Management of hospitalised patients with dyspnea

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ACHAIKI IATRIKI | 2023; 42(3):137–145

Review

Virginia Anagnostopoulou, Christoforos K. Travlos, Dimitrios Velissaris

Department of Internal Medicine, University General Hospital of Patras, Patras 26504, Greece

Received: 09 Mar 2023; Accepted: 14 Jul 2023

Corresponding author: Virginia Anagnostopoulou, Tel.: +30 6971958892, E-mail:  virginia.anagnostopoulou@gmail.com 

Key words: Dyspnea, hospitalized patients, management

 

Abstract

Dyspnea is one of the most common symptoms that can be presented in hospitalised patients. Its perception differs from individual to individual and can be described in many different ways. However, according to its definition, “dyspnea is a subjective experience of breathing discomfort that consists of qualitatively distinct sensation that varies in intensity” and represents a differential diagnosis problem for the clinical doctor. Its causes are variant, while the accompanying clinical signs may not be specific for the underlying condition. Thus, its diagnosis and treatment are challenging. In this review, we aim to delineate the diagnostic process and present the therapeutic options in the management of patients that are hospitalised in the Department of Internal Medicine and manifest the symptom of dyspnea. We also provide insights into the specific treatment algorithms of the most common causes of dyspnea such as pneumonia, pulmonary embolism, Chronic Obstructive Pulmonary Disease, and asthma.

INTRODUCTION

Dyspnea, also known as shortness of breath or breathlessness, represents one of the most common cardinal symptoms in patients seeking medical care both at an outpatient and at an inpatient setting. The subjective nature of dyspnea, as it is a symptom and not a clinical sign, is responsible for the different descriptions patients use to express it: “difficulty of breathing, hunger of air, like breath hold, shortness of breath etc.”. Its manifestation varies among individuals and its pathophysiology is very complex. The aetiological factors of dyspnea are based on multiple underlying physiological alterations, also on social conditions that may trigger this kind of individualised response. The spectrum of the disorders manifesting with dyspnea is very broad, with pulmonary and cardiovascular diseases taking the lion’s share [1]. The differential diagnosis may be very challenging in daily clinical practice and, thus, an extensive clinical history and a thorough clinical examination are of the greatest importance. The evaluation and management of patients with dyspnea varies, depending mainly on the clinical setting. A specific clinical approach should be followed in hospitalised patients presenting the symptom of dyspnea, as the wide range and the severity of the related co-morbidities may cause life-threatening conditions. In this review, we aim to analyse the mechanisms and the different causes of dyspnea, the clinical manifestations and the management of patients in the inpatient setting of the Department of Internal Medicine in order to shed more light in the demanding approach of the hospitalised patients with dyspnea.

Definition of dyspnea

According to the Consensus Statement of the American Thoracic Society [2], the term dyspnea is defined as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” and may be either acute or chronic. The characterisation of dyspnea as acute is “when it appears suddenly or within at most a few hours in a patient who has not previously complained of shortness of breath” and as chronic if “lasting longer than one month” [2,3]. The different sensations that patients experience and describe as dyspnea are the feeling of not enough air in inspiration, description of effort of breathing, chest tightness and inability of deep breathing [4]. The assessment of dyspnea should be evaluated by the severity of these sensations and the degree of the involved distress. Especially, in hospitalised patients, dyspnea is more likely of acute onset and its management depends mainly on the underlying cause.

PATHOPHYSIOLOGY OF DYSPNEA

Dyspnea occurs when there is a mismatch between the need for ventilation and the physical breathing. Every moment the brain assesses via the afferent receptors whether the efferent-motor commands to the ventilatory muscles are able to provoke the necessary lung movements in order to retain a normal airway pressure and air flow. If the correspondence to the motor command is not appropriate, then the dyspnea becomes more intense sending signals to the sensory cortex that are interpreted as a sensation of muscular effort and breathlessness [2,5,6].

CAUSES OF DYSPNEA

There is a wide range of conditions and diseases that can manifest with dyspnea with the following [3] being the most common ones that should be considered in differential diagnosis:

  • Upper airway obstruction: This can be caused from a foreign body into the trachea, angioedema (most related to NSAIDS, ACE inhibitors), anaphylaxis (drugs, food allergies) and laryngeal, pharyngeal inflammation (epiglottitis, tonsillitis)
  • Lower airway disorders: COPD, asthma, and aspiration (mainly due to mental status disorders, neurological dysphagia)
  • Conditions affecting the pulmonary parenchyma: pneumonia, acute respiratory distress syndrome, neoplasms (superior vena cava syndrome, pneumothorax, pleural effusion)
  • Cardiac aetiology: pulmonary embolism, aortic dissection, pulmonary hypertension, acute pulmonary oedema, acute myocardial ischaemia, acute valvular regurgitation, acute pericarditis, arrhythmias, cardiomyopathies
  • Neuromuscular diseases: Myasthenia gravis, Guillain Barre syndrome, Duchene muscular dystrophy, stroke, motor neuron disease
  • Chest wall disorders: Unstable chest, thoracic trauma
  • Anaemia
  • Metabolic acidosis
  • Sepsis
  • Psychogenic causes (anxiety)

However, during hospitalisation a patient will present most of the times the symptom of acute dyspnea, with the aetiologic causes being more specific. Acute central nervous system impairments (stroke), acute cardiac (acute coronary syndrome, pericardial effusion) and pulmonary causes (exacerbation of COPD, hospital-acquired infection, pulmonary embolism, pleural effusion) represent the most common causes of dyspnea in the inpatient setting. Other conditions, like musculoskeletal trauma (rib fracture), acute abdomen, ascites and allergic reaction may also provoke the symptom of dyspnea.

Clinical evaluation and management of hospitalised patient with dyspnea

The goal of the initial assessment of a patient with dyspnea is to recognise the characteristics of dyspnea, its type, and any accompanying symptoms. A detailed patient’s medical and social history and a thorough clinical examination can provide much information regarding the type of dyspnea (acute dyspnea or exacerbation of a chronic condition), and its individual characteristics (orthopnoea, trepopnoea, platypnoea). By this way, the severity of dyspnea and the degree of urgency are determined. Warning signs that require immediate attention must be considered carefully as the cause of dyspnea may be life-threatening for the patient. These ‘red flags’ include dyspnea that occurs out of an emotional or exercise setting, mental status alterations, accompanying tachypnoea, chest wall retractions, hypotension, chest pain, cyanosis, stridor, unstable arrhythmia [4]. Nevertheless, under any circumstances and regardless of the cause of dyspnea the following steps are required:

  1. Evaluation of patient according to ABCDE (Airway, Breathing, Circulation, Disability, Exposure)
  2. Clinical stabilisation
  3. Concomitant development of differential diagnosis algorithm for the determination of the cause of dyspnea

Clinical examination

In order to find the underlying cause of dyspnea, the thorough clinical examination is of major importance and may provide crucial findings to help in the limitation of differential diagnosis. The most important findings from clinical examination and the associated underlying cause are presented in Table 1 [7].

Relevant special investigations

Laboratory tests

A Complete Blood Count and Metabolic Panel should be done in all hospitalised patients with dyspnea. Evaluation of inflammatory markers needs to be done for exclusion of inflammation. The NT pro BNP (B-type natriuretic peptide) can be also measured to rule out heart failure as a cause of acute dyspnea, High sensitivity Cardiac troponin to rule out ACS and D-Dimers can be used to exclude pulmonary embolism (PE). However, there is evidence that its negative predictive value is poor in hospitalised patients, especially after several days of hospitalisation, or in patients >60 years of age [4].

Imaging tests

Chest radiograph is the first line imaging modality that can be used to help the attending physician to identify the cause of dyspnea in the hospitalised patient [8]. This examination may confirm the diagnosis of pneumonia, pleural effusion, pneumothorax or cardiogenic pulmonary oedema. More specific investigations like V-Q scan and computed tomography of pulmonary arteries (CTPA) are proved to be useful to rule out the diagnosis of PE. A normal V-Q scan is reliable in the exclusion of PE, while a high probability V-Q scan has a positive predictive value of over 90% for the diagnosis of PE [9].

Other diagnostic tests

The heart ultrasound can be diagnostic for conditions like acute cardiogenic pulmonary oedema, valvulopathies, pulmonary hypertension, pericardial effusion, and restrictive pericarditis, which can be manifested with dyspnea. Also, spirometry is useful in the evaluation of obstructive airway disorders.

Management

The goal in a patient with dyspnea is to treat the underlying cause and relieve his/her symptoms. The latter can be achieved by placing the patient in the most appropriate position, providing supplemental oxygen, and adopting relevant medication maneuvers. The treatment of the underlying cause is condition specific.

We provide below the management algorithms for the most common causes of dyspnea in hospitalised patients in the Department of Internal Medicine.

Pneumonia

A hospitalised patient may suffer mainly from two types of pneumonia: Hospital-acquired pneumonia and Ventilator-associated pneumonia [10].

Hospital-acquired pneumonia (HAP) is diagnosed in patients with clinical features and imaging consistent with pneumonia, occurring >48 hours after admission to the hospital and excluding any infections present at the time of admission.

Ventilator-associated pneumonia (VAP) requires clinical features concerning new pneumonia with positive respiratory samples developing >48 hours following endotracheal intubation and mechanical ventilation.

When the physician suspects that the patients may suffer from one of these types of pneumonia, the first step in management is to proceed to new imaging tests after the onset of the new symptoms. A chest radiograph is easy to obtain and can provide with evidence of parenchymal lung involvement confirming the diagnosis. However, computed tomography (CT) scan is considered the gold standard for detection of pulmonary infiltrates, but its use is limited due to the inability to be performed at the bedside.

The laboratory tests are also of great importance in establishing the diagnoses and in monitoring the progress of the disease (inflammatory marker), while microbiology test can be of tremendous value in hospitalised patients, particularly those with severe sepsis or septic shock, as determining a causative organism can significantly improve mortality.

While no severity scoring system has been well validated in patients with HAP, once the diagnosis of pneumonia is established, antibiotic treatment should be initiated without delay. In patients with HAP, empiric antibiotic treatment should be adjusted to the individual risk factors for antibiotic resistance rather than disease severity. Empiric antibiotics should cover S. aureus, Pseudomonas, and nosocomial gram-negative bacilli, based mainly on the colonisation of each Department.

Adjunctive therapies to deal with dyspnea in patients with HAP should be considered. Non-invasive positive pressure ventilation and oxygen delivered through high-flow nasal cannula (HFNC) have been studied in patients with acute respiratory failure and they have been shown to decrease intubation rates and mortality. Venturi masks and nasal oxygen can also be used as alternatives, based on patients’ clinical condition and medical history.

Hospitalised patients with impaired swallowing (chronic obstructive pulmonary disease, neurological diseases such as stroke), impaired consciousness (acute stroke, head injury, brain lesions), increased chance of gastric contents reaching the lung (reflux and tube feeding), and impaired cough reflex (medications, stroke, dementia) may develop pneumonia due to aspiration. Patients with this type of pneumonia may present with dyspnea as well. The same process with the other types of pneumonia should be followed for the diagnosis and treatment [11]

Pulmonary Embolism (PE)

PE should be considered in all patients with acute dyspnea. The most common clinical features are acute onset of dyspnea (> 75% of cases), tachycardia and tachypnoea (up to 50% of cases), sudden pleuritic chest pain (~ 20% of cases), cough and hemoptysis, and associated features of Deep Vein Thrombosis (DVT), e.g., unilaterally painful leg swelling [12,13].

The initial evaluation of patients with suspicion of PE typically includes laboratory studies, chest X-ray, electrocardiogram, blood gas, D-Dimers, CT chest, ventilation/perfusion scintigraphy (V/Q) scan and computed tomography pulmonary angiogram CTPA.

ECG

ECG related findings in patients with PE are sinus tachycardia, signs of right heart strain, SIQIIITIII-pattern, new right bundle branch block (incomplete or complete), T-wave inversion in V1–V4, atrial fibrillation.

D-Dimers

The normal value of D-dimers (Normal levels: < 500 ng/mL) has a high negative predictive value to exclude PE [14]. An increased value requires further testing as it may be present in other situations like myocardial infarction, pneumonia, sepsis, malignancies [15].

CTPA

CTPA is the most precise test for the diagnosis of acute PE in hospitalizsed patients (14). Intraluminal filling defects of pulmonary arteries are considered a direct finding of PE. Also, a wedge-shaped infarction with pleural effusion is almost pathognomonic for PE [16,17].

Ventilation/perfusion scintigraphy (V/Q scan)

V/Q scan is an alternative to CTPA in patients with contraindications for iodinated IV contrast. The absence of perfusion in normally ventilated areas of the lung (mismatch) suggests PE [14,16].

Chest x-ray

Characteristic findings at chest X ray in PE are the: [16]

Hampton hump: a wedge-shaped opacity in the peripheral lung with its base at the thoracic wall; caused by pulmonary infarction and not specific for PE

Westermark sign: an area of lung parenchyma lucency caused by oligaemia secondary to occlusion of blood flow

Normal chest X-ray in a patient with dyspnea and hypoxemia, raises the suspicion for PE.

Classification of PE

According to the American Heart Association (AHA) and American College of Chest Physicians (ACCP) guidelines PE is classified as: [18]

   – Massive PE is defined as: persistent hypotension of systolic blood pressure (SBP) < 90 mm Hg lasting >15 minutes or requiring inotropic support, pulselessness, or bradycardia < 40 beats/ minutes.

   – Sub-massive PE is: a PE without systemic hypotension (SBP >90 mm Hg) but with right ventricular (RV) dysfunction. RV dysfunction is based on either imaging (CTPA or transthoracic echocardiogram) or elevated biomarkers (BNP, NT-proBNP, or elevated troponin).

   – Low-risk PE is: an acute PE without hemodynamic instability and without RV dysfunction.

Treatment of PE

As general principles, we should provide oxygen therapy in hypoxic patients and treat PE based on severity and bleeding risk as shown in Table 2 [19-21].

Chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is characterised by airway obstruction due to inflammation of the small airways [22]. COPD begins with chronic airway inflammation that usually progresses to emphysema, a condition that is characterised by irreversible bronchial narrowing and alveolar hyperinflation. These changes cause a loss of diffusion area, which can lead to inadequate oxygen absorption and CO2 release, resulting in hypoxaemia and hypercapnia. Most affected individuals present with a combination of dyspnea and chronic cough with expectoration [23].

Clinical presentation and lung function tests are the key for the diagnosis, and typically show a decreased ratio of forced expiratory volume (FEV) to forced vital capacity (FVC). The disease severity and the extent of possible complications can be assessed by imaging studies such as chest x-ray, but they are not required to confirm the diagnosis. The patient’s oxygenation status can be assessed by aertial blood gas and pulse oximetry.

The staging system of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) should be used for the staging of patients with COPD. GOLD groups A-D are calculated based on the history of exacerbations and severity of symptoms (Table 3) [22].

Treatment

Treatment options depend on the GOLD group and mainly consist of short- and long-acting bronchodilators (beta-agonists and parasympatholytics) and glucocorticoids. Individuals with advanced disease may benefit from non-pharmacological treatment with oxygen supplementation and/or noninvasive ventilation [24].

More specifically, the treatment for each group is:

Group A: For a few symptoms and low risk of exacerbation the recommended treatment is a bronchodilator: LABA (Long-acting β2-receptor agonists) or LAMA (Long-acting muscarinic antagonists)

Group B: For many symptoms and low risk of exacerbation the recommended treatment is a bronchodilator: LABA or LAMA

Group C: For a few symptoms and high risk of exacerbation the recommended treatment is LAMA. During exacerbation LABA/Inhaled corticosteroids (ICS) is recommended

Group D: For many symptoms and high risk of exacerbation the recommended treatment is LAMA or LAMA + LABA or LABA/ICS.

Combination of LAMA + LABA is considered the best one for reduction of exacerbations.

In case of advanced disease long-term oxygen therapy (LTOT) and ventilatory support should be considered. LTOT increases survival in patients with COPD [22].

Asthma

Asthma is a chronic inflammatory disease of the respiratory system characterised by bronchial hyperresponsiveness, acute asthma exacerbations, and reversible airflow obstruction [25]. The cardinal symptoms of asthma are intermittent dyspnea, cough, and high-pitched expiratory wheeze. Symptoms remit in response to antiasthmatic medications or resolve spontaneously upon removal of the trigger.

The most common clinical features of asthma are dyspnea, orthopnoea, persistent dry cough, accessory respiratory muscles use and end-expiratory wheezes [26].

Management of a patient with asthma

The goals in the management of asthma are 1) to control the symptoms with antiasthmatic medication and adjunctive therapy, 2) to reduce the risk of exacerbations [27].

There are five levels of treatment with two “tracks” depending on the choice of reliever: ICS- formoterol (Track 1, preferred) or short-acting beta-agonists (SABA) (Track 2, alternative] [28]. All are described in Table 4.

Acute coronary syndrome (ACS)

Dyspnea can be present in patients with ACS. Supportive measures like oxygen therapy (2-4 L/min) provided with a face mask or nasal prongs should be considered in patients with severe dyspnea and signs of heart failure or shock. This support should aim to the maximum oxygen saturation rates according to the patients’ status and history. Also, pain relief medications (IV opioids) should be administered to relieve the pain and sedative drugs could be considered in agitated patients. Then the algorithm for the management of ACS should be followed [29].

Pleural effusion

Pleural effusion is often diagnosed using chest x-ray and ultrasound, but chest CT may be used for very small effusions [12]. Thoracentesis serves as both a diagnostic and therapeutic procedure: pleural fluid analysis can help identify the underlying cause and excess pleural fluid evacuation can provide symptomatic relief [30]. Treatment of pleural effusion often focuses on treating the underlying condition.

In unstable patients, e.g., those with dyspnea, respiratory failure, beginning of respiratory support should be considered along with urgent therapeutic thoracentesis [12,31].

Dyspnea in oncologic patient- Superior vena cava syndrome (SVC syndrome)

SVC syndrome is caused by the severe obstruction or occlusion of the SVC and can result in severe morbidity and mortality. Signs and symptoms of SVC syndrome are facial oedema, nonpulsatile distended neck veins, dyspnea and cough, arm oedema, syncope and headache, and confusion. Parenteral glucocorticoids and loop diuretic agents are commonly used medications in SVC syndrome to relieve symptoms. However, definitive treatment depends on the underlying condition and can include chemotherapy with or without radiotherapy, surgical bypass, or endovascular treatment such as angioplasty [32].

Dyspnea in critically-ill patients and in the context of palliative care

 Dyspnea is one of the most common symptoms in critically ill patients, mainly in patients suffering from cancer, with an estimated prevalence close to 50% [33]. Dyspnea may also be the most challenging symptom to treat than other symptoms (i.e.  pain) commonly seen in this category of hospitalised patients [34].

Several underlying mechanisms are related to the development of dyspnea in critically ill patients and the most common causes can be divided into:

  1. malignant: direct tumour effects (i.e. bronchial compression), malignant effusions (i.e. pleural, pericardial effusion) and treatment-related (i.e.  lobectomy or pneumonectomy)
  2. Non-malignant: due to comorbidities (i.e. congestive heart failure, asthma, COPD)

The management of dyspnea begins by the correction of the underlying cause. However, in the patients with refractory dyspnea and especially in the cases of irreversible causes the cornerstone of treatment is opioids. Their effectiveness has been evaluated in multiple studies [35-37].

The use of supplementary oxygen may improve dyspnea in hypoxemic patients (SaO2 < 88%) but it appears to have little benefit in dyspneic patients with normal SaO2 [38]. Nevertheless, supplementary oxygen is prescribed in the majority of dyspneic patients despite the lack of evidence.

The role of bronchodilators and increased cortisol requirements (given orally or nebulised) are always considered reasonable treatment options. Antibiotic step up is necessary in deteriorating patients with severe lung infections. Finally, in the cases of severe illness with a compromised airway settings of non-invasive and invasive ventilation are needed.

Dyspnea and compromised airway

In some cases, dyspnea may be caused by a compromised airway and then intubation may be indicated. Severe respiratory destress in situations like airway trauma with oedema, angioedema, epiglottitis, severe asthma, cystic fibrosis, lung parenchyma impairment and chest trauma, dictates urgent need for keeping airway patency. In all the aforementioned situations the goal is to prevent or to manage appropriately the respiratory failure.

Psychogenic causes of dyspnea

Some psychiatric disorders may manifest with breathlessness. Patients who experience severe anxiety feel the need for more air or they have the impression that the air in the room is not enough. Panic Attacks are another cause of dyspnea. The temporary feeling of choking is common in people who experience panic attacks. These disorders become more intense in the hospital setting, as parameters like fear, stress, and pain interfere in the psychology of the patient. Thus, psychological causes of dyspnea may be more prominent in the hospitalised patients.

CONCLUSIONS

Dyspnea is a very common symptom among hospitalised patients in the Department of Internal Medicine. Its causes are various, and the differential diagnosis may be challenging. Physician should always have in mind that they have to deal with a multifactorial condition, due to the wide range of comorbidities that requires appropriate management. The tools of patient’s history, clinical examination, and specific tests, as well as the management algorithms for each condition should be used effectively to lead to the treatment of the disorder that causes the symptom of dyspnea.

Conflict of interest: None to declare

Declaration of funding sources: None to declare

Author Contributions: VA & CKT did literature search and wrote the paper. DV wrote the paper and supervised co-authors.

REFERENCES
  1. Hauswaldt J, Blaschke S. [Dyspnea]. Internist (Berl). 2017; 58(9):925-36.
  2. Dyspnea. Mechanisms, assessment, and management: a consensus statement. American Thoracic Society. Am J Respir Crit Care Med. 1999;159(1):321-40.
  3. Rao AB, Gray D. Breathlessness in hospitalised adult patients. Postgrad Med J. 2003;79(938):681-5.
  4. Coccia CB, Palkowski GH, Schweitzer B, Motsohi T, Ntusi NA. Dyspnea : Pathophysiology and a clinical approach. S Afr Med J. 2016;106(1):32-6.
  5. Manning HL, Schwartzstein RM. Pathophysiology of dyspnea . N Engl J Med. 1995;333(23):1547-53.
  6. Nishino T. Dyspnea : underlying mechanisms and treatment. Br J Anaesth. 2011;106(4):463-74.
  7. Berliner D, Schneider N, Welte T, Bauersachs J. The Differential Diagnosis of Dyspnea. Dtsch Arztebl Int. 2016;113(49):834-45.
  8. Milos, Ruxandra-Iulia, Carmen B, Sebastian Rh, H. HB, Florian P, et al. Imaging in patients with acute dyspnea when cardiac or pulmonary origin is suspected. BJR|Open. 2023;5(1):20220026.
  9. Costello P, Gupta KB. Pulmonary embolism: imaging modalities–V/Q scan, spiral (helical) CT, and MRI. Semin Vasc Med. 2001;1(2):155-64.
  10. Lanks CW, Musani AI, Hsia DW. Community-acquired Pneumonia and Hospital-acquired Pneumonia. Med Clin North Am. 2019;103(3):487-501.
  11. Niederman MS, Cilloniz C. Aspiration pneumonia. Rev Esp Quimioter. 2022;35 Suppl 1(Suppl 1):73-7.
  12. Ron Walls RH, Marianne Gausche-Hill, Timothy Erickson, Susan Wilcox. Rosen’s Emergency Medicine: Concepts and Clinical Practice: Elsevier Health Sciences; 2022.
  13. Jana Hirmerova and Jitka Seidlerova and Zdenek C. The Prevalence of Concomitant Deep Vein Thrombosis, Symptomatic or Asymptomatic, Proximal or Distal, in Patients With Symptomatic Pulmonary Embolism. Clin Appl Thromb Hemost. 2018;24(8):1352-7.
  14. Raja AS, Greenberg JO, Qaseem A, Denberg TD, Fitterman N, Schuur JD. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015;163(9):701-11.
  15. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019;54(3):1901647.
  16. Moore AJE, Wachsmann J, Chamarthy MR, Panjikaran L, Tanabe Y, Rajiah P. Imaging of acute pulmonary embolism: an update. Cardiovasc Diagn Ther. 2018;8(3):225-43.
  17. Wilbur J, Shian B. Diagnosis of deep venous thrombosis and pulmonary embolism. Am Fam Physician. 2012;86(10):913-9.
  18. Essien EO, Rali P, Mathai SC. Pulmonary Embolism. Med Clin North Am. 2019;103(3):549-64.
  19. Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Advances. 2020;4(19):4693-738.
  20. Rivera-Lebron B, McDaniel M, Ahrar K, Alrifai A, Dudzinski DM, Fanola C, et al. Diagnosis, Treatment and Follow Up of Acute Pulmonary Embolism: Consensus Practice from the PERT Consortium. Clin Appl Thromb Hemost. 2019;25:1076029619853037.
  21. Stevens SM, Woller SC, Kreuziger LB, Bounameaux H, Doerschug K, Geersing GJ, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6):e545-e608.
  22. Global Initiative for Chronic Obstructive Lung Disease (GOLD).  Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease – 2022 Report .
  23. Macdonald G. Harrison’s Internal Medicine, 17th edition. – by A. S. Fauci, D. L. Kasper, D. L. Longo, E. Braunwald, S. L. Hauser, J. L. Jameson and J. Loscalzo. Internal Medicine Journal. 2008;38(12):932.
  24. Vogelmeier CF, Román-Rodríguez M, Singh D, Han MK, Rodríguez-Roisin R, Ferguson GT. Goals of COPD treatment: Focus on symptoms and exacerbations. Respir Med. 2020;166:105938.
  25. Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001-2010. NCHS Data Brief. 2012(94):1-8.
  26. National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, Full Report 2007. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7232/.
  27. Maselli DJ, Hardin M, Christenson SA, Hanania NA, Hersh CP, Adams SG, et al. Clinical Approach to the Therapy of Asthma-COPD Overlap. Chest. 2019;155(1):168-77.
  28. Reddel HK, Bacharier LB, Bateman ED, Brightling CE, Brusselle GG, Buhl R, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. Eur Respir J. 2022;58(1):35-51.
  29. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Jr., Ganiats TG, Holmes DR, Jr., et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228.
  30. Hooper C, Lee YC, Maskell N. Investigation of a unilateral pleural effusion in adults: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65 Suppl 2:ii4-ii17.
  31. Karkhanis VS, Joshi JM. Pleural effusion: diagnosis, treatment, and management. Open Access Emerg Med. 2012;4:31-52.
  32. Azizi AH, Shafi I, Shah N, Rosenfield K, Schainfeld R, Sista A, et al. Superior Vena Cava Syndrome. JACC Cardiovasc Interv. 2020;13(24):2896-910.
  33. Dudgeon DJ, Kristjanson L, Sloan JA, Lertzman M, Clement K. Dyspnea in cancer patients: prevalence and associated factors. J Pain Symptom Manage. 2001;21(2):95-102.
  34. Crombeen AM, Lilly EJ. Management of dyspnea in palliative care. Curr Oncol. 2020;27(3):142-5.
  35. Kamal AH, Maguire JM, Wheeler JL, Currow DC, Abernethy AP. Dyspnea review for the palliative care professional: treatment goals and therapeutic options. J Palliat Med. 2012;15(1):106-14.
  36. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of Dyspnea . Thorax. 2002;57(11):939-44.
  37. Ben-Aharon I, Gafter-Gvili A, Paul M, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea : a systematic review. J Clin Oncol. 2008;26(14):2396-2404.
  38. Abernethy AP, McDonald CF, Frith PA, Clark K, Herndon JE, 2nd, Marcello J, et al. Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory Dyspnea : a double-blind, randomised controlled trial. Lancet. 2010;376(9743):784-93.