Venous Thromboembolic Disease PE and DVT

  Dr. Kline discussed a scoring system referred to as the “PERC Rule” that is used to assess a patient’s risk for probability of PE in the emergency department.[1] It involves evaluating the presence or absence of 8 clinical criteria to arrive at a pretest probability. The criteria are (All must be yes)

1. age < 50 years
2. heart rate less than 100 beats per minute
3. room air oxygen saturations 95% or greater
4. no prior deep venous thrombosis [DVT] or PE
5. no recent trauma or surgery (4 weeks)
6. no hemoptysis
7. no exogenous estrogen
8. no clinical signs suggestive of DVT (Unilateral leg swelling on visual inspection

  Lessler AL et al. Testing Low-Risk Patients for Suspected Pulmonary Embolism: A Decision Analysis. Ann Emerg Med 2010;epub ahead of print. Study Question: What is the testing threshold for DVT/PE, the state of balance between the risk of the test and treatment and the benefit of treatment? In other words, above which pretest probability should we order a test (i.e. D-dimer and/or CTA)? Authors of the PERC rule had previously published that the testing threshold was 1.8% using similar methodology but different assumptions. Results: This decision analysis used the latest evidence, best available assumptions, and mathematical models and concluded that the overall testing threshold was 1.4%, lower than previously published. Limitations: A decision analysis is only as good as the assumptions made. Take Home: If someone is PERC negative, the risk for DVT/PE is 1%, low enough to avoid additional testing in such individuals. Level of Evidence: 2 Bonus: To remember the PERC rule, use HAD CLOTS. The patient must meet the following: no Hormones, Age < 50, no DVT/PE history, no Coughing blood, no Lower extremity swelling unilaterally, no O2 saturation <95, no Tachycardia ≥100, no Surgery/trauma within past 28 days. (from KeepingUpWith)     If the patient has none of the criteria specified, the pretest probability is less than 2%, and the patient will not benefit from an evaluation for PE. According to Kline, the PERC rule reliably forecasts a probability of PE below 2% in emergency department patients. This probability was derived from a large multicenter database, and has been validated at 4 different academic centers.[15,16] 6 hours with knees bent without walking=dvt riskgestalt and then perc Kline then described different clinical characteristics of patients who are at risk for PE. One myth that was de-bunked was the lack of association of smoking as a risk factor for PE in emergency department patients.[14,17] Next, the discussion turned to the increased incidence of PE during pregnancy. Specifically, the risk increases from 1/10,000 to 2/10,000 and is greatest in the postpartum period. PE represents the second most common cause of death in pregnancy. If you look at emergency department testing of pregnant patients, less than 5% who undergo work-up end up having a PE. What is clear is that the D-dimer is increased in most patients, less than 50% with PE have a DVT on ultrasound, the ventilation-perfusion (V/Q) scan is “normal” in two thirds of patients, and the risk of contrast material to the fetus is unknown.[17] In the postpartum period, due to a 5-fold increased risk of PE, approaches to evaluate for PE include a V/Q scan, or computed tomography (CT) angiography of the chest. Other options include venous Doppler ultrasound of the lower extremities and a V/Q scan (70% will be normal) or Doppler ultrasound of the lower extremities, or CT (with fetus shielded). A further option is to use the PERC rule and adjust the quantitative D-dimer upward in pregnancy: first trimester,

1. Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected PE. J Thromb Hemost. 2004;2:1247-1255.
2. Hogg K, Dawson D, Kline J. Application of pulmonary embolism rule-out criteria to the UK Manchester Investigation of Pulmonary Embolism Diagnosis (MIOPED) study cohort. J Thromb Haemost. 2005;3:592-593. Abstract
3. Tsai AW, Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002;162:1182-1189. Abstract
4. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ III. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143:697-706. Abstract

  Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Department of Emergency Medicine, Carolinas Medical Center, PO Box 32861, Charlotte, North Carolina 28323-2861, USA. Jkline@carolina.rr.com Overuse of the d-dimer to screen for possible pulmonary embolism (PE) can have negative consequences. This study derives and tests clinical criteria to justify not ordering a d-dimer. The test threshold was estimated at 1.8% using the method of Pauker and Kassirer. The PE rule-out criteria were derived from logistic regression analysis with stepwise backward elimination of 21 variables collected on 3148 emergency department patients evaluated for PE at 10 US hospitals. Eight variables were included in a block rule: Age 94%, no unilateral leg swelling, no hemoptysis, no recent trauma or surgery, no prior PE or DVT, no hormone use. The rule was then prospectively tested in a low-risk group (1427 patients from two hospitals initially tested for PE with a d-dimer) and a very low-risk group (convenience sample of 382 patients with chief complaint of dyspnea, PE not suspected). The prevalence of PE was 8% (95% confidence interval: 7-9%) in the low-risk group and 2% (1-4%) in the very low-risk group on longitudinal follow-up. Application of the rule in the low-risk and very low-risk populations yielded sensitivities of 96% and 100% and specificities of 27% and 15%, respectively. The prevalence of PE in those who met the rule criteria was 1.4% (0.5-3.0%) and 0% (0-6.2%), respectively. The derived eight-factor block rule reduced the pretest probability below the test threshold for d-dimer in two validation populations, but the rule’s utility was limited by low specificity. J Thromb Haemost. 2004 Aug;2(8):124   Journal of Thrombosis and Haemostasis Volume 3 Page 592 – March 2005 doi:10.1111/j.1538-7836.2005.01212.x Volume 3 Issue 3 LETTERS TO THE EDITOR Application of pulmonary embolism rule-out criteria to the UK Manchester Investigation of Pulmonary Embolism Diagnosis (MIOPED) study cohort K. HOGG*, D. DAWSON* and J. KLINE†The effect of introducing a structured approach to the diagnosis of pulmonary embolism in UK emergency departments has been complex. Unlike our US and Australasian counterparts, it can take several days to complete the pulmonary embolism investigative pathway, as delays for ventilation-perfusion and computed tomography (CT) scans are common. As in the US [1], a larger proportion of emergency department patients now undergo pulmonary embolism rule-out strategies. During pulmonary embolism exclusion patients can be admitted to hospital unnecessarily. Furthermore, patient care is passed from the emergency department to the admitting medical physician. On occasion, the admitting specialties disagree that exclusion of pulmonary embolism is necessary: for example, in the young well patient with isolated pleuritic chest pain. The PERC rule [2] provides a standardized approach to assessing such patients prior to commencing a rule-out strategy. The Manchester Investigation of Pulmonary Embolism Diagnosis study (MIOPED study) is a prospective cohort study which recruited 425 patients with pleuritic chest pain. Between February 2002 and May 2003 patients presenting to Manchester Royal Infirmary’s emergency department with pleuritic chest pain were consented and recruited. Exclusion criteria included pneumothorax, electrocardiogram (ECG) changes of myocardial infarction, ischemia or pericarditis, pregnancy, trauma within 4 weeks, age under 18 and patients previously recruited to the study. Pulmonary embolism was excluded with combined normal IL d-dimer test and low clinical probability, a normal ventilation-perfusion scan or a low probability ventilation-perfusion scan with low clinical probability, normal CT pulmonary angiography with low clinical probability or normal digital subtraction pulmonary angiography. All patients were followed-up clinically for 3 months. Pulmonary embolism was confirmed by a high probability ventilation-perfusion scan with high clinical probability, positive CT pulmonary angiography or a positive digital subtraction angiography. The mean age was 38.3 years (SD 15.0) with 51.1% of the cohort female. Eighty-eight per cent of patients scored a low Wells’ clinical probability of pulmonary embolism, 8.7% moderate and 3.3% high clinical probability. Mean PaO2 was 11.8 kPa (SD 2.2) and PaCO2 5.1 kPa (SD 0.7). Five per cent were tachycardic and 25% tachypnoeic, 20% had an elevated white cell count and 13% an abnormal chest X-ray. The prevalence of pulmonary embolism was 5.3%. All patients had complete data for the PERC decision rule. Two hundred and sixteen patients fulfillled all eight factors (age 94%, no unilateral leg swelling, no hemoptysis, no recent surgery, nor prior thromboembolism and no oral hormone use). Within this subgroup, three patients had pulmonary embolism (1.39%, 95% CI 0.5-4.0%). The sensitivity of the PERC rule was 86.4% (95% CI 65.1-97.1%), specificity 53.9% (95% CI 48.9-58.9%) and negative likelihood ratio 0.25 (95% CI 0.09-0.62). In comparison, 3.2% (95% CI 1.7-5.6%) of the Wells’ low clinical probability group had pulmonary embolism. During the MIOPED study Manchester Royal Infirmary saw 100 000 patients per year. Four per cent of presentations involved chest pain and a quarter of these were cases of pleuritic chest pain. Thus, on average, three patients per day presented with pleuritic chest pain. As demonstrated by our study, the prevalence of pulmonary embolism among this population is low. The PERC rule offers a method for screening these patients without taking a blood test for d-dimer level and subjecting patients with a false positive d-dimer to unnecessary diagnostic imaging. Of the remaining 201 patients who could not have pulmonary embolism ruled out using the PERC decision rule, 79% scored low Wells’ clinical probability, 15% moderate and 6% high clinical probability. Applying the PERC rule in retrospect to our cohort, only 159 patients (with low clinical probability) would require a d-dimer analysis. Of these, 69 had a positive IL test d-dimer and would require diagnostic imaging, in addition to 42 patients who scored a moderate or high clinical probability. The total number of patients requiring further imaging would have been reduced from 186 (44.6%) to 111 (26.6%). The obvious disadvantage of the PERC rule is that it would have missed three cases of pulmonary embolism. In comparison, using the Wells’ clinical probability score in combination with d-dimer missed two patients with pulmonary embolism. Despite the limitations, the PERC rule remains an objective and useful decision rule, and represents one of the first attempts to address the potential for over investigation of pulmonary embolism in low-risk patient groups. ———- (1) Wolf SJ, et al. Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department Am J Emerg Med 2008; 26 181-185       The original ‘PERC rule’ study by Kine et al (2004) excluded patients with these characteristics:

• patients in whom shortness of breath is not the most important, or equally most important, presenting complaint
• cancer
• thrombophilia
• strong family history of thrombophilia
• beta blockers that may mask tachycardia
• patients with transient tachycardia
• patients with amputations
• patients who are massively obese and in whom leg swelling cannot be reliably ascertained
• with baseline hypoxemia in whom a pulse oximetry reading <95% is long-standing

However, since the derivation study there has been two validation studies. One of the validation studies (Kline et al, 2008) was a multi-center study that included patients with a primary complaint of shortness of breath or chest pain. Thus, I think that the PERC rule can be safely applied to patients with chest pain as the primary complaint. (From LitFL Blog) Further, Dr. Kline just showed that normalization of any abnormal vital signs doesn’t lower probability of PE (Acad Emerg Med 2012;19:11) SR of PERC (Ann Emerg Med 2011; Singh et al.) showed Sens 97%, Spec 23%, LR – 0.17, LR + 1.24 Another PERC SR (Ann Emerg Med 2012;59:517)  

Age adjustment of D-dimer

Increased specificity with no loss of sensitivity (BMJ 2013;346:f2492)    

Deep Venous Thrombosis

Saphenous vein is 1 finger anterior to medial malleolus assoc c type A blood.

ACEP DVT Clinical Policy (Annals EM 42:1, 2003)

Level B: If the patient has low pretest probability, the following can be used to exclude DVT

1. A negative ELISA or turbidimetric D-Dimer
2. A negative whole blood D-Dimer with a Low Prob Well’s Score
3. A negative whole blood D-Dimer for exclusion of proximal DVT

Level B: In patients with low pretest prob, one negative ultrasound is sufficient. Moderate and high probability patients require serial scanning to r/o DVT   10-20% of calf DVTs propogate and may embolize

Phlegmasia Cerulea Dolens (PCD)

fulminant form of DVT pain, extraordinary edema, and cyanosis of the affected extremity. near-total or total occlusion of extremity venous outflow Massive sequestration of fluid in the affected extremity may produce hypovolemia and systemic hypotension. development of gangrene is a late sign and is associated with significant morbidity and mortality.   Any acute condition in the iliac or femoral veins, especially a DVT or an ileofemoral thrombosis can cause a REFLEX ARTEROLAR SPASM on the arterial side. This spasm can be relieve by a sympathectomy, a sympathetic block, or at times a spinal anesthesia. (Research by Alton Ochsner in the 1930s). This reflex arteriolar spasm results in a “MILK LEG” or a white appearance of Phlegmasia, ALBA dolens. (MAttox) Standard treatment includes bed rest, elevation, and systemic heparinization. 150u/kg followed by 40u/kg/hr infusion catheter-directed local thrombolytic therapy must be considered early, especially if no clinical response is noted from standard measures. Many interventional radiologists would consider thrombolysis upon presentation  

Well’s Criteria for DVT (Acad Emerg Med 9(6):561, 2002)

  1. Active cancer (ongoing treatment for 6 months, or palliative) 1 pt 2. Paralysis, paresis, or recent plaster immobilization of the lower extremities 1 pt 3. Surgery 3 days 1 pt 4. Thigh plus calf swelling on the affected side 1 pt   5. Tenderness along deep venous system 1 pt   6. Affected calf >3 cm larger than other side (measured 10 cm below tibial tuberosity) 1 pt   7. Pitting edema (greater in affected leg) 1 pt   8. Collateral superficial veins (no-varicosities) 1 pt   9. Alternative diagnosis as likely or greater than venous thrombosis -2 pts   Probability of venous thrombosis:   Low probability = 0 or less points (2-15%) Intermediate probability = 1 or 2 points (40-50%) High probability = 3 or more points (80-85%)   Alteration of scoring changed 0 or 1 point to DVT unlikely and 2 or greater to DVT likely. D-Dimer negative rules out DVT in the unlikely group, allows only time zero ultrasound in the likely group. If positive in the likely group, get a 1 week ultrasound. (NEJM 349:13, Sept 25, 2003)

Upper Extremity DVT

Primary upper-extremity deep vein thrombosis (UEDVT), the so-called Paget-Schroetter syndrome or idiopathic UEDVT, is rarely seen (2 per 100,000 persons per year).2 Subclavian-axillary vein thrombosis was first described independently by Paget and Von Schroetter in the nineteenth century.3,4 Patients with Paget-Schroetter syndrome have developed spontaneous UEDVT after strenuous occupational and sporting activity, including linotype operating, painting, cheerleading, rowing, wrestling, weightlifting, baseball pitching, or curtain hanging.1,5 UEDVT can be caused by compression of the subclavian vein at the thoracic outlet.5 Primary UEDVT occurs most commonly in young, otherwise healthy men, although both sexes and all age groups may be affected. It appears more often in the right arm, probably because this is the usual dominant limb and hence is involved most frequently in strenuous activity.6 The heavy exertion causes microtrauma to the vessel intima and leads to activation of the coagulation cascade. Significant thrombosis may occur with repeated insults to the vein wall, especially if mechanical compression of the vessel is also present.7 Patients with systemic congenital and acquired hypercoagulable states, such as a protein S, protein C, and antithrombin III deficiency, pregnancy, lupus, malignancies, or nephrotic syndrome, are prone to UEDVT. UEDVT is also more common in patients with a history of lower-extremity vein thrombosis.8,9,10,11 Secondary UEDVT develops in patients with central venous catheters, pacemakers, or cancer, and accounts for most cases of UEDVT. The vessel wall may be damaged during catheter insertion or during infusion of medication. Although once considered rare, UEDVT has become more common over the past several decades. This is directly related to the increasing use of vascular access devices (VADs) for chemotherapy, bone marrow transplantation, dialysis, and parenteral nutrition.1 UEDVT has been reported in up to one fourth of patients with these catheters.12 During the early 1990s, it was estimated that more than a half million VADs were implanted every year.13 More liberal use of ultrasonography to make the diagnosis, and an increased awareness by clinicians of this condition, may be contributing to the apparent increasing incidence of UEDVT.  

Iliofemoral DVT

management strategies (Ann Emerg Med 2011;57:590)

DVT in Trauma

(Ann Surg 2004;240:490-98) 2 point DVT ultrasound plus negative d-dimer was as god as full ultrasound protocol in a RCT (JAMA 2008;300(14):1653)

Pulmonary Embolism (PE)

The Articles

British Thoracic Society’s (BTS) Recommendations: Thorax 2003; 58: 470-484 (ACEP) Clinical Policy: Annals EM 2003;41:257-270 Hemodynamic Review Very disappointing NEJM review (55 references) (NEJM Sept 25, 2003; 349:13; 1247-1256)

Epidemiology

  50% of patients with DVT have perfusion defects on V/Q (ACEP) False Negatives 7% 1 week mortality, 13% 1 month mortality, 18% 3 month mortality (BTS57) False Positives Risks from anticoagulation, contamination of future medical interactions, high risk pregnancies, life/health insurance 80% of autopsy PEs were never found clinically (Feied Emedicine)   at two years, 3.8% progress to chronic thromboembolic pulmonary hypertension (NEJM Volume 350:2257-2264 May 27, 2004 Number 22 )   Isolated subsegmental clots only present 6% of the time in the pioped study (Stein et al)   Mortaility and Recurrence rates of ambulatory patients for PE is

Pathophysiology

  Virchow’s Triad: Stasis/Trauma/Hypercoagulability Embolism-Greek for to throw inside Calf Thrombi Almost all (90%) DVTs start in calf   25% of Lethal PE and 33% of Massive PE arose from isolated calf DVT in a huge autopsy study (Acta Chir Scand Suppl 478:1, 1977) they propagate to deep veins 80% of time (Arch Intern Med 153:2777, 1993) so the myth about not having to worry about calf emboli is just that   Can also be from upper extremities, especially c central lines Also from hypokinetic segments after right ventricular MI or severe diastolic dysfunction Amniotic fluid, fat, air, & tumor Fat-often passes into systemic circulation as well. Use high dose steroids Air-place pt in LLR, reports of successful drainage by catheter in RV Many cases of supposed primary pulmonary HTN are actually from PE

History

  Severe new onset asthma sx in an older pts-think PE Chest pain-pleuritic, can also give chest wall tenderness Near 100% of PEs are missed when concurrent with pneumonia Symptoms   Dyspnea 84%, Pleuritic chest pain 74%, Apprehension 59%, Cough 53%, Hemoptysis 30%, Sweating 27%, Nonpleuritic chest pain 14%, Syncope 31% (PIOPED)

Risk Factors

  20 % have no risk factors  

• History of DVT/PE

• • The largest risk factor, VTE recurrence rates >30% (Arch Intern Med160:761, 2000)

• Underlying Disease
  

  • AIDS, believed to be associated with lupus anticoagulant

  • IBD (UC and Crohns)
  • Malignancy. Chemotherapy is also an independent risk factor.
  • Polycytemia leads to increased risk of both arterial and venous clots. Thrombocytosis does not lead to increase risk of VTE
  • Pregnancy and Peripartum Period. ½ of Pregnancy associated PEs were in the first 15 weeks (Rosen’s)
  • The puerperium, defined as the 6-week period after delivery, is associated with a higher rate of thrombosis than pregnancy itself (Am J of EM, 7/06, pg 460).
  • SLE
  • Stroke
  • Varicose Veins-if you add any secondary risk factor, twice as likely to have VTE then cohort without varicosities

• Hematologic Factors

• · Protein C or S deficiencies. Can be acquired or inborn. · Antithrombin III Deficiency. Acquired through liver disease or inborn. Heparin will not work with these patients · Factor V Leiden, a point mutation that leads to resistance to activated Protein C · Plasminogen Deficiency or Defect · Lupus anticoagulant (LA). · Anticardiolipin antibody · Non-Type O Blood, especially Type A

• Endothelial Injury

• · Surgery · Central Venous Catheters. Can have thrombus present after only 24 hours. Femoral vein is associated with a much higher risk of VTE, but subclavian and IJ lines are also culprits, especially with use for nutrition or chemotherapy

• Factors Associated with Immobilization

• · Hospitalization · Obesity · General Anesthesia

• Medications

• · Estrogen replacement and Oral Contraceptives · Phenothiazines have cause elevations of lupus anticoagulant.  

  Risk factors for venous thromboembolism (BTS) Major risk factors (relative risk 5-20): Surgery*

• Major abdominal/pelvic surgery
• Hip/knee replacement
• Postoperative intensive care

Obstetrics

• Late pregnancy
• Caesarian section
• Puerperium

Lower limb problems

• Fracture
• Varicose veins

Malignancy

• Abdominal/pelvic (Cancer of the gastrointestinal and hepatobiliary tracts (Reference: NEJM, October 10, 2002, pg. 1192)
• Advanced/metastatic

Reduced mobility

• Hospitalization
• Institutional care

Miscellaneous

• Previous proven VTE

Minor risk factors (relative risk 2-4): Cardiovascular

• Congenital heart disease
• Congestive cardiac failure
• Hypertension
• Superficial venous thrombosis
• Indwelling central vein catheter

Estrogens

• Oral contraceptive
• Hormone replacement therapy

Miscellaneous

• COPD
• Neurological disability
• Occult malignancy
• Thrombotic disorders
• Long distance sedentary travel
• Obesity
• Other**

*Where appropriate prophylaxis is used, relative risk is much lower. **Inflammatory bowel disease, nephrotic syndrome, chronic dialysis, myeloproliferative disorders, paroxysmal nocturnal haemoglobinuria, Behçet’s disease. The nephrotic syndrome is a prothrombotic condition that is a risk factor for acute PE (NEJM, Vol. Vol. 358, No. 25).

Largest trial of risk factors to date (Ann Emerg Med 2010;55:307) in addition to non-cancer related thrombophilia, pleuritic chest pain, and family history in addition to standard Wells risk factors  

Minor Injuries

especially of the leg, may be a risk factor (Minor Injuries as a Risk Factor for Venous Thrombosis. Arch Intern Med. 2008;168(1):21-26.)

Psych Meds

An Unappreciated Risk Factor For Pulmonary Embolism Emergency Physicians are well familiar with the classic risk factors for the development of venous thromboembolism (VTE) and consider the presence or absence of such factors when judging the likelihood of pulmonary embolism in a particular patient. Such factors include immobilization, surgery, pregnancy, use of combined oral contraceptives, and malignancies. Much less attention has been paid, however, to an association between antipsychotic agents and the development of VTE. Reports show an association between clozapine and VTE (2,3) and a possible association between VTE and both olanzapine (Zyprexa) and risperidone (Risperdal) has been suggested in recent publications (4-6). The mechanism responsible for this possible adverse drug reaction is unknown, but it has been hypothesized that since antispychotics like olanzapine, risperidone, and clozapine have an affinity for 5HT2 receptors, they induce a serotonin increase, which in turn might provoke enhanced platelet aggregation, thereby increasing the risk for thrombosis (8). Clinicians should consider antipsychotic drug exposure as a potential risk factor of VTE. References: (1) Borras L, et al. Pulmonary thromboembolism associated with olanzapine and risperidone J Emerg Med 2008 Feb 16; [Epub ahead of print]. (2) Selten JP, Büller H. Clozapine and venous thromboembolism: further evidence J Clin Psychiatry 2003;64:609. (3) Hägg S, et al. Association of venous thromboembolism and clozapine Lancet 2000;355:1155–1156. (4) Hägg S, et al. Olanzapine and venous thromboembolism Int Clin Psychopharmacol 2003;18:299–300. (5) Waage IM, Gedde-Dahl A. Pulmonary embolism possibly associated with olanzapine treatment BMJ 2003;327:1384. (6) Kamijo Y, et al. Acute massive pulmonary thromboembolism associated with risperidone and conventional phenothiazines. Circ J. 2003;67:46–48. (7) Lacut K, et al. Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case-control study Fundam Clin Pharmacol 2007;21: 643-50. (8) Koga M, Nakayama K. Body weight gain induced by a newer antipsychotic agent. Acta Psychiatr Scand 2005;112:75–76.  

Oral contraceptives

Air Travel

A common, independent risk factor for VTE is oral contraceptive use. The mechanism for VTE development with oral contraceptive use is unclear; however, proposed mechanisms include an increase in blood viscosity, increased adhesiveness of platelets, and increased levels of clotting factors and fibrinogen, as well as a decrease in antithrombin III activity.3 Martinelli and colleagues recently evaluated whether individuals taking oral contraceptives are more likely to develop VTE during flights than those not receiving oral contraceptives.4 The study included 210 patients with VTE and 210 healthy controls. Thirty-one VTE patients (15%) and 16 controls (8%) reported air travel with an odds ratio of 2.1 (95% CI, 1.1-4.0). Air travel, therefore, resulted in a 2-fold increase in risk of VTE compared to those with no air travel. When only long-distance flights were included in the analysis, the relative risk was 3-fold higher. However, in patients taking oral contraceptives and traveling by air, there was a 14-fold increased risk of VTE with an odds ratio of 13.9 (95% CI 1.7-117.5) compared to women who did not fly and take oral contraceptives. Martinelli I, Taioli E, Battaglioli T et al. Risk of venous thromboembolism after air travel. Interaction with thrombophilia and oral contraceptives. Arch Intern Med 2003;163:2771-74. More evidence that flight is a risk (Br J Haematol. 2011 Dec;155(5):613-9)  

Travel and Risk for Venous Thromboembolism

Annals of Intern Med 2009;151(3): 3 fold higher risk, goes up every 2 hours       Hypercoaguable states can be inherited or acquired Inherited: Factor V Leiden, Hyperhomocysteinemia, Protein C or Protein S deficiency, Antithrombin III deficiency Acquired: Lupus anticoagulant, anticardiolipin antibodies, hyperhomocysteinemia  

Wells’ Criteria for PE (Thromb Haemost 2000, 83:416-420)

Criteria Points1. Suspected DVT 3.02. An alternative diagnosis is less likely than PE 3.03. Heart rate >100 beats/min 1.54. Immobilization or surgery in previous 4 weeks 1.55. Previous DVT/PE 1.56. Hemoptysis 1.07. Malignancy (On treatment, treated in past 6 mo, or pallaitive) 1.0   Score Range Mean Prob. of PE Risk Prob of PE % Pts c Score %3.6 Low 3.6 402-6 20.5 Moderate 20.5 53>6 66.7 High 66.7 7   Fantastic article shows that all of the discriminatory value in the Wells score is derived from the subjective question itself (Acad Emerg Med Volume 12, Number 10 915-920)   4 or less points=unlikely, more than 4=likely (JAMA 2006;295(2):172)  

Who Does not Need a Work-Up

Dr. Kline discussed a scoring system referred to as the “PERC Rule” that is used to assess a patient’s risk for probability of PE in the emergency department.[14] It involves evaluating the presence or absence of 8 clinical criteria to arrive at a pretest probability. The criteria are age younger than 50 years, heart rate less than 100 beats per minute, room air oxygen saturations greater than 94%, no prior deep venous thrombosis [DVT] or PE, no recent surgery or hemoptysis, no exogenous estrogen, and no clinical signs suggestive of DVT. If the patient has none of the criteria specified, the pretest probability is less than 2%, and the patient will not benefit from an evaluation for PE. According to Kline, the PERC rule reliably forecasts a probability of PE below 2% in emergency department patients. This probability was derived from a large multicenter database, and has been validated at 4 different academic centers.[15,16]  

1. Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected PE. J Thromb Hemost. 2004;2:1247-1255.
2. Hogg K, Dawson D, Kline J. Application of pulmonary embolism rule-out criteria to the UK Manchester Investigation of Pulmonary Embolism Diagnosis (MIOPED) study cohort. J Thromb Haemost. 2005;3:592-593. Abstract
3. Tsai AW, Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002;162:1182-1189. Abstract
4. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ III. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143:697-706. Abstract

  Kline then described different clinical characteristics of patients who are at risk for PE. One myth that was de-bunked was the lack of association of smoking as a risk factor for PE in emergency department patients.[14,17] Next, the discussion turned to the increased incidence of PE during pregnancy. Specifically, the risk increases from 1/10,000 to 2/10,000 and is greatest in the postpartum period. PE represents the second most common cause of death in pregnancy. If you look at emergency department testing of pregnant patients, less than 5% who undergo work-up end up having a PE. What is clear is that the D-dimer is increased in most patients, less than 50% with PE have a DVT on ultrasound, the ventilation-perfusion (V/Q) scan is “normal” in two thirds of patients, and the risk of contrast material to the fetus is unknown.[17] In the postpartum period, due to a 5-fold increased risk of PE, approaches to evaluate for PE include a V/Q scan, or computed tomography (CT) angiography of the chest. Other options include venous Doppler ultrasound of the lower extremities and a V/Q scan (70% will be normal) or Doppler ultrasound of the lower extremities, or CT (with fetus shielded). A further option is to use the PERC rule and adjust the quantitative D-dimer upward in pregnancy: first trimester, According to Kline, emergency department physicians miss PE in 2 types of patients: young, obese women taking oral contraceptives who have normal vital signs, and older patients with a comorbidity that could explain “PE-like symptoms” (eg, chronic obstructive pulmonary disease, congestive heart failure). Another important point to mention is that age older than 50 years seems to be a risk factor for PE according to Kline’s database, with age older than 50 consistently being the break point for a significant odds ratio.[18]   Kline also discussed the high association of PE and patients having surgery in the previous 4 weeks requiring general endotracheal anesthesia. The 90-day incidence of PE is 1/200 overall. The majority of postoperative PEs occur after hospital discharge, a median of 18 days for orthopedic or abdominal surgery. The mortality rate of diagnosed postoperative PE is greater than 25%.[17]    

Decision Analysis of when to Test

They found 2% through Pauker and Kassirer through a different method (Ann Emerg Med 2010;55:316)        

Wicki Score (Arch Intern Med 2001:161:92-97)

Criteria PointsAge 60-79 1Age>79 2Prior DVT/PE 2Recent Surgery 3Heart Rate >100 bpm 1PaCO2 236-39 1PaO2 449-60 360-71 271-82 1Chest Radiograph Platelike Atelectasis 1Elevation of hemidiaphragm 1   Score Range Mean Prob of PE % Patients with Score % Interpretation of Risk0-4 10 49 low5-8 38 44 moderate9-12 81 6 high

Kline Criteria for Safe Use of D-Dimer (Ann Emerg Med 2002;39:144-152)

Geneva Score

(Ann Intern Med 2006;144:165) low 7.9 (5.0-12.1) Intermediate 28.5 (24.6-32.8) High 73.7 (61.0-83.4)

Simplified Geneva Score

(Arch Intern Med 2008;68:2131)

• Age >65
• DVT or PE in Past
• Surgery with General or Leg Fracture within 1 month
• Active Cancer
• Unilateral Lower Limb Pain
• Hemoptysis
• Heart Rate ≥ 75
• Pain on lower limb deep venous palpation AND unilateral edema

1 point for eachLow 0-1Intermediate 2-4High ≥ 5

Clinical Gestalt and the Diagnosis of Pulmonary Embolism*

Conclusions: Accurate determination of the pretest probability of PE appears to increase with clinical experience. However, the difference in accuracy between inexperienced and experienced physicians is not sufficiently large to distinguish between the two when determining whether clinical gestalt or a clinical prediction rule should be used to determine the pretest probability of PE. ((Chest. 2005;127:1627-1630.))  

Physical Signs

  The physical examination findings early in submassive PE can be completely normal. The diagnosis must be considered in any patient with shortness of breath or chest pain.   · Tachypnea >16/min 92%. It is the only reliably present sign, but >16 describes almost every patient in an ED.   · Rales 58%   · Accentuated S2 53%   · Tachycardia >100/min 44%   · Fever >37.8°C 43% (Fever up to 39 is relatively common in PE, 13% (Chest. 2000 Jan;117(1):39-42.) · Diaphoresis 36%   · S3 or S4 gallop 34%   · Thrombophlebitis 32%   · Lower extremity edema 24%   · Cardiac murmur 23%   · Cyanosis 19%     Homans’ sign actually is spontaneous maintenance of the relaxed foot in abnormal plantar flexion, but has no prognostic value for DVT or PE.   Leg asymmetry: >3 cm difference in circumference at 10 cm below tibial tuberosity.   New wheezing may be appreciated. If pleural lung surfaces are affected, a pulmonary rub may be heard.     The spontaneous onset of chest wall tenderness without a good history of trauma is always worrisome, because patients with PE may have chest wall tenderness as the only physical finding (Arch Intern Med 144:2057, 1984)     PIOPED data—97% of patients with PE presented with dyspnea, tachypnea, or pleuritic pain; consider PE in patients with any of these 3 symptoms   Platelets coating a fresh emboli can release potent vasoconstrictors causing pulmonary hemodynamic consequences not expected from the size of the emboli alone. (Parrillo)  

Auxiliary/Lab Studies

Labs

· CBC, maybe you can argue this one based on polycythemia as a risk factor. Elevated WBCs are often seen with PE, as high as 20,000. (Chest 115:1329, 1999) · PT/PTT. Not needed unless the patient is on anticoagulation or has a clotting disorder, Excepting those circumstances, the test will not help diagnosis and is unnecessary before anticoagulation despite what the admitting team will claim.

• Large PEs can give elevated troponins that are not indicative of infarction (Arch Intern Med 162:79)

ABG

Many consultants would have you believe the ABG is a good screening test for PE. Unless the patient population you are dealing with is 20 year old post-op patients, it does not help at all (Even then, it does not help very much). For any PaO2 picked, the incidence of PE will be higher above than below that level. The same for Aa gradient, for any gradient chosen, the incidence of PE will be higher below that level. This is Gaussian mathematics. This was even known by surgeons in 1979 (Am J Surg 137:543, 1979) (Side note: Normal Aa=10+Age/10)   Stein et al looked at the PIOPED data to determine the usefulness of the   arterial blood gas. They compared patients with and without PE diagnosed   angiographically who had an ABG taken on room air. The patients were further   subdivided into those who had cardiopulmonary disease and those without   cardiopulmonary disease. Their results show that in a patient with no   cardiopulmonary disease and a normal or high PaO2 , normal or high PaCO2 and a   normal P (A-a)O2 , 38% had angiographically proven PE. In patients with   cardiopulmonary disease with the same ABG results, 14% had a PE. ABG therefore   is insufficient to diagnose PE, because too many patients with PE have normal   ABG results. (Chest. 1996 Jan;109(1):78-81)  

EKG

In patients with APE, negative T waves were commonly present in leads II, III, aVF, V1, and V2, but were less frequent in leads I, aVL, and V3 to V6 (p <0.05).Negative T waves in leads III and V1 were observed in only 1% of patients with ACScompared with 88% of patients with APE (p <0.001). The sensitivity, specificity, positivepredictive value, and negative predictive value of this finding for the diagnosis of APE were88%, 99%, 97%, and 95%, respectively. In conclusion, the presence of negative T waves inboth leads III and V1 allows APE to be differentiated simply but accurately from ACS in patients with negative T waves in the precordial leads. © 2007 Elsevier Inc. All rightsreserved. (Am J Cardiol 2007;99:817– 821)   Classic Signs are S1Q3T3 or tall p in II (p pulmonale), both are neither sensitive or specific for PE. (Stein PD, Dalen JE, McIntyre KM, et al. The electrocardiogram in acute pulmonary embolism. Prog Cardiovasc Dis 1975 Jan-Feb;17(4):247-257)   Sreeram looked at ekgs of confirmed PEs, reviewers said EKG probable for PE if 3 of following: RBBB especially with ST elevation or T inversion in V1, prominent S waves in I or AVL, shift of transition zone to V5, Q waves in III or aVF, RAD or indeterminate axis, low QRS voltage in the limb leads, T wave in inversions in III, aVF or V1-4. Only one false positive when ekg of patients without PE evaluated, but rate much higher if patients had lung disease. (Am J Cardio 1999, 4:73)   In another study, the most sensitive signs were tachycardia and incomplete RBBB (late R wave in aVR. S1Q3T3 was equally present in those with and without PE (AM J Cardiology 86:2000)   If you see new anterioseptal and inferior lead t-wave inversions, think very strongly about PE (Marriott)     SIQIII or SIQIIIT       T-wave inversions, especially in right precordial leads (V1-V3   Simultaneous t-wave inversions in the inferior and anterio-septal leads are even more specific           Don’t just think rule out MI when the ECG appears to show cardiac ischemia (from Mattu’s ACEP Lecture)   Kosuge et al. (Am J Cardiol 2007;99:817-821) compared patients with ACS and PE who had precordial T wave inversions in V1-V4. They found that in this select population, negative T waves in lead III were observed in only 15% of patient with ACS, compared with 88% of patients with Acute PE. . It is tempting to diagnose Wellens’ syndrome with anterior T wave inversions, but Wellens’ T waves simply look different, should have a longer QTc, generally don’t extend out to V6, and, most importantly, don’t have T inversion in lead III. (from steve smith ekg blog) 12-lead ekg findings are infrequent, but more frequent in PE than none PE patients in 1 cohort (Ann Emerg Med 2010;55(4):331), but no finding had an LR+ that is in any way useful  

Chest X-Ray

  Hampton’s hump (Wedge shaped infiltrate from infarction), Westermark’s sign (dilation of pulmonary vessels c possible cut-off sign) are exceedingly rare, especially if the patient presents soon after the onset of symptoms   Cardiac enlargement (27%), normal (24%), pleural effusion (23%), elevated hemidiaphragm (20%), pulmonary artery enlargement (19%), atelectasis (18%), and parenchymal pulmonary infiltrates (17%) (Chest 118:33, 2000)   Infiltrates and effusions are not at all rare and can mimic pneumonia or pulmonary embolism.   After 24-72 hours, loss of pulmonary surfactant often causes atelectasis and alveolar infiltrates that are indistinguishable from pneumonia on clinical examination and by x-ray.  

Diagnostic Strategy

  Before any further testing is done, the patient must be assigned a pretest probability as this will influence the interpretation.   Keep in mind that a false positive diagnosis is almost as bad as a false negative.

• Risk of coumadinization
• Now any time the patient comes into the ED with any complaint, it’s a PE
• Health Insurance

Jeff Kline’s Rapid Rule out strategy (Annals of Emergency Medicine 44(5) 2004, Pages 490-502) Figure 1. Reproductions of the management algorithms that were posted in the ED during the intervention phase. A, Primary method; B, Alternate method, for patients with contraindication to CT scanning (contrast allergy). CTA/CTV, CT angiography/CT venography; V/Q, ventilation-perfusion lung scan. Scintillation V/Q scanning could be used in the event of a contraindication to contrast. †To perform V/Q lung scanning and to arrange serial lower-extremity venous Doppler-ultrasonographic examinations of V/Q scanning was nondiagnostic. ‡Optional. §Including lower-extremity venous ultrasonography and selected use of pulmonary angiography for patients who have otherwise unexplained signs and symptoms consistent with pulmonary embolism.

Bayesian Network

Derived and validated (Ann Emerg Med 2005;45(3):282)  

D-dimers

algorithm from Life in the Fast Lane   Five types are currently available

• ELISA
  • Sensitivity of 97% and Specificity of 44%
  • 2 to 4 hours to perform
• Latex Agglutination
  • Sensitivity of 70% and Specificity of 76%
• Whole blood assay (Simplired)
  • Sensitivity of 89% and Specificity of 59%
  • 5 minutes to perform
• Turbidimetric assay
  • Sensitivity >95%
  • 2 hours for results
• Immunofiltration assay
  • Sensitivity of 95% and Specificity of 33%

For review of the five newest (J Thromb Haemo 2003, 1:976) Elmhurst: HemosIL D-Dimer. Cut off is 230 ng mL. validated in non-high pretest prob. Sens 100% Spec 46.8% (J Thromb Haemost 2005;3:2361)   Sinai:     Sensitivity is influenced by location of clot, small clots in sub-segmental branches lowers sensitivity. (J Resp Crit Care Med 165(3):345)     Sensitivity of ELISA 95% and specificity 45% (Annals 2002, 40:2)     False Positive D-Dimer: DIC, vaso-occlusive sickle cell crisis, acute cerebrovascular accident, acute coronary syndromes, atrial fibrillation, vasculitis, pneumonia and many cancers, including lung, prostate, cervical, and colorectal     Simplify D-Dimer by Kline (Chest 2006;129(6):1417) Low pretest and negative = 0.7% posttest Sens 80 Spec 72.5     One interesting study looked at the alveolar dead space fraction (Vd/Vt) in combination with latex agglutination D-dimers. Because an embolus decreases alveolar CO2 content, it can be assumed that the dead space fraction would increase. All patients in this study were ambulatory, with clinically suspected PE, and underwent V/Q scans for diagnosis. Blood samples less than 4 hours old were used with a latex agglutination antibody test. A capnometer was used to determine maximal expiration partial pressure of CO2 , and an ABG was drawn within 5 minutes. For every patient with a confirmed PE, either D-dimer or Vd/Vt were abnormal. For every patient with both test results normal, PE was excluded. In their conclusions, both tests together had a sensitivity of 100% and a specificity of   65%. (Annals Emerg Med Feb 2000;35) (Kline, JAMA 285:6) Kline and Wells studied feasibility of d-dimer + alveolar dead space measurements. The therapist measures the average of 3 deep exhaled CO2 measurements immediately preceding arterial puncture of the radial artery, followed by 3 more deep exhaled CO2 measurements, each separated by 30 seconds. The average of all 6 deep exhaled CO2 measurements is used to calculate the dead space from a modification of the Enghoff equation: Percentage alveolar dead space=100×(PaCO2-PetCO2)/Paco2. Kline et al considered a normal dead space to be less than 20%, whereas Rodger et al30 used 15% as the upper limit of normal (Annals EM 42:2, 2003)  

Higher D Dimer cut-off in older patients

May 3, 2010 by Cliff from ResusMe Filed under Acute Med, All Updates D-dimer levels below the conventional cut-off point of 500 µg/l combined with a “low/intermediate” or “unlikely” clinical probability can safely rule out the diagnosis in about 30% of patients with suspected pulmonary embolism. However, the D-dimer concentration increases with age and its specificity for embolism decreases, which makes the test less useful to exclude pulmonary embolism in older patients; the test is able to rule out pulmonary embolism in 60% of patients aged <40 years, but in only 5% of patients aged >80. A new, age dependent cut-off value was derived and then validated in two independent retrospective datasets from Belgium, France, the Netherlands, and Switzerland. They studied over 5000 patients aged >50 years. The new D-dimer cut-off value was defined as (patient’s age x 10) µg/l in patients aged >50. In 1331 patients in the derivation set with an “unlikely” score from clinical probability assessment, pulmonary embolism could be excluded in 42% with the new cut-off value versus 36% with the old cut-off value (<500 µg/l). In the two validation sets, the increase in the proportion of patients with a D-dimer below the new cut-off value compared with the old value was 5% and 6%. This absolute increase was largest among patients aged >70 years, ranging from 13% to 16% in the three datasets. The failure rates (all ages) were 0.2% (95% CI 0% to 1.0%) in the derivation set and 0.6% (0.3% to 1.3%) and 0.3% (0.1% to 1.1%) in the two validation sets. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ. 2010 Mar

Kline’s article on doubling hospital threshold in low risk PE patients

(J Throm Haem 2012;10:572)

ACEP D-Dimer recommendations:

(B) If low pretest possibility, negative quantitative D-dimer assay (turbidimetric or ELISA) excludes (B) Negative whole blood d-dimer with Well’s score (C) If low pretest probability of PE, a negative whole blood or immunofiltration d-dimer can exclude.

BTS’ recommendations for the use of d-dimer:

(B) A negative d-dimer test reliably excludes PE in patients with low (SimpliRed, VIDAS, MDA) or intermediate (Vidas, MDA) clinical probability; such patients do not require imaging for venous thromboembolic disease.   d-dimer not accurate if patient already taking anti-coagulation Anticoagulation & False Positive D-dimers A recent study found that many patients with apparently false-negative D-dimer values (ordered as part of an evaluation for venous thromboembolism) were concurrently taking anticoagulants at the time of diagnosis (1). Kline et al. suggested that concurrent warfarin therapy in a patient presenting with signs and symptoms of VTE might result in false-negative D-dimer values (2). A 2003 study showed that patients on low-molecular-weight heparin might have a false-negative D-dimer, and several other studies outside the EM literature highlight a similar phenomenon with warfarin (4-6). It is important to note that patients taking anticoagulants were excluded from the original influential studies of Wells et al. that described a model for safe management of patients with suspected pulmonary embolism (7). Certainly these findings mandate that the effect of anticoagulation on the D-dimer warrants further investigation. In the meantime, Emergency Physicians using D-dimer levels to determine the need for further radiologic investigation of possible VTE need to be aware of the possible effect. References: (1) Nordenholz KE, et al. Radiologic diagnoses of patients who received imaging for venous thromboembolism despite negative D-dimer tests Am J Emerg Med 2007;25: 1040-6. (2) Kline JA, et al. Diagnostic accuracy of a bedside D-dimer assay and alveolar dead-space measurement for rapid exclusion of pulmonary embolism: a multicenter study JAMA 2001;285:761-768. (3) Kraaijenhagen RA, et al. Can causes of false-normal D-dimer test [SimpliRED] results be identified? Thromb Res 2003;111:155-158. (4) Ahmed S, et al. Effect of low-dose warfarin on D-dimer levels during sickle cell vaso-occlusive crisis: a brief report Eur J Haematol 2004;72:213-216. (5) Kim SB, et al. Effects of fixed low-dose warfarin on hemostatic factors in continuous ambulatory peritoneal dialysis patients Am J Kidney Dis 2001;37:343-347. (6) Jafri SM, et al. Effects of warfarin on markers of hypercoagulability in patients with heart failure Am Heart J 1997;134:27-36. (7) Wells PS, et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism Ann Intern Med 1998;129:997-1005. (from emedhome)  

V/Q

    V/Q classification of patients who had angiography   Likelihood of positive angiogram   Percent of all PEs with this pattern   High probability   102/116(88%)   41   Nondiagnostic   144/560(26%)   57   (formerly intermediate)   105/322(30%)   41   (formerly low)   39/238(16%)   16   Normal perfusion   5/55(9%)   2   (PIOPED JAMA 1990;263(20):2753-59)   Intermediate had only a 75% interobserver reliability and Low only 70% (Radiology 1996 Apr 199(1):25-27) Normal Result was obtained by 129 patients in PIOPED, 55 went on to have angiogram, 5 of these 55 had a PE (9%). 79 more were followed clinically with no evidence of recurrence. Between 45-66% of high-prob v/q scans are false positive when the patient is low pretest probability (Thromb Research 2001;103:V225)   New study using V/Q to dispense with CTA (Chest 2011;139(6):1294)  

ACEP Recommendations

(A) Normal scan can effectively rule out PE in low and moderate pretest prob. patients, but not in the high group. A (B) In patients with low or moderate pretest probability and a non-diagnostic V/Q, use 1 of the following tests to exclude clinically significant PE

• Negative turbidimetric or elisa d-dimer
• Negative whole blood d-dimer with a Well’s score
• A single negative bilat leg doppler in low prob patients
• A negative serial bilat leg doppler in mod prob patients

(C) In patients with low or moderate pretest probability and non-diagnostic V/Q, a whole blood or immunofiltration D-dimer without Well’s criteria may be used to exclude PE.

Multidetector CT Angiogram

Should be 1st test if patient has cardiopulmonary disease. If patient has moderate or high pretest prob, negative result demands further testing. Metaanalysis yields 86% Sensitivity and 93% Specificity (Kline, Annals Emerg Med 2000, 35:168)   Multidetector Row Spiral CT: increases sensitivity and specificity Combined CTA/CTV: adds scan of pelvic thigh veins for DVT (J Thromb Haemostasis 1:1, 2003 Richman)   One study supports withholding anticoag in neg CT (Mayo Clin Proc 77:130 2002)   In 510 patients, single detector CT missed only 1 non-fatal PE (Annals Int Med 138:4, 2003)   CLINICAL OUTCOMES IN PATIENTS WITH SUSPECTED ACUTE PULMONARY EMBOLISM AND NEGATIVE HELICAL COMPUTED TOMOGRAPHIC RESULTS IN WHOM ANTICOAGULATION WAS WITHHELD. Donato AA, Scheirer JJ, Atwell MS, et al. Arch Intern Med 2003;163:2033-2038.   CT plus UTS missed only one PE (Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study. Lancet 2002;360:1914-20) (Also Eur Radiol 2002;12:1971-8)   Golden looked at SCTA and negative ultrasound, 3 moth f/u was .5% for serial UTS neg, 1.7% for one UTS neg.   (Radiology 2000,215:p.535-542) (Eur Radiology 2001,11:65-72) (Acta Radiology 200243:486-91) CLINICAL OUTCOMES IN PATIENTS WITH SUSPECTED ACUTE PULMONARY EMBOLISM AND NEGATIVE HELICAL COMPUTED TOMOGRAPHIC RESULTS IN WHOM ANTICOAGULATION WAS WITHHELD Click here to hear the Reviewer’s comments via MP3. Donato, A.A., et al, Arch Intern Med 163:2033, September 22, 2003 Another article on CTA c Delayed Venous (Am J Emerg Med 2004;22:301-306.)   Systematic Review shows CT is as accurate as pulmonary angiogram (JAMA, April 27, 2005—Vol 293, No. 16)  

PIOPED II

NEJM 2006;354(22):2317 Sens 83 Spec 96 CTA-V SENS 90 SPEC 95 if high prob pretest, need add. studies   Problem with this study is part of the gold standard was high prob V/Q, which we know from PIOPED I had over 50% FP rate in low prob pts. A large number fo the patients in PIOPED II were ruled in by high V/Q        

BTS Recommendations:

(B) CTPA is now the recommended initial lung imaging modality for non-massive PE (A) Patients with good quality negative CTPA do not require further investigation or treatment for PE. (B) CTPA or echocardiography will reliably diagnose clinically massive PE     Another article showing Spiral CT is good (JEM 2005;29(4):399)    

Dopplers

  Good yield if physical exam reveals a leg abnormality, otherwise only 10% will test positive 93% sensitive, 98% specific. Calf veins are not examined, but 5% of calf DVTs embolize   Prevalence of DVT in proven PE ranges from 36-45% (Br J Radiol 1998;71:1260)

Echocardiogram

TTE good in PEA codes to determine need for lytics to treat massive PE. Look for dilated Right Ventricle and Paradoxical Septal movement. (Emerg Med J 19:178 2002)  

Angiogram

  6% of PEs are subsegmental leading many to argue the necessity of angiogram if negative sCTA. However a reanalysis of the PIOPED data found that when subsegmental clots were the only angiographic abnormality, angiographers disagreed about the diagnosis in 1 out of 3 patients (66%). (JAMA 1990;263 2753)   In PIOPED, 4 of 675 negative angio patients died of an autopsy proven PE within 6 days (Circ 1992, Feb 85(2):462-468)   Imaging for PE in Pregnancy  

Charlotte Criteria

Prospective validation of Charlotte Decision Rule (ACAD Emerg Med 2005;12(1):20)  

Hemodynamic Consequences

The hemodynamic response to PE depends on the size of the embolus, coexistent cardiopulmonary disease, and neurohumoral effects ( 4 ). Acute PE increases pulmonary vascular resistance in a variety of mechanisms. These include hypoxic pulmonary vasoconstriction, physical obstruction of blood flow, and release of humoral factors, such as serotonin, thrombin, and histamine ( 6, 7). The healthy adult pulmonary circulation is a low-resistance and low-pressure circuit. Thus, an abrupt elevation in arterial pulmonary pressure resulting in an increased right ventricular afterload may lead to hypotension and hemodynamic perturbation that may further progress to clinically overt shock. Such an increase in right ventricular afterload can cause right ventricular dilation, hypokinesis, tricuspid regurgitation with annular dilation of the tricuspid valve, and ultimately right ventricular failure ( 7, 8). Right ventricular enlargement may also result in a leftward shift of the interventricular septum, resulting in underfilling of the left ventricle. Consequently, both systemic cardiac output and pressure decrease, potentially compromising coronary perfusion and producing myocardial ischemia, all contributing to left ventricular dysfunction further compromising systemic hemodynamics ( 7, 8). Increased right ventricular pressure may also compress the right coronary artery, diminish subendocardial perfusion, and limit myocardial oxygen supply ( 7, 8).    

Treatment

A paper reviewing the complete lack of evidence that heparin treats PE as opposed to preventing new DVT (Journal of the royal society of medicine 1981;74:675) In the absence of contraindications, anticoagulation should be started at the first suspicion of thromboembolic disease, without waiting for the results of diagnostic tests only in high-pretest probability patients Kline’s group reviewed the cut-off points for when the benefits outweigh the risks. Probably only in high-pretest (Paper)   fThe initial bolus of IV heparin should be 100-150 U/kg (80 U/kg is literature recs) The initial infusion of IV heparin should be 18 U/kg/hr. The aPTT should be checked every 6 hours until stable, and heparin dosing should be adjusted as follows: Survivors of PE at very high risk for pulmonary HTN Really the only article as heparin as a treatment for PE comes from (Anticoagulant Drugs in the treatment of PE Lancet 1960;June 18th:1309) Treatment group, no deaths or recurrences 5/35 deaths 5/35 patients with recurrence in untreated Until this one was just published… Early heparin (in the ED) seems to have mortality benefit in one study (Early Anticoagulation is Associated with Reduced Mortality for Acute Pulmonary Embolism –Chest)  

• Heparin: 80 then 18
• LMWH is 1st choice in non-massive
• Can give Heparin SC for treatment: Give IV bolus of 5000 U (or 80 U/kg) then 17,500 Units SC BID with PTT Q 6hrs
• Patients may ambulate as tolerated
• Thrombolysis with: tPA 100 mg over 2 hours or Reteplase 10 U Q 30 min x 2. (TNKase is probably best, but no literature)

Guidelines: (Chest 2004;126(3):Supplement)       Coagulopathy workup (protein C & S def, Factor V Leiden def/mutation, anti thrombin III and anticardiolipin antibody, ESR, Lupus anticoagulant).   Can see wbc demargin, elevated LFTs VQ-87% of positives will have pe, 41% of PEs will be high probability Intermediate-if assume pos wrong 70% of time, if assume neg wrong 41% Angiogram-will not see third order vessels. Must get views of entire tree. Only true negative 81-90% of the time. Heparin-100 u/kg then 18 u/kg/hr (15 mg protamine over 3 minutes) LMWH-1 mg/kg Q 12 or 1.5 mg/kg Q24 (both are off label dosing) (1 mg protamine reverses 1 mg) Coumadin-blocks protein C and S first, so must heparinize before. INR 2.5-3.5     Low Molecular Weight Heparins are Equal to UFH for the treatment of symptomatic and asymptomatic PE Fixed-dose low-molecular-weight heparin treatment appears to be as effective and safe as dose-adjusted intravenous unfractionated heparin for the initial treatment of nonmassive pulmonary embolism. Ann Intern Med. 2004;140:175-183  

Home Treatment

Kovacs MJ, Anderson D, Morrow B, et al. Outpatient treatment of pulmonary embolism with dalteparin. Thromb Haemost 2000;83:209-11.   LMWH, 10 mg Warfarin for two days, and then nomogram (Ann Intern Med 138:714, May 2003)   UFH can be given SQ at dose of 333 U/kg initial dose and then 250 U/kg BID both in and outpatient (JAMA 2006;296(8):935)   METHODS: In this double-blind study, 201 patients aged 18-98 with venous thromboembolism (VTE) managed at four Canadian centers who were not believed to be at high risk for major bleeding and were felt to be appropriate for outpatient management were randomized to nomogram-based treatment using either 5mg or 10mg initial warfarin doses for each of the first two days in addition to low-molecular-weight heparin (LMWH), which was given for a minimum of five days until the INR was therapeutic (above 1.9). Warfarin was given in the evening and INRs were measured daily prior to 10AM after the second day until a therapeutic range was achieved Warfarin doses after the second day were INR-based using the two nomograms RESULTS: A therapeutic INR was achieved in a mean of 4.2 days in patients receiving the 10mg initial warfarin dose vs. 5.6 days in those receiving the 5mg dose. Patients in the former group were more likely to achieve a therapeutic INR by day five (83% vs. 46%, p CONCLUSIONS: In patients with VTE, nomogram-based outpatient treatment with warfarin initiated at 10mg daily doses for the first two days produced therapeutic INRs more rapidly than use of 5mg initial doses.   Review of all 6 articles on use of UFH subcut to treat PE (Emergency Medicine Journal 2008;25:287-289) Expect the future use of ximelagatran, a warfarin-like drug, which does not require monitoring. (Lancet 2003 Nov 22; 361:1691) However ALT needs to be monitored for possible side effects.

Thrombolysis

Best Review (Chest 2009;135:1321) Absolute contraindications*

• History of intracranial hemorrhage
• Known intracranial neoplasm, arteriovenous malformation, or aneurysm
• Significant head trauma
• Active internal bleeding
• Known bleeding diathesis
• Intracranial or intraspinal surgery within 3 mo
• Cerebrovascular accident within 2 mo

Relative contraindications

• Recent internal bleeding
• Recent surgery or organ biopsy
• Recent trauma, including cardiopulmonary resuscitation
• Venipuncture at noncompressible site
• Uncontrolled hypertension
• High risk of left heart thrombosis
• Diabetic retinopathy
• Pregnancy
• Age > 75 yr

A proposed algorithm for the consideration of thrombolytic therapy in acute PE. * = massive PE with shock is the clearest indication for thrombolysis. To some clinicians, “hemodynamically unstable” refers to the presence of hypotension. To many clinicians, hypotension in the setting of acute PE is an indication for thrombolytic therapy. With hypotension, fluids should be administered in this setting and vasopressor therapy initiated when indicated. † = there is not a universal definition for “RV dysfunction,” but in clinical trials in general, any degree of RV dysfunction has sufficed for inclusion. Severe RV enlargement and dysfunction may portend a worse prognosis than mild dysfunction, but few data are available. Although the presence of positive biomarkers should be considered together with other criteria, these tests have not allowed for stratification of groups who will benefit from thrombolysis. ‡ = when hypoxemia is severe, requiring very high-flow oxygen, thrombolytic therapy can be considered, although no studies have proved beneficial in this setting. Very extensive clot burden by CTA or ventilation/perfusion scan, without hypotension or RV dysfunction may also suggest the need for thrombolytic therapy, but no proven mortality benefit has been demonstrated. Finally, extensive residual venous thrombosis in the setting of acute PE may also suggest the potential for increased mortality, but this has not been proven either. In such settings, patients should be carefully individualized. DVT = deep venous thrombosis.       1. hemodynamically unstable 2. decreased cardiopulmonary reserve 3. those expected to have recurrence (Aminocaproic acid can reverse bleeds) Comprehensive review (Am J EM 2009;27:84)   rTPA: 100 mg over 2 hours, no loading dose. Alteplase: 10 mg bolus followed by 90 mg over 2 hrs along with heparin infusion at 1000 units/hour. 100 mg over 120 minutes is the FDA dosing, but should be given by initial bolus, 50 mg bolus in truly sick patients. reteplase: 10-IU bolus x 2, 30 minutes apart Case report for TNKase (J Thromb Thrombolysis (2007) 23:101–105) In patients with massive PE (PE with shock), dose of .6 mg/kg of Alteplase over 15 minutes was used with good result. (Am J EM 21:5, Sept 2003)   One study shows no benefit in hemodynamically stable patients with submassive PEs (Chest 2001 120). But then a second study it was found that giving heparin plus alteplase reduced the incidence of needing to give alteplase, huh? (NEJM 347:15, 2002)   (B) Lyse hemodynamically unstable patients (C) Lyse stable patients with RV dysfunction on echo or Unstable patients with high index of suspicion for PE   SR of who to lyse (Emerg Med J 2005;22:766)   Review of Thrombolysis in Pregnancy (J Thromb Thrombolysis 2006;21(3):271) no large trials. may cause fetal demise. TNKase for right ventricular strain (Thrombosis Research 125 (2010) e82–e86) Article from the medical literature shows we probably underutilize TPA in unstable patients and there is a mortality benefit to using it (Am J Med. 2012 May;125(5):465-70)

Viagra

50 mg po was administered in a patient with hemodynamic consequences of massive PE (Inten Care Med 2006;32:452) inhibits GMP phosphodiesterase-5 causing nitric oxide mediated pulmonary vasodilation also inhibits hypoxic induced vasoconstriction took ~120 minutes to work then given tid   Inhaled NO may also have dramatic effects  

Outcomes

Mild PE has very little difference in treated and untreated groups with regards to death and recurrent PE, both fatal and non-fatal. (Chest 107:4, 1995, p. 931)   PEs with elevated troponins had in-hospital events (Circulation 2002;106:1263)

Cardiopulmonary bypass

If Arrest-B thoracotomy c massage of pulmonary vessels to milk saddle embolism PE in Pregnancy-post-partum endometriosis also a risk. V/Q is very low risk.

VTE Prophylaxis in the ICU

low dose heparin, LMH, and/or leg compression devices.

Venous Air Embolism

Place patient in LLR and give 100% oxygen

Fat Embolism

fever, pulmonary and cerebral dysfunction, hypoxemia after a long bone fracture Ptechiae (especially in buccal mucosa and axillary folds), retinal fat, fat in clotted blood, and diffuse pulmonary infiltrates are also signs. Incidence of ~10% after long bone or pelvic fractures. Can lead to DIC

Amniotic Fluid Embolism

Septic Pulmonary Embolism

from right sided endocarditis or peripheral vein thrombophlebitis Often associated with pulmonary infarction Staph, gram negatives, and anaerobes are all common

Tumor Embolism

heparin is not indicated may show no symptoms  

PE in Trauma / PostOp

over 1/3 of PEs happened between day 1-4 (J Trauma 2007;63:620)  

Hypercoagulable State

Hypercoagulability: too many tests, too much conflicting data.Hematology (Am Soc Hematol Educ Program). 2002;:353-68. Review. Arch Pathol Lab Med 2002;126:1281 Arch Pathol Lab Med—Vol 126, November 2002   Study with 10 yr follow-up showed lack of association between risk factors and recurrent thromboembolism (JAMA, May 18, 2005—Vol 293, No. 19 2353)         CLINICAL OUTCOMES IN PATIENTS WITH SUSPECTED ACUTE PULMONARY EMBOLISM AND NEGATIVE HELICAL COMPUTED TOMOGRAPHIC RESULTS IN WHOM ANTICOAGULATION WAS WITHHELD. Donato AA, Scheirer JJ, Atwell MS, et al. Arch Intern Med 2003;163:2033-2038. unstable angina or stable angina and coronary artery disease confirmed by angiography was followed to assess the risk of cardiovascular events associated with baseline erythrocyte glutathione peroxidase 1 activity and SOD. Blood was drawn under standardized conditions before coronary angiography   can use epoprostenol also nitric oxide Systematic Review of diagnosis of PE (BMJ 2005;331;259-) Prognosis Division of General Internal Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. aujesky@swissonline.ch

Vena Caval Filters

What Are the Incidences of PE and DVT Recurrences after Placement of Vena Cava Filters?

Not uncommonly, Emergency Physicians evaluate patients who present with a DVT while adequately anticoagulated. A management plan must then be formulated, and the question arises as to the efficacy of an IVC filter in such a setting. Vena caval interruption has been used in treatment of DVT to prevent PE since the early 1970s. A recent systematic review identified a single randomized trial (3) and 1 population-based study (4) that addressed this question; additionally, 107 case series have been reviewed in detail (1,5). The review concluded that available evidence suggests that vena caval filters may be only modestly efficacious in reducing recurrence of PE and do not affect mortality (this was felt to be level 2 evidence*) (1). A recently released clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians also addressed this question (2) and noted that the single available randomized trial (3) revealed that after 2 years of follow-up, filter placement with anticoagulation was associated with a slight reduction in symptomatic PE as compared with anticoagulation alone but filters were associated with a significant increase in recurrent DVT. It is the conclusion of the authors of this clinical guideline that overall, there is insufficient evidence to make recommendations regarding the use of IVC filters in this setting. Of note, retrievable vena caval filters have been recently approved for use in the US. These filters may be an attractive alternative to permanent vena caval filters for patients with a temporary contraindication to anticoagulation. Further information is necessary before their efficacy relative to permanent filters can be established. *Level 2 Evidence = limited-quality, patient-oriented evidence References: (1) Segal JB, et al. Management of venous thromboembolism: a systematic review for a practice guideline Ann Intern Med 2007;146(3):211-22. (2) Snow V, et al. The Joint American College Of Physicians/american Academy Of Family Physicians Panel On Deep Venous Thrombosis/pulmonary Embolism. Management of venous thromboembolism: a clinical practice guideline from the american college of physicians and the american academy of family physicians Ann Intern Med 2007;146: 204-10. (3) Decousus H, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group N Engl J Med 1998;338:409-15. (4) White RH, et al. A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism Arch Intern Med 2000;160:2033-41. (5) Hann CL, Streiff MB. The role of vena caval filters in the management of venous thromboembolism Blood Rev 2005;19:179-202.

Catheter Embolectomy

catheter thrombectomy for PE (Chest 2007;132:657) use for pts in which thrombolysis is not possible and they are hemodynamically unstable or subtotal or total filling defects in a main  

BEST REVIEW

(Chest 2002;121(3):877) Pathophysiology TOP Abstract Introduction Circulatory Model Pathophysiology Incidence and Presentation Basic Diagnostic Findings Diagnostic-Therapeutic Approach Special Considerations Conclusion References Mechanism of Cardiac Failure Cardiac failure from MPE results from a combination of the increased wall stress and cardiac ischemia that comprise RV function and impair left ventricular (LV) output. Research from animal models and evidence from clinical investigations clearly demonstrate that the impact of embolic material on the pulmonary vascular outflow tract precipitates an increase in RV impedance. This initiates the vicious pathophysiologic cycle depicted in Figure 4 . The degree of increase in RV impedance is predominantly related to the interaction of the mechanical obstruction with the underlying cardiopulmonary status.51 52 53 Additional factors reported to contribute to increased RV impedance include pulmonary vasoconstriction induced by neural reflexes,54 the release of humoral factors55 from platelets (ie, serotonin and platelet activating factor), plasma (ie, thrombin and vasoactive peptides C3a, C5a), tissue (ie, histamine), and systemic arterial hypoxia.56 The acute development of this increased RV impedance constitutes a pressure afterload on the RV and has multiple effects on RV and LV function. View larger version (26K): [in this window] [in a new window] Figure 4. Pathophysiologic cycle of MPE. Given the reciprocal relationship between RV stroke volume and vascular load, RV stroke volume will diminish with increasing load.57 Initially, the compensatory maintenance of CO is achieved by a combination of catecholamine-driven tachycardia and the utilization of the Frank-Starling preload reserve (the latter being responsible for RV dilatation). This increase in RV cavitary pressure and radius serves to significantly increase RV wall stress (wall stress = pressure x radius). This is the primary determinant of RV oxygen uptake, thus creating the potential for RV ischemia. With increasing RV load and wall stress, RV systolic function becomes depressed and CO begins to decrease. Interestingly, systemic BP may be adequately maintained by systemic vasoconstriction at this point.58 From the point of initial CO depression, it has been reported59 that increases in load sufficient to further decrease CO by 20% will result in a disproportionate increase in end-systolic volume compared to end-diastolic volume. Afterload mismatch has been used to describe the phenomenon of RV pressure work exceeding RV volume work in this setting.60 As a consequence of this mismatch, LV preload will decrease, given the ventricular alignment in series. LV preload is additionally impaired by decreased LV distensibility as a consequence of a leftward shift of the interventricular septum and of pericardial restraint, both of which are related to the degree of RV dilatation.61 62 63 It also has been suggested that MPE may impair LV function independently of preload mechanisms.64 In the presence of declining LV forward flow, MAP can be maintained only by catecholamine-induced vasoconstriction. A further decrease in LV flow results in systemic hypotension. RV coronary perfusion pressure (CPP) depends on the gradient between the MAP and the RV subendocardial pressure. Decreases in MAP associated with increases in RV end-diastolic pressure (RVEDP) impair the subendocardial perfusion and oxygen supply. Elevated right-sided pressures can further impair coronary perfusion and LV distensibility by increasing coronary venous pressure.65 Increased oxygen demands associated with elevated wall stress coupled with decreased oxygen supply have been shown to precipitate RV ischemia, which is thought to be the cause of RV failure.66 Clinical evidence of RV infarction as a consequence of the preceding condition has been demonstrated in patients with and without obstructive coronary disease.67 68 69 A reversal of PE-induced RV ischemia and RV failure can be accomplished by the infusion of vasoconstrictors to raise aortic pressure and to increase the coronary perfusion gradient.66 70 Translation of the pathophysiology of MPE into the previously discussed three-compartment hydraulic model of the circulation is shown in Figure 5 . Catecholamine-induced venoconstriction increases the PVC to maintain a pressure gradient for VR in response to the PE-induced RAP elevation. The impairment of RV hydraulic pump function compromises LV hydraulic output, which is manifested as systemic arterial hypotension. Thus, the model variables would reveal an increased RAP, a decreased CO, and an increased SVR. The clinical correlates would be jugular venous distention, a thready pulse, and cool extremities, respectively. View larger version (57K): [in this window] [in a new window] Figure 5. Hydraulic model of MPE. Gas Exchange Gas-exchange abnormalities in patients with PE are complex and are related to the size and character of the embolic material, the extent of the occlusion, the underlying cardiopulmonary status and the length of time since embolization.71 Hypoxemia has been attributed to an increase in alveolar dead space,72 right-to-left shunting,73 74 ventilation/perfusion (/)75 76 inequality, and a low mixed venous O2 level.71 The two latter mechanisms are proposed to account for the majority of observed hypoxia and hypocarbia before and after treatment.77 Low / ratios reportedly can develop as a consequence of the redistribution of blood flow away from the embolized area, resulting in overperfusion of the unembolized lung regions78 and atelectasis that initially develops distal to the embolic obstruction yet persists after early embolism dissolution and resultant reperfusion.73 Atelectasis may arise from a loss of surfactant and alveolar hemorrhage79 or an “air shift” phenomenon as regional hypocarbia related to regional hypoperfusion induces bronchoconstriction,80 both of which are compounded by humoral mediators released from platelet-laden emboli.81 Postembolic pulmonary edema and flow through a patent foramen ovale that is induced by high RAP also have been implicated.82 In patients with massive PEs and circulatory failure, it has been reported that the augmentation of a low CO with medical therapy can decrease the PaO2. This was attributed to an increase in physiologic shunting because of increased flow through areas with low / ratios and may explain some of the PaO2 variability in reported series.83 Role of Severity of Pulmonary Vascular Obstruction Without Prior CPD: It is particularly instructive to review the clinical manifestations of PE in patients without prior CPD because it allows for the examination of the pure effects of the disease and the specific compensatory responses. In this population, the clinical and physiologic manifestations of the disease are directly related to embolism size.37 84 85 Good correlation has been observed between the degree of angiographic obstruction and mean pulmonary artery pressure (mPAP), RAP, PaO2 and, pulse.37 84 85 In the absence of angiographic quantification, it has been suggested that a pulmonary vascular resistance (PVR) of > 500 dyne · s ·cm-5 is associated with > 50% obstruction.86 Depression of the PaO2 is frequent, occurs with as little as 13% obstruction, usually is the only clinical manifestation when the obstruction is 25%, and roughly quantitates the extent of the embolus.85 Pulmonary artery (PA) hypertension (normal mPAP, 20 mm Hg) is the next most frequent finding and begins to manifest only when 25 to 30% of the pulmonary vascular bed is obstructed.85 This represents an increase in mPAP in excess of that observed in similarly described degrees of nonembolic experimental obstruction, further implicating the previously described87 neurohumoral/hypoxia mechanisms as contributing culprits. Despite massive embolic obstruction of 50%, patients without prior CPD are unable to generate an mPAP of 40 mm Hg, which appears to be the maximal pressure that a healthy ventricle can generate.84 85 Either a single massive embolus or the cumulative incremental effects of multiple recurrent emboli totaling 75% obstruction would necessitate an mPAP of 40 mm Hg and, consequently, would precipitate RV failure.88 Accordingly, mPAP values of 40 mm Hg represent either the baseline underlying CPD or the cumulative effects of multiple embolic events over a greater period of time, allowing for RV hypertrophy. Although correlated with the degree of anatomic obstruction, mPAP was not a reliable predictor of cardiac impairment. At high levels of mPAP (ie, 30 to 40 mm Hg), elevations or depressions in CO were observed.37 85 This suggests that the range of RV failure is narrow with individual patient variation and that an mPAP of 30 to 40 mm Hg should be considered to represent severe pulmonary hypertension in patients without prior CPD.37 85 The relationship between PVR and the degree of anatomic obstruction is hyperbolic and not linear. A dramatic increase in PVR occurs when obstruction exceeds 60%.89 Insofar as pressure = flow x resistance, it should be recognized that mPAP can be less than expected in the presence of massive obstruction if the RV is failing and cannot generate forward flow.32 Increased RAP in the setting of PE almost always indicates severe pulmonary vascular obstruction in the absence of other CPD. RAP elevation is directly related to mPAP but occurs less frequently and is unusual until mPAP is 30 mm Hg and obstruction exceeds 35 to 40%. RAP is consistently elevated with an mPAP of 30 mm Hg, and it has been reported that a RAP of 10 mm Hg is generated by an obstruction 50%, whereas obstruction 25% is associated with a RAP of 10 mm Hg.84 85 However, it should be recognized that substantial obstruction (ie, 30%) can occur without significant elevations in RAP in this population.85 Elevations in RAP reflect the compensatory use of the Frank-Starling preload mechanism. Thus, RAP can be elevated without a decrease in CO in patients with PE, but, as a corollary, a decrease in CO without an increase in RAP should suggest an alternative non-PE diagnosis. Significant elevations in RAP indicate severe RV outflow obstruction providing a reliable index of the degree of encroachment on RV reserve. In patients without prior CPD, CO is characteristically normal or elevated despite substantial anatomic obstruction.85 A hypoxically mediated sympathetic response that augments inotropic/chronotropic responses and venoconstriction is reported to be the responsible mechanism.90 91 The latter results in the creation of a more favorable pressure gradient for VR, resulting in an augmented Frank-Starling preload response. This is consistent with the observation that CO is initially maintained by increased stroke volume rather than increased heart rate.85 A decrease in CO is unusual without at least a 50% obstruction.85 The inadequacy of these mechanisms results in cardiac failure that is characterized by RV dilatation and by increased mPAP that is associated with an increased RAP and a predominantly chronotropic response. Insofar as BP is the product of CO and SVR (ie, BP = CO x SVR), it is likely that hypotension will ensue when systemic vasoconstriction is inadequate to generate pressure in response to decreasing flow. Thus, it appears that there exists a hierarchic series of compensatory cardiovascular responses related to the magnitude of the embolic event, with hemodynamic instability defining exhaustion and the failure of the available compensatory measures. With Prior CPD: In contrast to patients without prior CPD, patients with prior CPD characteristically manifest a greater degree of cardiovascular impairment with a lesser degree of pulmonary vascular obstruction.92 In the Urokinase Embolic Pulmonaire massive PE trial, 93 90% of the patients who presented in shock had prior CPD, and 56% of the patients with prior CPD presented in shock, compared to 2% of patients without CPD. Massive obstruction of 50% is uncommonly reported in this population, which suggests that patients with prior CPD who sustain such a massive embolic event often do not survive to be studied or entered into clinical trials. In patients with prior CPD, it has been shown that the level of mPAP is disproportionate to the degree of angiographic obstruction when compared to patients without prior CPD. In a group of patients with prior CPD and a mean angiographic obstruction of only 23%, significant elevations in mPAP were reported. The increased mPAP directly correlated with pulmonary capillary wedge pressure (PCWP),92 which suggests that increased mPAP in this population is predominately related to the critical opening pressure for pulmonary flow rather than to incremental resistance in the pulmonary vasculature.94 This degree of obstruction is below the threshold to elicit increased mPAP in patients without prior CPD. In the group with prior CPD, the average mPAP was 40 mm Hg, which was the maximum seen in patients without prior CPD.92 With prior CPD, the predictive value of the PaO2 and RAP to define the extent of the vascular obstruction was lost. In contrast to patients without prior CPD, RAP was shown to be an unreliable indicator of the severity of the event, limiting its usefulness as the sign of an extensive and life-threatening vascular obstruction.92 Despite a lesser degree of obstruction, CO was uniformly below normal and

independent of the magnitude of the obstruction and the level of pulmonary hypertension. Therefore, it appears that no consistent relationship exists between the degree of cardiovascular and RV functional impairment and the magnitude of the embolic obstruction in patients with prior CPD. As such, hemodynamic and RV functional status can be misleading as measurements of the effect of the embolic event and clearly illustrate that the estimation of the role and severity of PE in this population is predicated on the consideration of the preembolic cardiopulmonary status and the magnitude of the embolic obstruction. Determining the relative contributions of cardiopulmonary status and embolism magnitude to the postembolic hemodynamic presentation is difficult yet intuitively appealing, as such a characterization could have therapeutic and prognostic implications. The ratio of the mPAP to the percentage of angiographic obstruction has been proposed to distinguish between instances in which the PE is the primary determinant of the hemodynamic abnormality vs those instances in which the prior cardiopulmonary status dominates.95 In patients with prior CPD, a ratio 1.0 was consistently found, which suggests a greater pulmonary hypertensive response per unit of vascular obstruction that is consistent with less reserve in the system.95 Heparin When PE is first suspected, patients should receive heparin at therapeutic doses until PE is excluded, provided that no contraindications to anticoagulation are present.255 Large doses of heparin given as a bolus can precipitate hypotension, which is thought to be related to histamine release as the hemodynamic response can be blocked by histamine 1 and 2 receptor blockers.256 257 The efficacy of heparin is attributed to an impairment of clot propagation and the prevention of recurrent PE.258 The risk of recurrent venous thromboembolism is highest in the early stages,259 260 and, because recurrent PE is reported to be the most common cause of death in hemodynamically stable patients,3 41 it is crucial to rapidly achieve a therapeutic level of anticoagulation. An inability to establish an early therapeutic level for the activated partial thromboplastin time (aPTT) is associated with a higher rate of recurrence261 262 and impairs the efficacy of anticoagulation therapy with warfarin.263 A weight-based heparin nomogram has been shown264 to achieve a therapeutic aPTT more rapidly and to more effectively prevent the recurrence of venous thromboembolism. Although it has been demonstrated that a course of heparin therapy of 4 to 5 days, with warfarin initiated on day 1, is as effective as the traditional course of heparin therapy of 9 to 10 days,265 266 this has not been studied in patients with MPE. For this population, it is recommended that heparin therapy be given for 7 to 10 days and that the initiation of warfarin therapy be delayed until the aPTT is at a therapeutic level for 3 days.267 Patients with massive PEs reportedly have higher heparin dose requirements, and substantial amounts of heparin may be needed to ensure that therapeutic anticoagulation is rapidly achieved and sustained.268 When large doses of heparin are required (ie, 40,000 U/d), the optimal heparin dose can be determined by antifactor Xa heparin levels.269 Although low-molecular-weight heparin has been shown to be safe and effective in treating patients experiencing submassive PEs with proximal DVT,10 11 its use in patients experiencing massive PEs or MPEs remains unstudied.270 It has been proposed that undergoing anticoagulation therapy with heparin will prevent the accretion of new fibrin on the thrombus, thereby facilitating lysis by thrombolytic agents and reducing the risk of re-extension after thrombolysis.271 The greater the angiographic and scintigraphic resolution observed with urokinase (UK) therapy compared to heparin therapy on day 1 in the UPET has been ascribed to a synergism between the UK and the heparin administered during the diagnostic workup prior to randomization.45

1. Casthely, PA, Yoganathan, D, Karyanis, B, et al (1990) Histamine blockade and cardiovascular changes following heparin administration during cardiac surgery. J Cardiothorac Anesth 4,711-714[Medline]
2. Kanbak, M, Kahraman, S, Celebioglu, B, et al (1996) Prophylactic administration of histamine 1 and/or histamine 2 receptor blockers in the prevention of heparin- and protamine-related haemodynamic effects. Anaesth Intensive Care 24,559-563[ISI][Medline]

1. Verstraete, M, Miller, GA, Bounameaux, H, et al (1988) Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation 77,353-360 [Abstract/Free Full Text]

Thrombolytic Therapy Thrombolytic therapy in patients experiencing PEs has been extensively reviewed and will be discussed only briefly.272 273 Although no definitive mortality data exist, thrombolytic therapy is uniformly acknowledged as the treatment of choice in hemodynamically unstable patients with PE.272 273 274 This should be interpreted similarly for patients without CPD and massive PEs or in patients with submassive PEs and CPD who are manifesting shock or cardiovascular collapse.267 In the PIOPED, thrombolytic therapy was considered to be the standard of care for patients with “shock or major disability.” The investigators considered it “unethical” to treat this group with heparin alone.48 Several points regarding thrombolytic therapy and MPE should be stressed. First, when assessed by angiography, perfusion scans, hemodynamic measurements, or ECHO, thrombolytic therapy has been shown to produce more rapid (ie, 2 to 24 h) clot lysis when compared to heparin therapy in all trials16 35 41 47 159 275 except two.45 48 No trial has reported any difference in the degree of embolic resolution after days 5 to 7. Given the hyperbolic relationship between PVR and vascular obstruction, slight decreases in obstruction (to 60%), as would be expected with thrombolysis, can significantly reduce PVR and alleviate RV stress.89 However appealing the rapid resolution of embolic obstruction may be, only one trial69 has demonstrated a mortality outcome benefit. This small trial of only eight patients should be viewed with caution. All four patients randomized to thrombolytics were treated within 4 h of presentation, whereas those patients randomized to heparin therapy had previously failed to respond to it and had experienced recurrent PEs with severe respiratory failure. Second, there does not appear to be any difference in the effectiveness of thrombolytic agents, provided that they are given in equivalent doses over the same time frame.158 276 Third, bolus therapy with recombinant tissue plasminogen activator (rt-PA) [0.6 mg/kg/15 min] is equivalent to the traditional 100 mg/2 h.46 277 Fourth, IV rt-PA appears to be equivalent to intrapulmonary rt-PA.156 Fifth, bleeding complications from thrombolytic therapy can be substantial. From pooled analysis, the overall incidence of major hemorrhage associated with PE thrombolysis is reportedly 12% and appears to be similar among thrombolytic agents.273 Fatal hemorrhaging is thought to occur in 1 to 2% of patients.278 The reported incidence of intracranial hemorrhaging ranges from 1.2 to 2.1%272 273 279 and is fatal in at least 50% of cases.273    

Troponins

(Circulation. 2007 Jul 24;116(4):427-33.)CONCLUSIONS: Elevated troponin levels identify patients with acute pulmonary embolism at high risk of short-term death and adverse outcome events.

COPD Patients

Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors Isabelle Tillie-Leblond, MD, PhD; Charles-Hugo Marquette, MD, PhD; Thierry Perez, MD; Arnaud Scherpereel, MD, PhD; Christophe Zanetti, MD; André-Bernard Tonnel, MD, PhD; and Martine Remy-Jardin, MD, PhD Annlas of Int Med 21 March 2006 | Volume 144 Issue 6 | Pages 390-396   Background: Diagnosis of pulmonary embolism (PE) is difficult in patients with chronic obstructive pulmonary disease (COPD) and exacerbation. Objective: To evaluate PE in patients with COPD and exacerbation of unknown origin and explore factors associated with PE. Design: Prospective cohort study. Setting: University-affiliated hospital in France. Patients: 211 consecutive patients, all current or former smokers with COPD, who were admitted to the hospital for severe exacerbation of unknown origin and did not require invasive mechanical ventilation. Measurements: Spiral computed tomography angiography (CTA) and ultrasonography within 48 hours of admission and assessment of the Geneva score. Patients were classified as PE positive (positive results on CTA or negative results on CTA and positive results on ultrasonography) or PE negative (negative results on CTA and negative results on ultrasonography or negative results on CTA and no recurrence of PE at follow-up 3 months later). Results: 49 of 197 patients (25% [95% CI, 19% to 32%]) met the diagnostic criteria for PE. Clinical factors associated with PE were previous thromboembolic disease (risk ratio, 2.43 [CI, 1.49 to 3.94]), malignant disease (risk ratio, 1.82 [CI, 1.13 to 2.92]), and decrease in PaCO2 of at least 5 mm Hg (risk ratio, 2.10 [CI, 1.23 to 3.58]). A total of 9.2% (CI, 4.7% to 15.9%) of patients with a low-probability Geneva score received a diagnosis of PE. An exploratory analysis suggested that substituting malignant disease for recent surgery in the Geneva score might improve its performance in excluding PE in this sample who were more likely to have malignant disease than to have had recent surgery. However, this improvement seems insufficient to exclude PE with enough certainty to withhold therapy for low-risk patients on the basis of the modified score. Limitations: This study was done in only 1 center. Patients with COPD requiring invasive mechanical ventilation in the intensive care unit were not included. The upper bound of the 95% CI for the low probability of PE according to the Geneva score is too high to rule out PE. The classification of COPD exacerbation of unknown origin was based on the clinician’s assessment, not on a standard evaluation for all patients. Conclusion: This study showed a 25% prevalence of PE in patients with COPD hospitalized for severe exacerbation of unknown origin. Three clinical factors are associated with the increased risk for PE. The Geneva score and the modified Geneva score should be prospectively evaluated in patients with COPD.    

CT is better than V/Q–duhhh

Computed Tomographic Pulmonary Angiography vs Ventilation-Perfusion Lung Scanning in Patients With Suspected Pulmonary Embolism A Randomized Controlled Trial JAMA. 2007;298(23):2743-2753.

Line Infections

Staph Aureus line infection is associated with venous thrombosis (Crit Care Med 2008;36:385)     The puerperium, defined as the 6-week period after delivery, is associated with a higher rate of thrombosis than pregnancy itself (Am J of EM, 7/06, pg. 460).       Sostman HD, et al. Acute pulmonary embolism: sensitivity and specificity of ventilation-perfusion scintigraphy in PIOPED II study. Radiology. 2008 Mar;246(3):941-6. Epub 2008 Jan 14. wow this one takes the cake; after botching PIOPED II, they now go further…       An Unappreciated Risk Factor For Pulmonary Embolism (Emedhome) Emergency Physicians are well familiar with the classic risk factors for the development of venous thromboembolism (VTE) and consider the presence or absence of such factors when judging the likelihood of pulmonary embolism in a particular patient. Such factors include immobilization, surgery, pregnancy, use of combined oral contraceptives, and malignancies. Much less attention has been paid, however, to an association between antipsychotic agents and the development of VTE. Reports show an association between clozapine and VTE (2,3) and a possible association between VTE and both olanzapine (Zyprexa) and risperidone (Risperdal) has been suggested in recent publications (4-6). The mechanism responsible for this possible adverse drug reaction is unknown, but it has been hypothesized that since antispychotics like olanzapine, risperidone, and clozapine have an affinity for 5HT2 receptors, they induce a serotonin increase, which in turn might provoke enhanced platelet aggregation, thereby increasing the risk for thrombosis (8). Clinicians should consider antipsychotic drug exposure as a potential risk factor of VTE.References: (1) Borras L, et al. Pulmonary thromboembolism associated with olanzapine and risperidone J Emerg Med 2008 Feb 16; [Epub ahead of print]. (2) Selten JP, Büller H. Clozapine and venous thromboembolism: further evidence J Clin Psychiatry 2003;64:609. (3) Hägg S, et al. Association of venous thromboembolism and clozapine Lancet 2000;355:1155–1156. (4) Hägg S, et al. Olanzapine and venous thromboembolism Int Clin Psychopharmacol 2003;18:299–300. (5) Waage IM, Gedde-Dahl A. Pulmonary embolism possibly associated with olanzapine treatment BMJ 2003;327:1384. (6) Kamijo Y, et al. Acute massive pulmonary thromboembolism associated with risperidone and conventional phenothiazines. Circ J. 2003;67:46–48. (7) Lacut K, et al. Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case-control study Fundam Clin Pharmacol 2007;21: 643-50. (8) Koga M, Nakayama K. Body weight gain induced by a newer antipsychotic agent. Acta Psychiatr Scand 2005;112:75–76.

PE During Pregnancy

Evaluation of Suspected Pulmonary Embolism During Pregnancy To the Editor: In his Editorial, Dr Glassroth1 suggests that during pregnancy ventilation-perfusion lung scanning is preferred to computed tomographic pulmonary angiography (CTPA) because radiation dosage is higher with CTPA. However, with respect to the fetus the opposite is true: CTPA exposes the fetus to less radiation.2-3 The more important CTPA-related radiation risk during pregnancy is to the breasts,4 a risk that may be offset by the use of breast shields.5 In general, when pulmonary embolism is suspected during pregnancy, CTPA is the preferred study. 1. Glassroth J. Imaging of pulmonary embolism: too much of a good thing? JAMA. 2007;298(23):2788-2789. FREE FULL TEXT 2. Groves AM, Yates SJ, Win T; et al. CT pulmonary angiography versus ventilation-perfusion scintigraphy in pregnancy: implications from a UK survey of doctors’ knowledge of radiation exposure. Radiology. 2006;240(3):765-770. FREE FULL TEXT 3. Winer-Muram HT, Boone JM, Brown HL, Jennings SG, Mabie WC, Lombardo GT. Pulmonary embolism in pregnant patients: fetal radiation dose with helical CT. Radiology. 2002;224(2):487-492. FREE FULL TEXT 4. Hurwitz LM, Reiman RE, Yoshizumi TT; et al. Radiation dose from contemporary cardiothoracic multidetector CT protocols with an anthropomorphic female phantom: implications for cancer induction. Radiology. 2007;245(3):742-750. FREE FULL TEXT 5. Hopper KD, King SH, Lobell ME, TenHave TR, Weaver JS. The breast: in-plane x-ray protection during diagnostic thoracic CT: shielding with bismuth radioprotective garments. Radiology. 1997;205(3):853-858. ABSTRACT (JAMA)   Ventilation–perfusion lung scanning or computed tomographic pulmonary angiography (CTPA) should be performed.30 Ventilation–perfusion lung scanning delivers a higher fetal dose of radiation than does CTPA (640 to 800 µGy vs. 3 to 131 µGy); perfusion scanning alone will reduce the radiation exposure.30,39,40 However, the radiation dose delivered to mothers is higher with CTPA than with scintigraphy (2.2 to 6.0 mSv vs. 1.4 mSv).39,40 Women with suspected venous thromboembolism should be advised that ventilation–perfusion scanning carries a slightly higher risk of childhood cancer in offspring than does CTPA (1 case in 280,000 vs. <1 in 1 million) but carries a lower risk of maternal breast cancer (the lifetime risk is up to 13% greater with CTPA than with ventilation–perfusion scanning).30 NEJM Volume 359:2025-2033 November 6, 2008   (3) Bates S, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition) Chest 2008;133(6)(suppl):844S-886S.

PE in Trauma

maybe clots are forming in the lung de novo rather than from leg dvt, but maybe not (Arch Surg 2009;144:928)

PE Mortality

PE mortality did not drop, we are just finding a ton more non-symptomatic tiny PEs (Arch Intern Med 2011;171(9):831) Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism The EINSTEIN–PE Investigators March 26, 2012 (10.1056/NEJMoa1113572) as good seemingly

Contrast Induced Nephropathy in the w/u of PE

More patients had CIN than were dx with PE (Academic Emergency MedicineVolume 19, Issue 6, pages 618–625, June 2012)

Lactate

Seems to predict PE prognosis (Ann Emerg Med. 2013 Mar;61(3):330-8)

Hestia

Kline prefers this score over the PESI (Thromb Haemost 2013;109:47)

Troponin

The Prognostic Value of Undetectable Highly Sensitive Cardiac Troponin I in Patients with Acute Pulmonary Embolism.

Right Ventricular Dilation

In moderate or high pretest prob patients, RV dilation (>1.0) had a sens of 50% and a spec of 98% (Ann Emerg Med 2014;63(1):16)