DVT in 2010, accompanying a history of hyperlipidemia (she is taking atorvastatin for this).  

- Systemic lupus erythematosus (SLE): Pleurisy with pleuritic chest pain with or without pleural effusions, shortness of breath or dyspnea, pulmonary embolism, lupus pneumonitis, chronic lupus interstitial lung disease, pulmonary hypertension, complement-mediated pulmonary leukoaggregation, alveolar hemorrhage, or infection may be related to lupus disease. Hemoptysis may indicate diffuse alveolar hemorrhage, a rare, acute, life-threatening pulmonary complication of SLE.

- Systemic Sclerosis: shortness of breath on exertion and at rest, nonproductive cough, atypical chest pain, fatigue, dyspnea, and hypertension may be present, joint pain, limitation of movement, joint swelling, and muscle pain may be present.

- Hyperventilation Syndrome: sudden onset of dyspnea, chest pain, patients with chronic HVS present with similar symptoms, including recurrent chest pain, dyspnea, and neurologic deficits, and usually have had many similar presentations in the past.

- Pneumonia can also present with dyspnea, tachypnea and chest pain. The patient's WBC count is elevated as well, which might support this diagnosis.

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)

I believe the patient has a pulmonary embolism based on these factors:

> She is taking oral contraceptives, which increases the risk of blood clotting, especially in women over the age of 35.

> She frequently undergoes long flights; this immobilization decreases venous flow and thus increases the risks of a blood clot and DVT development and subsequently an embolus formation that can travel up to her pulmonary arteries. Her physical exam also showed swelling on her lower extremities, most likely due to the venous stasis and edema.

> Her history of hyperlipidemia, which is a major causative factor for arteriosclerosis which then may lead to thromboembolic conditions.

> D-Dimer of 2000 micrograms/Liter is indicative of a positive predictive value, since normal values are 500 micrograms/Liter or less. D-Dimer is a by-product of intrinsic fibrinolysis; thus, elevated levels occur in the presence of a recent thrombus.

> Troponin I levels are in the normal range, therefore indicating MI is most likely not the cause of her symptoms.

> Radiologist impression of X-ray is normal, with no acute finding therefore rule out pneumonia.

> ECG according to cardiologist interpretation: sinus tachycardia otherwise normal ECG; this correlates with an ECG of a recent PE patient, according to the Merck manuals on pulmonary embolism. 

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

> d -Dimer already came back positive so this is one way to confirm a PE.

> CT angiography is the preferred imaging technique for diagnosing acute PE. It is rapid, accurate, and highly sensitive and specific. It can also give more information about other lung pathology (Ex. demonstration of pneumonia rather than PE as a cause of hypoxia or pleuritic chest pain). The sensitivity of CT angiography is highest for PE in the main pulmonary artery and lobar and segmental vessels. Sensitivity of CT angiography is lowest for emboli in subsegmental vessels (about 30% of all PEs).

> V/Q scans in PE detect areas of lung that are ventilated but not perfused. In our patient, she shows a normal ventilation scan, but decreased perfusion scan. Therefore evidence supporting a PE.

> Duplex ultrasonography is a safe, noninvasive, portable technique for detecting leg or arm (particularly femoral vein) thrombi. A clot can be detected by showing poor compressibility of the vein or by showing reduced flow by Doppler ultrasonography. The test has a sensitivity of > 95% and a specificity of > 95% for thrombus. 

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

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

See learning objective 1.

Hypoxic vasoconstriction: When there is decreased alveolar partial pressures of oxygen, the body undergoes pulmonary vasoconstriction (hypoxic vasoconstriction) in order to reduce blood flow to poorly ventilated areas where the oxygenated blood flow would be wasted. Blood flow is instead directed towards better-ventilated regions where the gas exchange would be adequate and efficient. This is an example of an adaptive mechanism during hypoxemic conditions and it minimizes the V/Q imbalance.    

b. 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)

See learning objective 1.

c. What is a V/Q scan? How is it performed?

A ventilation–perfusion (VQ) scan is a nuclear medicine scan that uses radioactive material 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 (pulmonary embolism). A VQ scan also can detect poor blood flow in the lungs' blood vessels and uneven air distribution, and it can provide pictures that help doctors prepare for some types of lung surgery. The 8 standard views are anterior, posterior, left anterior oblique (LAO), right posterior oblique (RPO), right anterior oblique (RAO), left posterior oblique (LPO), and right (RT) and left (LT) lateral.

A VQ scan is carried out in two parts. In the first part, radioactive material is breathed in and pictures or images are taken to look at the airflow in the lungs. In the second part, a different radioactive material is injected into a vein in the arm, and more images taken to see the blood flow in the lungs.

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

Oxygen supplementation should be administered to patients who are suspected of having an acute PE in order to establish blood oxygen saturation levels >90%. Since our patient has an oxygen saturation of 96%, she does not require supplemental oxygen, and thus she is considered hemodynamically stable. Administering oxygen to a patient that is hemodynamically unstable would help reverse the high V/Q ratio.

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

This perfusion scan is abnormal, showing multiple peripheral perfusion defects in both lungs. With the presence of a normal chest x-ray and normal ventilation scan, this perfusion scan indicates high probability for acute pulmonary embolism. 

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 criteria of well’s score that would indicate further testing)

> Echocardiography may show a clot in the right atrium or ventricle, but it is most commonly used for risk stratification in acute PE. The presence of RV dilation and hypokinesis may suggest the need for more aggressive therapy.

> Additional Cardiac marker testing is evolving as a useful means of stratifying mortality risk in patients with acute PE. Cardiac marker testing can be used adjunctively if PE is suspected or proven. Elevated brain natriuretic peptide (BNP) and pro-BNP levels may signify RV dysfunction; however, these tests are not specific for RV strain or for PE.

> Thrombotic disorder (thrombophilia) testing should be done for patients with PE and no known risk factors, especially if they are < 35 yr, have recurrent PE, or have a positive family history.

> Pulmonary arteriography is also still used together with right-heart catheterization in assessing whether patients with chronic thromboembolic pulmonary hypertension are candidates for pulmonary endarterectomy.

>Clinical Calculator: DVT Probability: Wells Score System: 

Further testing was indicated on this patient due to her history of DVT in 2010 and a history of hyperlipidemia. 

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)

According to American College of Chest Physicians (ACCP) guidelines, immediate therapeutic anticoagulation should be initiated for patients in whom DVT or pulmonary embolism is suspected. Anticoagulation therapy reduces mortality rates from 30% to less than 10%

Anticoagulant options:

- Tissue plasminogen activator (t-PA): when delivered directly to a thrombosed area through a catheter, it is effective in activating plasminogen to plasmin, which in turn can dissolve some intravascular clots.

- Heparin: causes the blood-clotting time to increase from a normal of about 6-30 minutes or more. It immediately prevents and slows further development of a thromboembolic condition.

- Warfarin (a coumarin): causes the plasma levels of prothrombin and factors 7, 9, 10 to decrease. This causes the coagulant activity of the blood to decrease by about 50% of normal by the end of 12 hours and to about 20% of normal by the end of 24 hours.

* Anticoagulation is the mainstay of therapy for PE, initial anticoagulation followed by maintenance anticoagulation is indicated for patients with acute PE to prevent clot extension and further embolization as well as new clot formation.

Newer treatments:

Einstein PE trial:

The purpose of this trial was to compare the efficacy and safety of XARELTO® (rivaroxaban) with standard therapy in 4832 patients with confirmed PE (with or without symptomatic DVT). XARELTO® was proven at least as effective as the standard of care (enoxaparin + warfarin). The data showed comparable rates of the composite of major bleeding and clinically relevant nonmajor bleeding across treatment groups and lower rates of major bleeding for XARELTO®

Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting blood coagulation factor Xa (FXa), rivaroxaban decreases thrombin generation. Based on in vitro studies, rivaroxaban demonstrated selective inhibition of both free and clot-bound FXa as well as FXa in the prothrombinase complex.

See figure 2 on mechanism of action of Xarelto (rivaroxaban) below. 

References:

- Dr. Els’ lecture 6: Pulmonary Blood Flow

- Costanzo, Linda S. Physiology. 5th edition.

- A Maziar Zafari, MD, PhD. Myocardial Infarction Clinical Presentation. http://emedicine.medscape.com/article/155919-clinical

- Daniel R Ouellette, MD, FCCP. Pulmonary Embolism. http://emedicine.medscape.com/article/300901-overview

- Robert A Schwartz, MD, MPH. Systemic Sclerosis Clinical Presentation. http://emedicine.medscape.com/article/1066280-clinical

- Merck Manuals Professional Edition: Pulmonary Disorders:  Pulmonary Embolism (PE). http://www.merckmanuals.com/professional/pulmonarydisorders/pulmonary-embolism-pe/pulmonary-embolism-pe

- VQ scans: http://www.insideradiology.com.au/pages/view.php?T_id=65#.Vk1J7PmrTjY

https://www.nhlbi.nih.gov/health/health-topics/topics/lvq

http://www.stritch.luc.edu/lumen/MedEd/Radio/curriculum/Medicine/NM_vq.htm

- Victor F Tapson, MD. Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults. http://www.uptodate.com/contents/overview-of-the-treatment-prognosis-and-follow-up-of-acute-pulmonary-embolism-in-adults

- Guyton, A. C., & Hall, J. E. (2000). Hemostasis and blood coagulation. Textbook of Medical Physiology. 11th ed. Philadelphia: WB Saunders Co, 457-468.

- https://www.xareltohcp.com/about-xarelto/about-factor-xa.html