Case #3

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 who 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 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:

General: 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 right leg, left 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”

1. Differential Diagnosis: Conditions that can account for acute onset dyspnea, chest pain, and tachypnea

Given the patient’s history of dyspnea, chest pain, and tachypnea, any of at least the following 5 disorders could be the underlying cause of the patient’s symptoms: Acute respiratory distress syndrome, Acute Pulmonary Embolism, Systemic Lupus Erythematous, Systemic Sclerosis Associated Interstitial Lung Disease, as well as Hyperventilation Syndrome (Up to Date).  

These disorders are generally defined as follows:

Acute respiratory distress syndrome: an inflammatory lung disease such that oxygen is prevented from entering the lungs, which is caused by fluid build up in the alveolar sacs. The patient typically presents with damage to the hyaline membranes or alveolar walls, alveolar inflammation, or alveolar edema. (Medline/ Up to Date)

Systemic Lupus Erythematous: An autoimmune disorder in which the immune system attacks healthy cells and tissues, damaging organs, joints, and blood vessels. (Medline)

Systemic Sclerosis Associated Interstitial Lung Disease: An autoimmune disorder in which there is endothelial cell dysfunction causing fibroblast dysfunction, and excess collagen production and fibrosis, damage to small blood vessels. Immunologically, there are problems, such that patients have increased interleukin-8, tumor necrosis factor-alpha, and certain macrophage proteins. There are also high levels of anti-topoisomerase antibodies and anti-fibroblast antibodies. (Article Below)

Hyperventilation Syndrome: A condition where there is increased minute ventilation, which exceeds the body’s normal metabolic demands. (Medscape) There is generally decreased arterial carbon dioxide partial pressure resulting in a range of hemodynamic changes including chest pain, dyspnea, palpitations, and diaphoresis. (Up to date)

Lastly, Acute Pulmonary Embolism may be implicated, but will be discussed in the subsequent because it is suspected to actually be the top diagnosis for the cause of these symptoms.

2. Top Diagnosis: Pulmonary Embolism

Past Medical History: The patient’s past medical history includes: hyperlipidemia, deep vein thrombosis in 2010, and asthma.

Hyperlipidemia

>Hyperlipidemia is a risk factor for deep vein thrombosis. Patients with hyperlipidemia have more fat in the blood than there should be.

> According to the literature, one suggestion as to the underlying connection between hyperlipidemia and DVT, could be that hyperlipidemia causes impaired regulation of coagulation factors like the tissue factor pathway inhibitor (TFPI). Specifically, it is associated with decreased endothelial cell associated TFPI, which may cause DVT.

> Hyperlipidemia is also associated with increased thrombomodulin, which causes the increase of clot formation in blood vessels, and may be associated with DVT pathogenesis.( http://www.sciencedirect.com/science/article/pii/S0049384897001928)

Deep Vein Thrombosis

 >This is perhaps the most relevant part of the patient’s history. According to the literature, Acute Pulmonary Embolism leads to blockage of a pulmonary artery and is typically caused by deep vein thrombosis, or a substantial clot in the leg. >This clot breaks apart and travels to the lung, causing low blood oxygen levels, permanent lung damage, and systemic organ damage to organs that do not receive blood as a result of the clot.  If the clot is large, and not undetected, it can result in death. (Medline)

Asthma

>In a recent study published in the European Respiratory Journal, 648 people with asthma were surveyed and it was discovered that the incidence of pulmonary embolism was higher than amongst the general population. >Specifically, severe asthma is associated with a 9 fold increased risk of pulmonary embolism as compared with the general population, while mild to moderate asthma is associated with a 3.5 increased risk.  (http://www.medscape.com/viewarticle/776545)

Medication Effects of PE:  

>Medications include: Atorvastatin-20mg daily, Albuterol-PRN, and oral Contraceptive Pills-once daily.

> The patient takes the atorvastatin for hyperlipidemia, and albuterol as needed for asthma, and these diseases were previously discussed as risk factors for pulmonary embolism.

>In addition, the usage of oral contraceptive pills is also associated with pulmonary embolism. While it is not clear as to what type of contraceptive the patient takes, estrogen and progesterone is associated with increased venous thromboembolism because these factors increases plasma fibrinogen, coagulation factor activity, as well as platelet aggregation.  (http://www.ncbi.nlm.nih.gov/pubmed/2960241)  

Physical Examination and Review of the Systems:

>The presentation of cold chills, or hot flashes may be present but are not usually common.  

(http://www.ihealthdirectory.com/pulmonary-embolism/)

>However, the fever, which is usually a low-grade is very commonly associated with pulmonary embolism (Merk), along with hemoptysis, and again history of DVT.

>The Patient usually presents with dyspnea, which this patient has. Dyspnea is often caused by emboli or pneumothorax. However, pneumothorax is usually the underlying cause in a healthy patient, whereas pulmonary embolism is considered in a patient with a history of DVT. (http://www.nwprimarycare.com/Journal%20Articles/Acute%20Dyspnea.pdf)

>The chest radiograph shows abnormalities, and the EKG suggests tachycardia, which while is not specific for pulmonary embolism, is commonly associated with this disorder.

Lab Result Indications:

D-dimer value is abnormal

>The D-Dimer value of 2000 micrograms/Liter is indicative of a positive predictive value for pulmonary embolism, since normal values are 500 micrograms/Liter.

White blood count values are abnormal

>The normal white blood cell count should be between 4,500 and 10,000 white blood cells/ microliter (https://www.nlm.nih.gov/medlineplus/ency/article/003643.htm ).

>According to the literature, there reason behind the prevalence of leukocytosis with pulmonary embolism is unknown.

>However, pulmonary embolism is usually associated with other conditions that cause leukocytosis. Perhaps, because the patient also suffers from edema, the elevated white blood cell count, is indicative of inflammation.

> Also, according to the literature, it is an independent predictor of short-term mortality/ hospital readmission. (http://www.ncbi.nlm.nih.gov/pubmed/23674436)

3. Tests to Confirm Top Diagnosis

D-Dimer Testing:

>The D-dimer is a product of fibrinolysis.

>The D-dimer is elevated, therefore, if a patient previously incurred a thrombus. >According to the literature, this test is highly sensitive for the absence of a pulmonary embolism (negative predictive value of 95%).

>However, high levels of d-dimer are commonly associated with DVT and pulmonary embolism, but are not as sensitive as testing for the absence of pulmonary embolism. Thus, this test should be followed by more tests. (Merk)

CT Testing:

This test is a highly sensitive and specific test, that can be used to diagnose acute PE. (Merk)

V/Q ScanTesting:

>Not as specific as the CT testing, but can be used to detect areas that receive ventilation but are not perfused. However, this test is highly sensitive. I

>If the results show intermediate V/Q mismatch, there is a 30 to 40% probability of pulmonary embolism, but if there is a high probability scan, there is an 80 to 90% chance of a pulmonary embolism. (Merk)

Duplex Ultrasonography:

This is a noninvasive test to investigate if there is a thrombus. Specifically, it shows that the vein has poor compressibility or reduced blood flow. It is both highly specific and sensitive ( both >95%). (Merk)

4. V/Q Scan Results:

Ventilation perfusion ratio (V/Q ratio) and hypoxic vasoconstriction

> V/Q ratio: The ratio of alveolar ventilation (VA) to pulmonary blood flow (Q). >Pulmonary blood flow is regulated by the arteriolar, or alveolar partial pressure of oxygen.

>A decrease in alveolar partial pressure of oxygen causes pulmonary vasoconstriction, which is also called hypoxic vasoconstriction. This is actually one of the body’s adaptive mechanisms because it is meant to reduce pulmonary blood flow to areas that are poorly ventilated and to where blood flow is therefore wasted.

>Blood flow is directed away and towards the areas where there is high ventilation so that there can be better gas exchange, and therefore a better chance of ventilation and perfusion matching.  

b. V/Q defect/ Regional V/Q mismatch/West Zones

>V/Q mismatch can be caused when ventilation occurs in areas that are not perfused which occurs when you have a pulmonary embolism or blood flow obstruction.

>You have wasted ventilation, physiologic dead space, and no gas exchange. Another cause of VQ mismatch is when you have a right to left shunt (Costanzo) caused by a defect in the wall between the right and left ventricles.

>According to the literature, 50%, of the cardiac output can be routed to the left ventricle and never enter the pulmonary circulation. Hypoxemia occurs, because there is not enough cardiac output delivered to receive oxygen from the lungs. (Costanzo).

> V/Q mismatch normally exists in the lungs as perfusion is not uniform when patients are in the upright position.

>Perfusion actually increases from the top to the bottom of the lung. The lung is divided into 3 main zones, apex (top- zone 1), mid-lung region (zone 2), and the base (zone 3). In zone 1 or apex, the ventilation is higher than blood flow, because of physiological dead space, so there is a higher V/Q ratio. Whereas in zone 3 or the base, there is an excess of perfusion than ventilation, so there is a shunting of blood flow, which causes there to be a low V/Q ratio. In the zone 2, flow is pulsatile and intermediary between zone 1 and zone 3.

c. V/Q scan

This is a nuclear medicine scan that uses radioactive material (radiopharmaceutical) to examine airflow (ventilation) and blood flow (perfusion) in the lungs. The goal of the scan is to look for evidence of any blood clot in the lung such as a pulmonary embolism. It can also detect uneven air distribution in the lung and guide the surgeon as to what type of lung surgery to perform.

d. A-a gradient, Supplemental O2, effect on V/Q ratio

>The A-a gradient differentiates alveolar and arterial oxygen pressure difference. PAO2 is refers to the alveolar oxygen pressure and PaO2 refers to the arterial oxygen pressure. It allows us to diagnose whether the oxygen is equilibrating in a normal manner between the gas in the alveoli and the blood in the pulmonary capillaries. If the A-a gradient is greater than 10mmHg, there is a problem with gas exchange.

> In the case, this patient is experiencing a pulmonary embolism. As explained previously, in this condition, there is physiologic dead space and therefore, not efficient oxygen and carbon dioxide exchange.

>The V/Q ratio is low, because there is increased blood flow to the area around the alveoli , and decreased ventilation. Providing 100% oxygen will increase ventilation, thus increasing the V/Q ratio, and improving the health of this patient.

e.What is the interpretation of the scan below (Fig 1)?

>This is a perfusion lung scan with technetium-99m macroaggregated albumin. Generally there are 8 standard views. They 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.  

>This scan is abnormal, as we can see multiple peripheral defects in perfusion in both lungs, which is indicated by the fact that the perfusion and ventilation scans do not have the same appearance. Specifically, we see for example in the posterior view for of the lung, perfusion is damaged, and is indicated by the fact the scan is light and non-uniform as compared to the dark scan for ventilation. Also the LAO60 scan, is characteristic for wheezing.

>Based upon what one would expect for a normal chest x-ray or normal ventilation scan, this ventilation/perfusion scan indicates high probability for acute pulmonary embolism.

5. Additional Testing? Where did the embolus come from? Well’s Score?

The following additional tests could be performed and reconfirm data:

>ECG- tachycardia or suggestion of right atrium clot (Merk)

> Cardiac marker testing- mortality risk for PE (Merk)

 >Thrombotic disorder (Thrombophilia) testing- for patients with known PE risk factors (Merk)

>Pulmonary arteriography- patients that have catheter-based thrombolytic therapy; pulmonary angiography is used for assessment of catheter placement (Merk)

The Well’s Score:

 Used by physicians to rule out a pulmonary embolism. There is a point value system for a variety of factors and cumulative scores suggest the probability of PE, before all tests are performed for diagnosing a PE.

> For example, patients whose probability for PE is unlikely may only need

D -dimer testing to confirm that they do not have a PE.

>A negative D -dimer test (< 0.4 μg/mL) is highly indicative of the absence

 of PE.

> The following two pictures show specifically how the Well’s Score isused to test for Pulmonary Embolism as well as Deep Vein Thrombosis which is linked as a causal factor for pulmonary embolism.

6. 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)

For patients with PE the following treatment should be performed:

>Immediate therapeutic anticoagulation should be initiated for patients. Anticoagulation therapy reduces mortality rates from 30% to less than 10%. They delay coagulation processes. Use heparin to increase clotting time and warfarin to decrease prothrombin and factors 9,7, and 10.

>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 minutes to 30 or more minutes. 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.

(“Hemostasis and Blood Coagulation” Textbook of medical physiology 11th edition by Arthur Guyton, MD)

>Einstein trial of oral rivaroxaban (active ingredient)- Xarelto (commercial name):

Purpose: to compare efficacy and safety of rivaroxaban with standard therapy in patients with PE (with or without DVT)
Rivaroxaban is an oral factor Xa inhibitor
It is an anticoagulant and be used for initial PE treatment as well as in long term maintenance anticoagulation therapy
Safety: Showed lower rates of bleeding for patients that took rivaroxaban and has fixed dosing unlike warfarin
Extended treatment proven to significantly reduce the recurrence rate of DVT/PE as compared to a placebo
Downside: there is no current treatment to remove reverse the anticoagulation if bleeding does occur

Bibliography

Up to Date: for ARDS

http://www.uptodate.com/contents/acute-respiratory-distress-syndrome-clinical-features-and-diagnosis-in-adults?source=search_result&search=acute+respiratory+distress+syndrome&selectedTitle=1%7E150

Medline for ARDS:

https://www.nlm.nih.gov/medlineplus/ency/article/000103.htm

Medline for PE:

https://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v%3Aproject=medlineplus&v%3Asources=medlineplus-bundle&query=Pulmonary+Embolism

Scleroderma Lung Disease

http://err.ersjournals.com/content/22/127/6#T1

Hyperventillation Syndrome

http://emedicine.medscape.com/article/807277-overview