Tag Archives: respiratory

Croup: ED-focused Highlights

Authors: James Costakis, MD (EM Resident Physician, UW/Harborview, Seattle, WA), Siobhan Thomas-Smith, MD (Pediatrics Resident Physician, Seattle Children’s Hospital, Seattle, WA), and Rebekah Burns, MD (Pediatric Emergency Attending Physician, Seattle Children’s Hospital, Seattle, WA) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Case 1

A 2-year-old boy presents with sudden onset of cough and difficulty breathing that woke him from sleep. Parents thought his breathing was labored and brought him to the ED. He has a history of reactive airway disease but has never been hospitalized.

Vitals in the ED:

Temperature 100F, heart rate 110, blood pressure 90/60, respiratory rate 30, oxygen saturation 98% on room air.

Exam is remarkable for a fatigued boy who refuses to speak. He has stridor at rest, tracheal tug, and moderate intercostal retractions. You do not appreciate wheezing on exam. He has a mild scattered erythematous rash on his chest and arms.


Case 2

A 10-year-old boy presents with fever and vomiting. Parents report two days of fever up to 104F, associated with myalgias, nausea, and mild cough. Vomiting was prominent today, and parents are worried that he is dehydrated. For the past day, his voice has become slightly hoarse, and his breathing audible.

Vitals in the ED:

Temperature 103F, heart rate 120, blood pressure 110/70, respiratory rate 26, oxygen saturation 91% on room air.

Exam is remarkable for suprasternal and supraclavicular retractions, as well as audible stridor at rest.


Physiology of Croup

Croup is a spectrum of illness characterized by varying degrees of inflammation in the upper respiratory tract, with possible involvement of the lower respiratory tract. Patients may have laryngotracheitis, laryngotracheobronchitis, or laryngotracheobronchopneumonitis. In 75% of cases, parainfluenza virus is responsible [6]. Otherwise, RSV, metapneumovirus, influenza, adenovirus, coronavirus, or even mycoplasma can cause a similar syndrome [6,8]. Some patients have recurrent bouts of upper airway edema causing a croup-like syndrome, which is referred to as spasmodic croup. This is thought to be potentially related to hypersensitivity to viral antigens.


Classic presentation

Croup primarily affects children from 6 months to 3 years of age, with a peak incidence of 5% per year in 2-year-olds [8]. Boys are 1.4 times more likely than girls to develop croup [8]. Typically, it occurs in the late fall or early winter [8]. Patients may or may not complain of a short prodromal upper respiratory infection. The acute phase of illness is characterized by stridor, barky cough, hoarseness, and sometimes fever. Symptoms often come on abruptly at night. Within 48 hours, most patients have recovered, but they may have lingering upper respiratory symptoms for about a week [4,9].


Diagnosis of Croup

Croup is diagnosed clinically. Chest X-ray and respiratory viral panel are sometimes used when one is considering an alternative diagnosis, but otherwise do not meaningfully affect the patient’s clinical course and are not recommended in uncomplicated croup [12].

The differential diagnosis of croup includes other causes of upper airway obstruction, gastroesophageal reflux, and allergic syndromes such as angioedema or spasmodic croup.

Other causes of upper airway obstruction include:

  • Bacterial tracheitis
  • Laryngomalacia
  • Tracheomalacia
  • Vascular rings
  • Epiglottitis (unlikely if vaccinated)
  • Foreign body aspiration
  • Peritonsillar abscess
  • Retropharyngeal abscess
  • Tracheo-esophageal fistula

A high index of suspicion for these alternative diagnoses is critical, particularly in patients who are presumptively diagnosed with croup but fail to follow the expected clinical course. Some red flags include:

  • Failure to respond to racemic epinephrine after 30 minutes
  • Trouble handling secretions
  • Oxygen requirement
  • Wheezing


How to Identify Sick Patients

Croup is common, accounting for 15% of ED visits by children with respiratory complaints and for 5% of ED admissions in children under 6 years of age [4,5]. Luckily, croup is usually a mild syndrome requiring minimal intervention – about 85% of children presenting to the ED have mild croup [10]. Only 1 to 3% of children with croup are intubated, and even then the mortality rate of children intubated for croup is only 0.5% [4]. Even so, early identification and aggressive treatment are critical in this subgroup of very sick children in order to maintain this low mortality rate.

How can we quickly identify patients who are in more severe respiratory distress? The Westley croup score has been around since the 1970’s and might help predict which patients need racemic epinephrine [3]. The score stratifies patients based on level of consciousness, cyanosis, stridor, air entry, and retractions. However, the score is typically used in research studies to quantify the efficacy of an intervention, and it has not been prospectively validated to predict mortality, intubation, or hospital admission.

At Seattle Children’s Hospital, a child is considered to have “severe” croup when they have stridor at rest, plus one of the following [17]:

  • Moderate intercostal retractions
  • Tachypnea
  • Agitation or restlessness
  • Fatigue
  • Difficulty speaking or feeding

These patients warrant racemic epinephrine, as discussed below. Notably, decreasing stridor can be an ominous sign, just as decreasing wheezing can suggest impending respiratory failure in asthmatics. Be on the lookout for lethargy, increasing fatigue, and worsening mental status. In the lethargic patient with decreasing stridor, decreased level of alertness, and hypoxemia, intubation may be required.



Historically, cool mist or humidified air was used to treat croup, but they are no longer recommended as studies have consistently failed to show clinical improvement with these interventions [13-15]. The primary adjuncts to support of airway, breathing, and circulation are dexamethasone and racemic epinephrine.

Dexamethasone has been found to improve the Westley score at 6 and 12 hours (but not at 24 hours), with a NNT of 5 to improve the score [2]. Patients typically require less epinephrine, spend less time in the ED or hospital (by about 12 hours), and have fewer return visits or readmissions (RR of return or readmission 0.5) when treated early with dexamethasone [2].

The dose of dexamethasone is 0.6 mg/kg, rounded to the nearest 2mg, up to a maximum dose of 16mg. Lower doses may be as effective, but some studies have seen more patients improved at 12 hours with the higher dose [16]. At Seattle Children’s Hospital, all children with croup of any severity receive dexamethasone. Repeat doses are rarely given [17].

Racemic epinephrine may help by causing mucosal vasoconstriction and decrease subglottic edema. It has been found to improve symptoms at 30 minutes, but the effect is normally gone by 2 hours [1].

The dose of racemic epinephrine is 0.5 mL of nebulized 2.25% solution, diluted in 3 mL of normal saline. At Seattle Children’s, this is given as soon as possible to children with “severe” croup, and can be re-dosed every 2 hours up to 3 times [17]. Further doses are typically given as an inpatient, and failure to improve after 3 doses suggests a possible alternative or concomitant diagnosis. This medication is most commonly given to those with stridor at rest.

There is conflicting data on whether heliox can be beneficial in croup. Most studies assessing heliox have looked at children with moderate to severe croup [18]. Heliox may improve the croup score, even compared to racemic epinephrine, starting at 90 minutes and lasting up to 4 hours, but no difference was found after 4 hours [18]. Overall, the data are conflicting, and at this point it is impossible to make a strong recommendation on administration of heliox. Currently, it may be considered as an adjunct therapy in a patient with severe croup with only partial response to racemic epinephrine.



Patients may have stridor with activity and still do well at home. However, stridor at rest warrants further intervention. Children should be able to talk and feed with minimal retractions. At Seattle Children’s, patients must be on room air and must not have received racemic epinephrine in the 2 hours prior to discharge [17].

Patients not meeting discharge criteria within 2 hours of dexamethasone are likely to require admission. Respiratory distress despite multiple doses of racemic epinephrine suggests likely need for ICU care and consideration of ENT consultation for direct laryngoscopy.


Case Resolution

Case 1

This patient may have classic laryngotracheitis from parainfluenza. The viral exanthem is non-specific. However, if you are concerned about anaphylaxis, it would not be wrong to administer intramuscular epinephrine. Otherwise, his stridor at rest and moderate intercostal retractions warrant racemic epinephrine in addition to dexamethasone.

Case 2

This patient is older than most patients with classic croup. Given his fever, age, and poor oxygenation, he requires consideration of a broad differential. Chest X-ray and viral panel are reasonable. He may have influenza causing a croup-like syndrome with stridor and respiratory distress, and may benefit from racemic epinephrine to decrease upper airway inflammation.


Pearls & Takeaways

  • Do not routinely obtain chest X-ray or respiratory viral panel in children with uncomplicated croup.
  • In patients who fail to respond to racemic epinephrine, or who are in significant respiratory distress, the differential must be initially very broad, with particular concern for bacterial tracheitis.
  • All patients with croup of any severity can benefit from dexamethasone.
  • Racemic epinephrine can help for a short time, and if it doesn’t, broaden your differential.


References / Further Reading

  1. Bjornson C, Russell K, Vandermeer B, Klassen TP, Johnson DW. Nebulized epinephrine for croup in children. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD006619.
  2. Russell KF, Liang Y, O’Gorman K, Johnson DW, Klassen TP. Glucocorticoids for croup. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD001955.
  3. Westley CR, Cotton EK, Brooks JG. Nebulized racemic epinephrine by IPPB for the treatment of croup: a double-blind study. Am J Dis Child. 1978 May;132(5):484-7.
  4. Johnson DW. Croup. BMJ Clin Evid. 2009; 2009: 0321.
  5. Cherry JD. Clinical practice. Croup. N Engl J Med. 2008;358(4):384–391.
  6. Rihkanen H, Rönkkö E, Nieminen T, et al. Respiratory viruses in laryngeal croup of young children [published correction appears in J Pediatr. 2008;153(1):151]. J Pediatr. 2008;152(5):661–665.
  7. Mazza D, Wilkinson F, Turner T, Harris C. Evidence based guideline for the management of croup. Aust Fam Physician. 2008 Jun;37(6 Spec No):14-20.
  8. Denny FW, Murphy TF, Clyde WA Jr, Collier AM, Henderson FW. Croup: an 11-year study in a pediatric practice. Pediatrics. 1983;71(6):871–876.
  9. Bjornson CL, Johnson DW. Croup. 2008;371(9609):329–339.
  10. Bjornson CL, Johnson DW. Croup-treatment update. Pediatr Emerg Care. 2005;21(12):863–870.
  11. Chan A, Langley J, Leblanc J. Interobserver variability of croup scoring in clinical practice. Paediatr Child Health. 2001;6(6):347–351.
  12. Swingler GH, Zwarenstein M. Chest radiograph in acute respiratory infections. Cochrane Database Syst Rev. 2008;(1):CD001268.
  13. Scolnik D, Coates AL, Stephens D, Da Silva Z, Lavine E, Schuh S. Controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments. JAMA. 2006;295(11):1274–1280.
  14. Moore M, Little P. Humidified air inhalation for treating croup. Cochrane Database Syst Rev. 2010;(9):CD002870.
  15. Moore M, Little P. Humidified air inhalation for treating croup. Fam Pract. 2007;24(4):295–301.
  16. Kairys SW, Olmstead EM, O’Connor GT. Steroid treatment of laryngotracheitis: a meta-analysis of the evidence from randomized trials. Pediatrics. 1989;83(5):683–693.
  17. seattlechildrens.org/pdf/croup-pathway.pdf
  18. Moraa I, Sturman N, McGuire T, van Driel ML. Cochrane Database Syst Rev. 2013 Dec 7;(12):CD006822.

Interstitial Lung Diseases: Evaluating for an Acute Exacerbation

Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC)

A 55 year-old female with a history of idiopathic pulmonary fibrosis and pulmonary hypertension (prednisone, sildenafil, and bosentan therapy) presents with a three day history of cough, chills, and shortness of breath.  As you enter the room, you see the patient leaning forward in her bed, gasping.

The bedside monitor alarms with a HR of 132, RR of 28, SpO2 of 84% on room air.  Physical exam is significant for end-expiratory wheezing and accessory muscle use.  While opening a non-rebreather mask and starting supplemental oxygen, your mind buzzes with thoughts of NIPPV, an EKG, a chest xray, a VBG, and antibiotics, but is there more that you should consider?  Does the patient’s previous diagnosis of idiopathic pulmonary fibrosis (IPF) change your management?

Let’s take a minute to discuss interstitial lung diseases and the importance of identifying acute exacerbations.

Diagnosing an Interstitial Lung Disease

While this piece centers on the management of an acute exacerbation of an interstitial lung disease (ILD), let’s first review the approach to diagnosing an ILD:

The term “interstitial lung disease” currently represents greater than 200 non-malignant pulmonary conditions, characterized by varying degrees of parenchymal and interstitial inflammation and fibrosis.1-5  Individuals suffering from undiagnosed ILD often present to healthcare providers with complaints of shortness of breath, persistent dry cough, chest pain with exertion, and even syncope (described in the setting of an ILD resulting in pulmonary hypertension and subsequent right heart failure).3,6

In this patient population, emergency department (ED) evaluation begins as all others: with an assessment of the ABCs.  After initial stabilization, history and physical examination will dictate the requirement of an assessment for: myocardial infarction, aortic dissection, congestive heart failure, myocarditis, pericarditis, endocarditis, pericardial effusion, valvular dysfunction, cardiac arrhythmia, pulmonary embolism, pneumonia, and pleural effusion, among others.3

Depending upon the patient’s hemodynamic status and emergency department findings, settings which incite concern for an underlying primary lung pathology or systemic disease associated with pulmonary compromise, often prompt inpatient or outpatient specialist consultation for advanced imaging, tissue sampling, pulmonary function testing, and laboratory analysis.3

Specialist consultation and evaluation allows for a definitive diagnosis of ILD and performance of subgroup analysis.  The subgroup classification system identifies conditions associated with an underlying systemic disorder, those with a known trigger, and those that are idiopathic in nature.  Tables 1-3 below contain examples; not all-encompassing.1,3

For an excellent review of historical and clinical clues suggesting ILD upon initial patient encounter, see Keith Meyer’s Diagnosis and Management of Interstitial Lung Disease:

Meyer K. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014; 2:4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215823/

Associated with a Systemic Disorder1-5
Scleroderma Sarcoidosis
Polymyositis Langerhans Cell Histiocytosis
Dermatomyositis Amyloidosis
Systemic Lupus Erythematosus Pulmonary Vasculitis
Rheumatoid Arthritis Gaucher’s Disease
Mixed Connective Tissue Disease Nieman-Pick Disease
Neurofibromatosis Tuberus Sclerosis

Table 1. ILDs Associated with a Systemic Disorder

Identified Etiology1-5
Antibiotics (nitrofurantoin, sulfasalazine) Silicosis
Antiarrhythmics (amiodarone, tocainide, propanolol) Asbestosis
Anti-inflammatories (gold, penicillamine) Coal Worker’s Pneumoconiosis
Anticonvulsants (dilantin) Berylliosis
Chemotherapeutic Agents (mitomycin C, bleomycin, etc.) Talc Pneumoconiosis
Radiation Therapy Siderosis
Oxygen Toxicity Stannosis (Tin)
Narcotics Hypersensitivity Pnemoitis (Bird breeder’s or Farmer’s lung)

Table 2. ILDs with a Known Trigger

Idiopathic Pulmonary Fibrosis
Non-specific Interstitial Pneumonia

Table 3. Idiopathic ILDs

Note: the term ILD is synonymous with interstitial pulmonary disease, diffuse parenchymal lung disease, and interstitial pneumonia.1,3

The Epidemiology of ILD

As international standards for the diagnosis of ILD are lacking and disease terminology is highly variable, the true incidence and prevalence of ILD is difficult to ascertain.2  The largest U.S. study of ILD (n=2,936; patient population localized to Bernalillo County, NM), utilizing physician referral data, histopathology reports, ICD discharge diagnoses, and death certificate information, identified the incidence of ILD as 31.5 per 100,000/yr in males and 26.1 per 100,000/yr in females, with a male prevalence of 80.9 per 100,000, and a female prevalence of 67.2 per 100,000.7  Autopsy data revealed the estimated prevalence of pre-clinical or undiagnosed ILDs as 1.8% among all deaths.7,8  The most common incident diagnoses amongst both sexes were pulmonary fibrosis and IPF.

Economic data for the majority of ILD subgroup classifications are lacking; however, a 2002 study of private health insurance medical and pharmacy claims, performed by Weckyer et al., demonstrated the mean patient healthcare charges related to IPF as $33,304 – $40,707 per patient per year, with hospital admissions accounting for 71-73% of these expenses.2,9

Identifying ILD Exacerbations

In a patient with a previously diagnosed ILD, an exacerbation is defined as an acute lung injury (new onset bilateral pulmonary infiltrates, PaO2/FiO2 ≤ 300, and PAWP ≤ 18) in the absence of heart failure, pulmonary infection, pulmonary embolism (PE), aspiration, or drug reaction.4,10-13  Acute exacerbations have been documented in patients with the subgroup classifications of IPF, IPF associated with a connective tissue disease, chronic hypersensitivity pneumonitis, desquamative interstitial pneumonia, and asbestosis.4  Patients with these diagnoses may present to the ED with acute shortness of breath, cough, fever, or wheezing.3,6,10  In addressing this population, the role of the emergency physician is to provide acute resuscitation while initiating an evaluation for the previously detailed underlying etiologies.10,11

As mentioned, ED assessment begins with addressing ABCs, therefore a word on airway and breathing:

Oxygenation and Ventilation Support in Patients with ILD

Gas exchange abnormalities (ABG/VBG) or respiratory distress may dictate the employment of therapeutic options including nasal cannula, non-rebreather, non-invasive positive pressure ventilation, or intubation and mechanical ventilation.  The requirement for NIPPV or intubation in a patient with ILD is ominous.  Studies of patients with IPF experiencing acute respiratory distress demonstrated no mortality benefit from the utilization of NIPPV,14-16 and an average median survival time of 18.0 days [95% CI 9.0-25.0] in patients failing NIPPV, and 90 days [95% CI 65.0-305.0]  in those with successful NIPPV therapy (n = 18, p < 0.0001).12

 Ventilation strategies for patient with varying degrees of lung fibrosis previously centered on limiting barotrauma through the utilization of low tidal volumes (similar to the ARDSNet protocol);10 however, a recent case series of 94 patients with IPF demonstrated no improvement in patient outcomes with employment of this strategy.17  Increased levels of PEEP were also associated with increased short-term mortality.16  Overall, the vast majority of patients experiencing respiratory failure secondary to an acute exacerbation of an ILD perish in intensive care units.12,18

Let’s now address our C – Circulation:

Hemodynamic Instability

Hemodynamic instability in a patient with ILD may occur secondary to the acute exacerbation (hypercapnic respiratory failure resulting in hypoxemia and cardiovascular collapse), heart failure, acute coronary syndrome, infectious pulmonary pathology resulting in sepsis, or PE.10,19

In evaluating the hemodynamically unstable patient consider the following:19

  • EKG to evaluate for signs of heart strain, STEMI, NSTEMI, or ST-T changes concerning for ischemia.
  • Point of care ultrasound to evaluate for pleural effusions (left-sided heart failure), cardiomegaly (heart failure), right atrial/right ventricular dilation (PE), or right ventricular free wall dilation/ paradoxical septal shift toward the LV during early diastole (pulmonary hypertension20).
  • Antibiotic therapy for all patients presenting with SIRS criteria (temperature >38.0°C or <36°C, heart rate >90 bpm, respiratory rate > 20 or PCO2 < 32 Torr).

History, Physical Examination, and Evaluation

History and physical examination are paramount in assessing underlying etiologies of the patient’s symptoms, as treatment goals vary dramatically according to diagnosis (i.e. an acute exacerbation requiring respiratory support and admission to an ICU setting for bronchoalveolar lavage, vs. afterload reduction and potential diuresis in the setting left-sided heart failure, vs. the maintenance of euvolemia in the setting of pulmonary HTN precipitating right-sided heart failure vs. early antibiotic therapy and fluid resuscitation in the setting of sepsis, vs. anticoagulation in the setting of a PE).

When stable, the patient should be questioned regarding:

  • His/her specific ILD diagnosis (i.e. – eosinophilic pneumonia, scleroderma, etc.)
  • Current medical therapy or changes in medical therapy
    • Many patients are treated with chronic corticosteroids or immune modulators (methotrexate, infliximab, mycophenalate, etc.)
      • Bosentan, a treatment for pulmonary hypertension, is known to worsen fibrosis.4
    • Medical co-morbidities (ACS risk stratification/PE & DVT risk stratification)
    • Fevers or viral prodrome
    • Symptoms of right- or left-sided heart failure (orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, etc.)
    • History of acid reflux (predisposes to aspiration pneumonia and ARDS4)

Of note, studies have demonstrated an increased risk of thromboembolism in patients previously diagnosed with IPF.  A review of 218,991 decedent records contained in the US Multiple Cause-of-Death mortality database identified a prevalence of venous thromboembolism of 1.74% in patients with IPF vs. 1.34% (p<0.0001) in the general population (overall OR 1.34, 95% CI 1.29–1.38).21  IPF should be considered an independent risk factor for thromboembolism.

All patients with the diagnosis of an ILD presenting to the ED with chest pain, shortness of breath, fever, cough, or in acute respiratory failure should undergo the following evaluation:19

  • CBC, CMP, troponin, BNP, VBG/ABG, and lactate
  • Urinalysis, urine culture, and blood cultures are highly recommended for all patients, with or without SIRS criteria, given steroid and immune-modulator therapy.
  • Imaging:
    • Chest radiograph in patients with pre-existing ILD lacks sensitivity in identifying new opacities.10
    • High resolution CT (HRCT) is recommended as it demonstrates increased sensitivity in detecting radiographic abnormalities (ground glass opacities or a new organizing pneumonia), lacks iodinated contrast, and is able to differentiate an acute exacerbation of ILD from an interstitial pneumonia, aspiration pneumonia, or ARDS (these conditions lack the traditional honeycombing pattern).20
    • CTPA is required for the evaluation of pulmonary embolism if concern is present for PE, and this modality demonstrates a positive predictive value of 96% for pulmonary hypertension in individuals in which the maximum transverse diameter of the pulmonary artery is greater than the diameter of the proximal ascending aorta.22

Disposition and Treatment

At this point in the clinical encounter you have diagnosed an acute lung injury in your patient with a history of ILD.  You have ruled out cardiac pathology, pulmonary infection, aspiration, and pulmonary embolism.  Depending on the patient’s respiratory and hemodynamic status, your patient may be undergoing a trial of NIPPV or intubated and ventilated.  What comes next?

  • Experts recommend the initiation of broad-spectrum antibiotic therapy in all patients with an acute exacerbation of an ILD given the potential for immunosuppression.19
  • Attempts should me made to temporize with NIPPV. While there is no statistically significant mortality benefit, patients who successfully complete NIPPV may survive to hospital discharge.12
  • Consult pulmonology to discuss patient medication regimens, ventilation strategies, the possibility of corticosteroid and immune-modulator treatment, and performance of the recommended bronchoalveolar lavage (samples for culture).10
    • As an aside: Randomized controlled trials of corticosteroid therapy for acute exacerbations of ILD (patients with IPF and sarcoidosis) have failed to demonstrate a survival benefit.13,23 Cyclosporin A therapy in the setting of acute IPF exacerbation has also failed to demonstrate mortality benefit.11
  • Admit the patient to the ICU – progression to ARDS is common. All-cause mortality associated with acute exacerbations of ILD is estimated as 70%.4

Returning to the Case

Our 55 year-old patient with a history of IPF is in respiratory distress.  Based upon our above discussion, we would initiate a trial of NIPPV (guided by mental status examination and serial VBGs), and begin our efforts to rule out underlying etiologies according to our history and physical examination.  Our evaluation would include an EKG, +/- an US.  HR and RR dictate early antibiotic therapy.  HRCT or CTPA would be our imaging modalities of choice.  If our laboratory studies and imaging led us to a diagnosis of an acute exacerbation of the patient’s IPF, pulmonology would be consulted, and the patient admitted to the ICU.

Patients with ILD presenting with complaints related to the pulmonary system have a significant risk of mortality.  Close monitoring of respiratory status and early disposition may allow survival to hospital discharge.


Key Pearls

  • Airway and breathing => keep in mind, there is a 70% mortality associated with an acute ILD exacerbation; intubated patients most commonly perish in the ICU.4,12,18
  • In the hemodynamically unstable patient, perform an EKG + bedside US.
    • Hemodynamic instability in the setting of an ILD exacerbation results from progressive hypercapnia and subsequent hypoxia with cardiovascular collapse.
  • In the stable patient, elicit a thorough history – patients with IPF, IPF associated with a connective tissue disease, chronic hypersensitivity pneumonitis, desquamative interstitial pneumonia, and asbestosis may experience acute exacerbations.4
  • Initiate an evaluation to rule out cardiac pathology, pulmonary infection, aspiration, pulmonary embolism, and medication effect.
  • If the aforementioned evaluation identifies an ALI without etiology => presume ILD exacerbation, initiate broad-spectrum antibiotics, consult pulmonology, and admit to the ICU.
  • HRCT is a great chest imaging modality, but if concerned for PE, obtain CTPA.


References / Further Reading

  1. Mikolasch T, Garthwaite H, Porter J. Update in diagnosis and management of interstitial lung disease. Clin Med. 2016; 16(Suppl 6):s71-s78.
  2. Raghu G, Nyberg F, Morgan G. The epidemiology of interstitial lung disease and its association with lung cancer. Br J Cancer. 2004; 91(Suppl2): S3-S10.
  3. Lacamera P. Interstitial Lung Disease. Ferri’s Clinical Advisor 2017. p.690-692. Elsevier, Philadelphia, PA.
  4. Kim R, Meyer K. Therapies for interstitial lung disease: past, present and future. Ther Adv Respir Dis. 2008; 2(5):319-338.
  5. Churg A, Wright J, Tazelaar H. Acute exacerbations of fibrotic interstitial lung disease. Histopathology. 2011; 58(4):525-530.
  6. Wilcox S, Kabrhel C, Channick R. Pulmonary hypertension and right ventricular failure in emergency medicine. Ann Emerg Med. 2015 66(6):619-628.
  7. Coultas D, Zumwalt R, Black W, Sobonya R. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med. 1994; 150:967-972.
  8. Coultas D, Hughes M. Accuracy of mortality dat for interstitial lung diseases in New Mexico, USA. Thorax. 1996; 51:717-720.
  9. Weycker D, Oster G, Edelsberg J, Bradford W, Happel D, et al. Economic costs of idiopathic pulmonary fibrosis. Chest. 2002;122:150S.
  10. Disayabutr S, Calfee C, Collard H, Wolters P. Interstitial lung diseases in the hospitalized patient. BMC Med. 2015; 13:245.
  11. Collard H, Moore B, Flaherty K, Brown K, Kaner R, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007:176:636-643.
  12. Kubo H, Nakayama K, Yanai, Suzuki T, Yamaya M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest. 2005; 128(3): 1475-1482.
  13. Kim D, Park J, Park B, Lee J, Nicholson A, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J. 2006; 27(1):143-150.
  14. Vianello A, Arcaro G, Battistella L, Pipitone E, Vio S, et al. Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis. J Crit Care. 2014; 29(4):562-567.
  15. Yokoyama T, Kondoh Y, Taniguichi H, Kataoka K, Kato K, et al. Noninvasive ventilation in acute exacerbation of idiopathic pulmonary fibrosis. Intern Med. 2010; 49(15):1509-1514.
  16. Nava S, Rubini F. Lung and chest wall mechanics in ventilated patients with end stage idiopathic pulmonary fibrosis. Thorax. 1999; 54(5):390-395.
  1. Fernandez-Perez E, Yilmaz M, Jenad H, Daniels C, Ryu J, Hubmayr R, et al. Ventilator settings and outcome of respiratory failure in chronic interstitial lung disease. Chest. 2008; 133:1113-1119.
  2. Blivet S, Philit F, Sab J, Langevin B, Paret M, Gueri C, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001; 1(20):209-212.
  3. Papiris S, Manali E, Kolilekas L, Kagouridis K, Triantafillidou C, et al. Clinical review: idiopathic pulmonary fibrosis acute exacerbations – unravelling Ariadne’s thread. Crit Care. 2010; 14(6):246.
  4. Voelkel N, Quaife R, Leinwand L, et al. Right ventricular function and failure.  Circulation 2006; 114: 1883-1891.
  5. Sprunger D, Olson A, Huie T, Fernandez-Perez E, Fischer A, et al. Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease. Eur Respir J. 2012; 39(1):125-132.
  6. Fujimoto K, Taniguchi H, Johkoh T, Kondoh Y, Ichikado K, et al. Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol. 2012. 22:83-92.
  7. Tan RT, Kuzo R, Goodman LR, et al. Utility of CT scan evaluation for predicting 
pulmonary hypertension in patients with parenchymal lung disease. Medical 
College of Wisconsin Lung Transplant Group. Chest 1998;113:1250-1256.

Controversies of Thrombolytics for Pulmonary Embolism

Author: Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Jamie Santistevan, MD (@Jamie_Rae_EMdoc, EM Resident, University of Wisconsin) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Screen Shot 2016-05-24 at 2.18.18 PM

Pulmonary embolism (PE) is a disease with significant morbidity and mortality, with an annual incidence of 100,000 cases in the U.S. which increases with age, from 1 per 1500 in early life to 1 in 300 per year above age 80 years.1,2 As providers know, the clinical presentation varies, with up to 25% of patients experiencing sudden death, while other patients with large thrombus burden experiencing few symptoms.3

The American Heart Association (AHA) and European Society of Cardiology (ESC) classify acute pulmonary embolism into three different categories: non-massive, submassive, and massive. Acute management and treatment is based on the patient, vital signs, and signs of clinical shock/instability. 4,5 Mortality for PE can reach 17% in the first three months,6 but rates of mortality in massive PE reach 30-50%.7,8 Increased mortality is seen in patients older than 70 years and those with congestive heart failure, chronic obstructive pulmonary disease, cancer, presence of one lung, hypotension, tachypnea, hypoxia, altered mental status, renal failure, prior cerebrovascular accident (CVA), right ventricular (RV) dysfunction, and elevated cardiac biomarkers.9-17

The benefits of thrombolysis is established for massive pulmonary embolism,18 but the use of thrombolytics for submassive PE is controversial in the literature due to different definitions of submassive PE, different outcomes and definitions of benefit, and the risk of life threatening hemorrhage. Thrombolytic use may reduce intravascular thrombus size and pulmonary resistance; however, there is risk of major bleeding, including intracerebral hemorrhage (ICH). Thus, the conundrum for physicians and patients.

Definitions of PE: Massive and Submassive

The definitions for massive PE, submassive PE, and nonmassive PE are shown in Table 1. 5,19 Unfortunately, many guidelines classify acute PE using different nomenclature including non-massive or low-risk, submassive or moderate/intermediate-risk, and massive or high-risk. We will use non-massive, submassive, and massive for classification of PE in this post.

Table 1 – PE Definitions and Criteria4,5,19,23

Type of PE Definition
Massive Pulselessness, persistent bradycardia with rate less than 40 bpm, and signs of shock or sustained hypotension.

–       Sustained hypotension includes SBP <90 mm Hg for >15 minutes, SBP of <100 mm Hg in a patient with a history of hypertension, or a >40% reduction in baseline SBP. Decrease in blood pressure must not be due to arrhythmia, hypovolemia, sepsis, or left ventricular (LV) dysfunction.


Submassive Normal or near-normal systolic blood pressure (SBP > 90 mm Hg) with evidence of cardiopulmonary stress including RV dysfunction or myocardial necrosis.

–       Defined by RV dilatation on echo (RV diameter divided by LV diameter greater than 0.9), RV systolic dysfunction on echo, BNP > 90 pg/mL, N-terminal pro-BNP >500 pg/mL, or ECG changes (new right bundle-branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion).

–       Myocardial necrosis is defined by elevation in troponin I or T over laboratory normal value or above the patient’s baseline.

Nonmassive No signs of clinical instability, hemodynamic compromise, or RV strain (US or biomarkers).


Submassive PE accounts for approximately 20% of all PE. Though mortality is 5%, morbidity can be severe, with increased risk of pulmonary hypertension, impaired quality of life, persistent RV dysfunction, and recurrent thrombus formation.17-19

Current Guidelines

There are several guidelines for thrombolytic use in PE from the American Heart Association (AHA), The American College of Chest Physicians (ACCP), European Heart Association (EHA), and The American College of Emergency Physicians (ACEP), which are summarized in Table 2.4,5,19,23

Table 2 – Thrombolytic use in submassive and massive PE4,5,19,23

Guideline Submassive PE Massive PE
American Heart Association (AHA) Fibrinolysis may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and low risk of bleeding complications (Class IIb; Level of Evidence C). Fibrinolysis is reasonable for patients with massive acute PE and acceptable risk of bleeding complications (Class IIa; Level of Evidence B).
The American College of Chest Physicians (ACCP) In the majority of patients with acute PE and no hypotension, no thrombolytics should be given (Grade 1B).


In patients with acute PE, SBP < 90mmHg, and low to moderate risk of bleeding, thrombolytic therapy is recommended (Grade 2B).


Thrombolytic therapy is recommended for patients with acute PE who decompensate after starting anticoagulation and have low bleeding risk (Grade 2C).


European Heart Association (EHA) Routine use of thrombolysis in non-high-risk patients is not recommended, but may be considered in selected patients with intermediate-risk PE and after thorough consideration of conditions increasing the risk of bleeding. Thrombolytic therapy is the first-line treatment in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension, with very few absolute contraindications.
The American College of Emergency Physicians (ACEP) At this time, there is insufficient evidence to make any recommendations regarding use of thrombolytics in any subgroup of hemodynamically stable patients. Thrombolytics have been demonstrated to result in faster improvements in right ventricular function and pulmonary perfusion, but these benefits have not translated to improvements in mortality.


Administer thrombolytic therapy in hemodynamically unstable patients with confirmed PE for whom the benefits of treatment outweigh the risks of life-threatening bleeding complications.* (Level B)

Consider thrombolytic therapy in hemodynamically unstable patients with a high clinical suspicion for PE for whom the diagnosis of PE cannot be confirmed in a timely manner. (Level C)

*In centers with the capability for surgical or mechanical thrombectomy, procedural intervention may be used as an alternative therapy.



Thrombolytics include alteplase, tenecteplase, and streptokinase. Before providing a thrombolytic medication, review the contradictions and discontinue heparin. Contraindications include prior intracranial hemorrhage (ICH), known structural intracranial cerebrovascular disease, suspected aortic dissection, known malignant intracranial neoplasm, ischemic stroke within three months, recent surgery encroaching on the brain or spinal cord, and recent closed-head or facial trauma with fracture or intracerebral injury.

Alteplase can be given as a full bolus at 10mg IV, followed by 90mg IV over 2 hours for patients greater than 65kg. For patients less than 65kg, adjust dosing so the medication does not exceed 1.5mg/kg. Half dose treatment can also be used, with alteplase given at 50mg IV bolus. Tenecteplase is dosed as a bolus, but it is not FDA approved for PE. Dosing for tenecteplase is weight-adjusted, with an IV bolus of 30-50mg over 5 seconds with a 5mg increase every 10kg from 60kg to 90kg.4,5

PE and Cardiac Arrest – Thrombolytics

Patients with cardiac arrest provide an opportunity for bedside ultrasound (US) if suspecting PE. Evaluation of RV size and function is vital in these circumstances. If findings on US are consistent with PE such as RV dysfunction and/or enlargement, consideration should be given for systemic thrombolysis, catheter-directed thrombolysis, or surgical embolectomy. Cardiothoracic surgery should be consulted.4,5,28,29

Massive PE – Thrombolytics

Thrombolysis is recommended for massive PE, as well as for patients undergoing cardiopulmonary resuscitation with US evidence of massive PE. Most guidelines state thrombolysis in patients with hemodynamic instability and massive PE is acceptable.4,5,19,23 A meta-analysis including 154 patients with massive PE found thrombolysis decreased the risk of death and recurrent PE from 19% to 9.4%, with an odds ratio of 0.45 (95% CI 0.22 to 0.9).5 For massive PE, the NNT to prevent recurrent PE or death with thrombolysis was found to be 10. The number needed to harm (NNH) was 8, however.31 A separate study by Thabut et al. estimated the number needed to harm to be 17.32

Submassive PE – Thrombolytics

Several recent studies and meta-analyses have evaluated the use of thrombolytics in submassive PE. Of note, these studies vary in their outcomes and definitions for PE.31,32 The MAPPET-3 trial in 2002 was a double blinded, randomized clinical trial including 256 patients with PE and pulmonary hypertension or RV dysfunction, but otherwise stable. Patients were given heparin with 100mg of alteplase or heparin and placebo, with a primary end point of in-hospital death or clinical deterioration. No difference was found for mortality, but for patients treated with heparin alone, more cases of deterioration were found (24.6% compared to 10.2%, P=0.004). No change in bleeding was found between groups.33

The MOPPET trial in 2013 was a single center, unblinded randomized trial with 121 patients with PE, but this study differs in that it used half dose thrombolytics. This study is arguably the best supporter of thrombolytic use in PE. These patients had RV dysfunction, and these patients demonstrated greater rates of tachypnea, hypoxia, and tachycardia, potential signs of clinical decompensation. The moderate-risk PE patients were defined as > 70% thrombus in the lobar or main pulmonary arteries (by computed tomographic pulmonary angiography), rather than using biomarkers or RV dysfunction. The investigators used moderate-risk PE, instead of submassive PE. However, these patients had smaller incidence of RV enlargement (21%) and RV dysfunction (6%). The interventional group received thrombolytics at half dose, or 50mg alteplase, rather than full dose. The investigators used an anatomical definition of submassive PE based on the extent of thrombus. The primary outcome of pulmonary hypertension, as defined by echocardiography at 28 months, was decreased in the thrombolytic group (16% of patients vs. 57%, P < 0.001, NNT 2). No bleeding was found in either group, which brings in to question the quality of data collection. Unfortunately no functional outcome was assessed, and no short-term outcomes were evaluated. This 41% difference in the primary endpoint is suspicious due to use of surrogate outcomes, rather than direct patient outcome. The investigators did not use symptoms plus echocardiographic findings, but echocardiographic findings alone. Evaluating pulmonary hypertension may reflect quality of life and exercise tolerance, but this is not for certain.34

The PEITHO trial is the largest double-blinded multicenter randomized control trial to date on submassive PE with 1006 patients which included patients with confirmed PE, abnormal RV on echocardiography or CT, and a positive troponin. Patients were randomized to heparin and placebo versus heparin plus weight-based tenecteplase bolus. The primary endpoint included death or hemodynamic collapse after 7 days, which was reduced in the thrombolytic group (2.6% vs. 5.6%, OR 0.44, 95% CI 0.23-0.87, P=0.02), but with an overall difference in hemorrhage of 9% between the groups. Those given thrombolytics also displayed 2% greater incidence of ICH. Major bleeding risk was greatly increased in patients over 75 years.35

The TOPCOAT trial evaluated 83 patients with submassive PE randomized to tenecteplase with heparin or placebo with heparin. A short-term endpoint of death, need for intubation, or surgical thrombectomy was evaluated at 5 days, and the patients returned at 6 weeks for repeat echocardiogram and 6 minute walk test. Patient perception of wellness was measured. Thrombolytic use was associated with higher probability of favorable composite outcome. At three months, composite outcomes of recurrent PE or poor functional capacity of SF 36 score were assessed. Unfortunately, the only independent variable in the study statistically significant was self-assessment of health at 90 days using SF-36 (a survey used for a variety of disease endpoints).36

Several meta-analyses have evaluated thrombolytic use in submassive PE. These meta-analyses have included the prior mentioned studies. Chatterjee in JAMA evaluated mortality benefits and bleeding risks in hemodynamically stable patients with RV dysfunction receiving thrombolysis. The analysis evaluated 2115 patients, finding a number need to harm (NNH) of 18 for major bleeding, which was not significant for patients less than 65 years, with a number needed to treat (NNT) of 59 for all-cause mortality benefit. The absolute risk reduction for mortality was 1.12%. The included studies have significant heterogeneity with varying definitions of instability, bleeding, RV dysfunction, and medication dosing.37 Nakamura et al. conducted a meta-analysis of 6 studies with 1510 patients, finding a larger absolute risk difference for death of 1.6% (not significant).38 The Cochrane database conducted a systematic review of 18 studies with 2197 patients, but the researchers state the low quality of evidence, large heterogeneity, and significant bias limits providers. Thrombolytics were associated with reduced odds of death (OR 0.57 with 95% CI 0.29-0.89), and higher rates of major and minor bleeding (OR 2.90 with 95% CI 1.95-4.31).39

A fourth meta-analysis found a significant mortality difference for patients given thrombolytics, which disappeared when the massive PE patients were removed from analysis. A significant increase in rates of major bleeding was found in the thrombolytic group.40 One meta-analysis evaluated thrombolytics versus anticoagulation in 1247 patients with submassive PE. This study found a significant reduction in recurrent PE or death (OR 0.37, 95% CI 0.21-0.66), with a significant increase in non-major bleeding (OR 4.12, 95% CI 2.37-7.17). However, major bleeding was not increased.41 All of these meta-analyses include studies with significant heterogeneity and differing definitions of submassive PE.

Catheter-Directed Treatment

Catheter-directed thrombolysis utilizes a catheter to direct thrombolytics with ultrasound assistance. A 2014 industry-sponsored study evaluated 59 patients with acute PE and RV enlargement based on echocardiogram, with patients randomized to ultrasound-directed thrombolytic with unfractionated heparin and heparin alone. RV dilatation at 24 hours was improved in the catheter-directed thrombolytic group. No bleeding complications were found in the intervention group. 28 The SEATTLE II trial was a multicenter, single-arm trial which evaluated US-facilitated, catheter-directed, low-dose thrombolysis. Investigators included 31 patients with massive PE and 119 patients with submassive PE. Treatment decreased RV dilatation, reduced pulmonary hypertension, decreased clot burden, and minimized risk of ICH. One patient suffered major bleeding with a groin hematoma and transient hypotension. 29

What should the emergency physician do?

For the patient with massive PE, the AHA, ACCP, EHA, and ACEP recommend thrombolytics.4,5,19,23 Literature supports thrombolytic use in the patient with submassive PE to reduce long-term pulmonary hypertension, but increased bleeding risk is present.

TOPCOAT and MOPPET demonstrate a benefit in long-term outcomes when using thrombolytics in patients with submassive PE. The question is whether the benefits provided to the patient outweigh the risk of major bleeding, specifically ICH at 2%. Studies have utilized different primary outcomes, so how patients may truly benefit is uncertain, except for long-term pulmonary hypertension.34,36 Patients with no prior lung disease and ample pulmonary reserve may show little benefit with thrombolytics, while the patient with conditions such as heart failure or obstructive lung disease may have greater benefit but at the same time increased risk for bleeding with thrombolytics, as demonstrated in the PEITHO trial.35 The trials also utilize differing protocols and doses. The risk of utilizing thrombolytics is major bleeding, particularly ICH. PEITHO demonstrated a bleeding rate of 11.5% with full dose tenecteplase, compared to 2.4% in the heparin alone group. However, this trial utilized heparin drips targeting aPTT levels of 2-2.5 times the upper limit of normal with full dose thrombolytics.35 The JAMA meta-analysis found a NNH of 18 for major bleeding (increased risk in those over 65).37 No increased risk of bleeding was present in patients less than 65 years.33-41

Shared Decision-Making

In submassive PE, the benefits and risks of bleeding should be discussed in a shared decision-making model with the patient, family, and admitting team, with thrombolytics considered on a case-by-case basis. The AHA, EHA, and ACCP support thrombolytics in patients with submassive PE and low bleeding risk.4,5,19

1) Patient factors including comorbidities, age, medications, and independence/functional ability must be taken into account. Patients over 65 years of age or with significant comorbidities have significant increased bleeding risk compared to younger patients.

2) The absence of contraindications must be ensured.

3) The entire picture including clinical course, ultrasound, biomarkers (troponin and BNP), and CT results should be considered.

4) Clinical decompensation including hypoxia, worsening tachypnea or tachycardia, and even brief episodes of hypotension requires consideration of thrombolysis.

If the patient is a thrombolytic candidate with bleeding risk, using half dose thrombolytics while discontinuing anticoagulation can demonstrate improved long-term functional outcomes, with lower risk of bleeding. If thrombolytics at a one-time half dose is not sufficient, a second similar dose can be provided while observing the patient for clinical improvement or decline. Starting anticoagulation after a period of observation for bleeding and decompensation may reduce bleeding.42

Catheter-directed treatments provide a separate avenue for management. With an extremely low risk of major bleeding, these agents are optimal first line treatment options, especially in patients with increased risk of bleeding (such as patients over 65 years of age), patients with clinical decompensation, and in patients who fail to improve with initial thrombolytics.28,29,43


– Submassive PE presents a challenge for physicians. Current literature including meta-analyses have inconsistent definitions of submassive PE, lack functional outcomes, have differing primary outcomes and assessments, and use different treatment protocols with thrombolytics and anticoagulation agents.

– Support exists for improvement in long-term outcomes with thrombolytics, with increased risk of major bleeding in high-risk patients.

– The risks and benefits of thrombolytic treatment should be considered on a case-by-case basis.

Shared decision-making with the patient discussing the risks and benefits of treatment is recommended.

– Further studies that assess risk stratification, functional outcomes, and treatment protocols with thrombolytic dosing are needed.


References/Further Reading:

  1. Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004 Jul;117(1):19-25.
  2. Heit JA. The epidemiology of venous thromboembolism in the community: implications for prevention and management. J Thromb Haemost 2006 Feb;21(1):23-29.
  3. Lucena J, Rico A, Vázquez R, Marín R, Martínez C, Salguero M, Miguel L. Pulmonary embolism and sudden-unexpected death: prospective study on 2477 forensic autopsies performed at the Institute of Legal Medicine in Seville. J Forensic Leg Med 2009 May;16(4):196-201.
  4. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:2276-2315.
  5. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123:1788-1830.
  6. Brembilla-Perrot B, Miljoen H, Houriez P, Beurrier D, Nippert M, Vançon AC, de la Chaise AT, Louis P, Mock L, Sadoul N, Andronache M. Causes and prognosis of cardiac arrest in a population admitted to a general hospital; a diagnostic and therapeutic problem. Resuscitation 2003;58:319-327.
  7. Torbicki A, Gali N, Covezzoli A, et al. Right heart thrombi in pulmonary embolism. Results from the International Cooperative Pulmonary Embolism Registry. J Am Coll Cardiol 2003;41:2245- 2251.
  8. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17(4):259.
  9. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-1389.
  10. Konstantinides S, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism. Results of a multicenter registry. Circulation 1997;96:882-888.
  11. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism. A meta-analysis. Circulation 2007;116:427-433.
  12. Kucher N, Wallmann D, Carone A, et al. Incremental prognostic value of troponin I and echocardiography in patients with acute pulmonary embolism. Eur Heart J 2003;24:1651-1656.
  13. Aujesky D, Obrosky S, Stone RA, et al. A prediction rule to identify low-risk patients with pulmonary embolism. Arch Intern Med 2006;166:169-175.
  14. Jimenez D, Uresandi F, Otero R, et al. Troponin-based risk stratification of patients with acute nonmassive pulmonary embolism. Systematic review and metaanalysis. Chest 2009;136:974-982.
  15. Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest 2004;125:1539-1545.
  16. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism. A systematic review and meta-analysis. Am J Respir Crit Care Med 2008;178:425-430.
  17. Stein PD, Matta F, Janjua M, et al. Outcome in stable patients with acute pulmonary embolism who had right ventricular enlargement and/or elevated levels of troponin I. Am J Cardiol 2010;106:558-563.
  18. Bailén MR, Cuadra JA, Aguayo De Hoyos E. Thrombolysis during cardiopulmonary resuscitation in fulminant pulmonary embolism: a review. Crit Care Med 2001;29:2211-2219.
  19. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bournameaux H, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149(2):315-352.
  20. Kuo WT, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009;20(11):1431-1440.
  21. Engelberger RP, Kucher N. Catheter-based reperfusion treatment of pulmonary embolism. Circulation 2011;124(19):2139-2144.
  22. Kucher N, Boekstegers P, Müller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Müller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Härtel D, Grünwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129(4):479-486.
  23. Fesmire FM, Brown MD, Espinosa JA, Shih RD, Slivers SM, Wolf SJ, Decker WW. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med 2011;57:628-652.
  24. Rudd KM, Phillips EL. New oral anticoagulants in the treatment of pulmonary embolism: efficacy, bleeding risk, and monitoring. Thrombosis 2013;2013:973710.
  25. Becattini C, Vedovati MC, Agnelli G. Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: a review of the literature. Thromb Res 2012 Mar;129(3):392-400.
  26. Lanitis T, Hamilton M, Quon P, Browne C, Masseria C, Cohen AT. Cost-Effectiveness of Apixaban Compared to Low Molecular Weight Heparin/ Edoxaban for Treatment and Prevention of Recurrent Venous Thromboembolism. Value Health 2015 Nov;18(7):A375-6.
  27. Hernandez C, Shuler K, Hannan H, Sonyika C, Likourezos A, Marshall J. CAUSE: cardiac arrest ultra-sound exam—a better approach to managing patients in primary non-arrhythmogenic cardiac arrest. Resuscitation 2008 Feb;76(2):198-206.
  28. Borloz MP, Frohna WJ, Phillips CA, Antonis MS. “Emergency department focused bedside echocardiography in massive pulmonary embolism.” J Emerg Med 2011 Dec;41(6):658-660.
  29. Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. The SEATTLE II Study. J Am Coll Cardiol Intv 2015;8:1382.
  30. Stein PD, Alnas M, Beemath A, Patel NR. Outcome of pulmonary embolectomy. Am J Cardiol 2007 Feb;99(3):421-3.
  31. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004 Aug 10;110(6):744-9.
  32. Thabut G, Thabut D, Myers RP, Bernard-Chabert B, Marrash-Chahla R, Mal H, Fournier M. Thrombolytic therapy of pulmonary embolism: a meta-analysis. J Am Coll Cardiol 2002 Nov;40(9):1660–1667.
  33. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002 Oct;347(15):1143-50.
  34. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol 2013 Jan 15;111(2):273-7.
  35. Meyer G, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014 Apr 10;370(15):1402-11.
  36. Kline JA, Nordenholz KE, Courtney DM, Kabrhel C, Jones AE, Rondina MT, Diercks DB, Klinger JR, Hernandez J. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost 2014 Apr;12(4):459-68.
  37. Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, Kumbhani DJ, Mukherjee D, Jaff MR, Giri J. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014 Jun 18;311(23):2414-21.
  38. Nakamura S, Takano H, Kubota Y, Asai K, Shimizu W. Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis. J Thromb Haemost 2014 Jul;12(7):1086-95.
  39. Hao Q, Dong BR, Yue J, et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev 2015 Sep 30;9:CD004437.
  40. Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2015 Mar 7;36(10):605-614.
  41. Chen H, Ren C, Chen H. Thrombolysis versus anticoagulation for the initial treatment of moderate pulmonary embolism: a meta-analysis of randomized controlled trials. Respir Care 2014 Dec;59(12):1880-7.
  42. Zhang Z, Zhai ZG, Liang LR, Liu FF, Yang YH, Wang C. Lower dosage of recombinant tissue-type plasminogen activator (rt-PA) in the treatment of acute pulmonary embolism: a systematic review and meta-analysis. Thromb Res 2014 Mar;133(3):357-63.
  43. Stein PD, Matta F, Steinberger DS, Keyes DC. Intracerebral hemorrhage with thrombolytic therapy for acute pulmonary embolism. Am J Med 2012 Jan;125(1):50-6