SD is defined as unexpected natural death from a cardiac cause (coronary disease, hypertrophic cardiomyopathy, valvular disease, no structural abnormalities)23) or non-cardiac cause (respiratory, cerebral, drug overdose, exsanguination, metabolic, sepsis, near drowning hypothermia trauma)24) that occurs within a short time interval (generally within 1 hour of onset of symptoms) in patients with no prior potentially-fatal condition.25)26)27). Most victims (>90%) have underlying cardiac abnormality.28) The most frequent cause of SD is coronary disease (80% of cases) with the risk of sudden cardiac death (SCD) being higher in men than in women and it increases with age due to the higher prevalence of coronary artery disease (CAD) in older individuals. Only a small percentage of patients show no structural abnormalities.29)30) The incidence of SD in the United States is 1 person per 1,000/year with SD being the initial clinical manifestation in 25–30% of patients with PE, and it accounts for approximately 1.3% of the total deaths in western countries.31)32) Seventy-five percent of SD cases include overweight/obese patients with 31% of these patients having history of psychiatric disorders in pharmacological treatment, supporting the recently-reported association between mental disorders and PE risk.33)34)35) The percentage of clinically unsuspected PE causing in-hospital SD has been reported to be as high as 50% to 80%.36)37) SD due to PE can occur in the presence of ACS, developing ventricular arrhythmia, or during non-shockable rhythm. Recently, Bougouin et al.35) showed in a large population-based registry that PE-related SCA is not rare, accounting for 3% of all SCA patients admitted in hospital alive. Moreover, this study highlighted that PE-related SCA should be suspected in cases of non-shockable rhythm, in women, and in those with prior thrombo-embolism.38) The cause of cardiac arrest is not easily recognized, especially when the initial rhythm is different from ventricular fibrillation; in the majority of cases, the mechanism of cardiac arrest in massive PE is pulseless electrical activity (PEA) (a syndrome characterized by the absence of a palpable pulse in an unconscious patient with organized electrical activity).

Non-cardiogenic pulmonary edema or ARDS occurs in a wide variety of clinical settings, such as hypovolemic shock, major trauma, and septicemia; it was described as a complication of classic PE by Windebank and Moran in 1973, although in this instance no pulmonary capillary wedge pressures were obtained. In 1982, Adrian et al. documented PE in patients with pulmonary edema while performing right heart catheterisation that showed normal post-capillary pressure, therefore excluding left ventricular (LV) failure as a cause of the pulmonary edema; moreover, the finding of pulmonary edema confined to unobstructed portions of the pulmonary capillary bed confirmed the diagnosis.

It has been proposed that the release of vasoactive substances from clots may lead directly to increased capillary permeability or to venous constriction and increased capillary hydrostatic pressure; in addition, it is possible that fibrin micro-emboli may injure pulmonary capillaries. All these possibilities may, of course, produce edema downstream of the obstruction. Another mechanism proposed has been a mal-distribution of blood flow causing some areas of a lung to be over-perfused, resulting in interstitial and alveolar edema.39)

In blood gas analysis, hypoxemia is considered a typical finding of APE, but up to 40% of these patients have normal arterial oxygen saturation and 20% have a normal alveolar-arterial oxygen gradient.40)41) However, when hypoxemia is present during PE dyspnea is the first symptom of respiratory failure as a consequence of hemodynamic disturbances. Hemodynamic disturbance includes low cardiac output resulting in desaturation of the mixed venous blood flow that together with areas of reduced flow (due to obstructed vessels) and areas in which flow is increased lead to ventilation-perfusion mismatch. In about one-third of patients' severe hypoxemia can be detected when right-to-left shunt (through a patent foramen oval [PFO]) is present. This is caused by an inverted pressure gradient between the right atrium and left atrium; in these clinical pictures hypocapnia is also often present. The chest X-ray is frequently abnormal, and although findings are usually non-specific in PE, they are useful for excluding other causes of dyspnea or chest pain.

The classic presentation of APE may be difficult or impossible to recognize in critically ill patients with respiratory failure. Symptoms are difficult to obtain and assess in patients who are intubated and receiving therapy with mechanical ventilation. In patients previously diagnosed with chronic obstructive pulmonary disease (COPD), the usual clinical manifestations of pulmonary emboli (symptoms, signs, chest X-ray film, electrocardiogram (ECG), and changes in arterial blood gas levels) are frequently already present due to the severe underlying pulmonary disease, and any superimposed manifestations of pulmonary emboli may not be evident. In this group, the ventilation/perfusion lung scan correlated poorly with pulmonary angiographic results and during examination at autopsy, the scan was generally insufficient to rule in or rule out pulmonary emboli. Currently, pulmonary angiography remains the only reliable technique to confirm or exclude PE.42)

PE is known to induce symptoms such as bronchial asthma therefore diagnosis of PE may be difficult if a previous history of asthma is present.43)69) However the mechanism behind bronchoconstriction in PE is not fully understood. It has been suggested that pharmacologically-active substances may be released at thrombo-embolic sites, leading to the excitation of specific chemoreflexes. Such agents include acetylcholine, histamine, serotonin, and the plasma kinins, all of which have bronchoconstrictor properties,11)12) suggesting that bronchoconstriction occurring with pulmonary emboli may be related to the presence of a substance whose activity or release is blocked by heparin, as evidence of bronchoconstriction in selected patients appears to represent an objective and sensitive, although nonspecific, index of PE.44)45)46) As discussed above, there is a broad differential diagnosis for chronic asthma. In adults, acute severe asthma is almost invariably associated with a diagnosis of chronic asthma. However, in PE, the onset of symptoms (principally breathlessness) varies from very acute (minutes) with a clear precipitant to more sluggish (days) with no clear trigger. Signs consistent with acute severe asthma include difficulty completing sentences, tachycardia, tachypnoea, and a widespread polyphonic wheeze with oxygenation often preserved, however older patients or those with more chronic disease baseline blood gas may be abnormal and this should always be considered. In order to make a differential diagnosis, routine investigations should include appropriate blood tests, 12-lead ECG, and chest X-ray to assess the presence and/or absence of an additional acute pathology (e.g. lobar pneumonia, pneumothorax) moreover an echocardiography could be performed in order to assess RV shape and function.47)

PE may be accompanied by fever and show evidence of pulmonary infiltrates at X-ray; in this case differential diagnosis from other diseases such as pneumonia is mandatory. The clinical features of pneumonia and PE are very different. PE has a more sudden onset, and the dyspnea is more prominent than cough and sputum. In addition, dyspnea-related PE has no radiological features and is not responsive to antibiotics with fever being a later phenomenon of the disease. Pneumonia, on the other hand, has a progressive onset with a more prominent cough, sputum, and fever that appears earlier. Usually chest pain is present in PE. Attention should be paid to young patients without obvious features of PE, and differentiation between pneumonia and PE should be carefully conducted in order to ensure timely diagnosis and appropriate treatment.48)

Right heart function and a hemodynamic picture play a key role in PE patient classification. The presence of hypotension is the most significant predictor of poor outcome, and defines patients with massive PE or high-risk PE. Normotensive patients with evidence of RV dysfunction, assessed by echocardiography, define the sub-massive category and are patients at intermediate risk of poor outcome.49) Shock or hypotension are present in 5–10% of PE patients with patients with myocardial injury or shock index (heart rate/systolic blood pressure [mmHg]) is >1 having the worst prognosis in which a rapid diagnosis and treatment are mandatory.50)51) A physical examination of these patients is extremely important: the jugular venous pulse is often elevated with a prominent V wave, a parasternal RV heave may be palpable. On auscultation, a tricuspidalic murmur with increased S2, and a right-sided S4 (in up to 25% of patients) may be present. In patients with RV failure, the ECG may show sinus tachycardia, signs of RV strain, re-polarization abnormalities, or ischemia including a complete or incomplete right bundle branch block with a right axis deviation (>90°) or S1Q3T3 pattern; other ECG features could be Qr in lead V1, ST elevation in V1, or pre-cordial T-wave inversions. T-wave inversions in the pre-cordial leads seems to correlate with both the severity of the PE and the presence of RV dysfunction with normalization being a sign of favorable outcome. Increased mortality has been shown in patients with AF, a low QRS voltage and premature ventricular contractions all reflecting the degree of RV failure and hemodynamic compromise.52)53)

The hemodynamic response to an APE depends on many factors, such as physiologic reaction to the vasoreactive substances released, the cardiopulmonary status of the patient at baseline and the size of the embolus and degree of pulmonary vasculature obstruction.54) A pulmonary vascular obstruction of >30% has been shown to correlate with the presence of RV dysfunction on echocardiographic examination.55)

Signs of RV dysfunction with dilation on the transthoracic echocardiogram (TTE) include: 1) a ratio of RV to LV end-diastolic diameter >1 in the apical four chamber view, or 2) an RV end diastolic diameter >30 mm and/or loss of inspiratory collapse of the inferior vena cava. In contrast to the global hypokinesis seen in PAH patients with RV failure, PE patients may exhibit sparing of the RV apex with hypokinesis of the RV free wall and base; a finding termed the “McConnell sign.” The McConnell sign has been shown to have a specificity of 94% and sensitivity of 77% for diagnosing PE56) echocardiographic examination can help in suggesting the presence of preexisting cardiopulmonary disease, such as chronic PAH.57)

Cariogenic pulmonary edema in PE patients may be due to78): 1) Occlusion of PA branch causing increased flow in the other branches causing high lung capillary pressure; and 2) compression of LV by dilated RV

Although the first scenario can be promptly diagnosed, PE in patients with pulmonary edema due to compression of LV by dilated RV can be difficult. In fact, this category of patients has a complicated clinical picture that may be impossible to solve on the basis of clinical presentation alone and without the help of technology such as echocardiography; in general, they have long standing dyspnea, bilateral pulmonary congestion at the physical examination with a dilated RV at echocardiographic examination, leading to left ventricle compression.58)59)

Chest pain pleuritic syndrome describes a scenario involving pulmonary infiltration and chest pain, where pain is correlated to breathing and to position; this clinical presentation is evidence of pulmonary infarction.60)61) with small distal emboli creating areas of alveolar hemorrhage, without hemodynamic relevance, resulting in hemoptysis, pleuritis, and pleural effusion which is usually mild.61)

PE with paradoxical embolism refers to the clinical phenomenon of thromboembolism originating in the venous vasculature and travelling through an intracardiac or pulmonary shunt into the systemic circulation.

Pulmonary hypertension and massive or sub-massive PE are the high-risk factors for paradoxical peripheral arterial embolism. PFO is the most common intracardiac shunt. The prevalence of a PFO appears to decrease with increasing age, with an incidence of 34% during the first 3 decades, 25% during the third to seventh decade, and <20% among octogenarians.79) Under physiological conditions, a pressure gradient is maintained between the left and the right atrium which results in passive closure of the PFO. In the case of increased right atrial pressure exceeding left atrial pressure, as observed at the end of Valsalva maneuvers (such as coughing, sneezing, squatting, defecation, and micturition), a transient right to left shunt may occur which may lead to presence of thrombi into the systemic circulation. A permanent increase in right-sided cardiac pressure, as observed after PE or other causes of pulmonary arterial hypertension, may result in a significant or possibly permanent right to left inter-atrial shunt, increasing the risk of paradoxical embolism.

Additional anatomical variations are also associated with PFO:

• The Eustakian valve is an embrionic remnant of the right valve of the sinus venous that in utero directs oxygenated venous blood from the inferior vena cava to the foramen ovale. The Eustakian valve gradually disappears after delivery in the majority of individuals, however residual prominent may direct venous blood to the fossa ovalis and cause significant right to left shunt in some individuals. PFO and residual prominent Eustakian valve are found to coexist (approximately 70% of cases), especially in patients with paradoxical embolism.80)

• The Chiari network, observed in 2–4% of the general population, is another embrionic remnant of the right valve of the sinus venous (in the right atrium) that results from incomplete re-absorption during embryonic heart development. It is frequently associated with PFO, right to left shunt, or an atrial septal aneurysm (ASA), all of which facilitate paradoxical embolism.

All intracardiac communication, including ventricular septal defects, have a certain risk for paradoxical embolism. By contrast patients with pulmonary arteriovenous malformations have a permanent right to left shunt, permitting the passage of thrombi or septic emboli into the systemic circulation.81)

The clinical picture resulting from intracardiac communication depends on the embolisation site, and can be associated with the following:

• AMI (STEMI): Paradoxical embolism through a PFO is the most likely cause of AMI, occurring in approximately 5/1,000 patients. While this is quite a low rate, the incidence is still high enough to warrant clinical attention especially in younger patients or in the case of RV infarction.82)83)84)

• Stroke: Cerebro-vascular accidents constitute the most frequent relevant clinical manifestations of presumed paradoxical embolism. The cause of stroke remains unidentified by routine diagnostic testing in about 40% of patients, known as the so-called cryptogenic stroke.85) PFO is increased more than 2-fold among patients with cryptogenic stroke compared with patients with conventional causes of stroke.

• Flank pain (due to acute renal infarction, flank pain with hematuria)86)

• Acute mesenteric ischemia (acute abdomen)87)

• Lower extremity embolism: cold and pulseless extremities secondary to peripheral arterial occlusion.88) Surgical thromboembolectomy efficiently reduces mortality rate compared to conservative management with thrombolysis or anticoagulation. Pulmonary hypertension and massive or sub-massive PE are the high-risk factors for paradoxical peripheral arterial embolism. For secondary prevention of paradoxical peripheral arterial embolism, combined medical therapy can result in a significant reduction of the risk of recurrent embolic events or death.89)90)

These cases demonstrate the high index of possible paradoxical emboli due to concurrent arterial and venous embolism. A correct and prompt diagnosis is extremely important and the use of echocardiographic examinations and more sensitive trans-esophageal echocardiography and transcranial doppler (TCD) sonography have a key role91) in the detection of a right to left shunt regardless of its location.

Syncope is defined as a transient loss of consciousness attributable to global cerebral hypoperfusion, further characterized by rapid onset, brevity, and spontaneous recovery. It is a common reason for arrival at the emergency department (ED), accounting for approximately 1% of attendances. In the United States, 30–40% of such patients are subsequently admitted for further investigation. The prevalence of PE among patients hospitalized for syncope is not well-documented however recent studies by Duplyakov et al.66) and the German register, Management Strategy and Prognosis of Pulmonary Embolism Registry (MAPPET) showed that the rate of syncope in patients with high-risk PE was 29.9% and 35% respectively.

Three possible mechanisms of syncope in patients with PE have been proposed:

• Syncope may be caused by thrombosis of more than 50% of the lung arterial system, which leads to a sidecrease gnicifcant decrese of cardiac output, followed by arterial hypotension and reduction of cerebral blood flow.

• A second mechanism causing syncope may be the activation of the vasovagal reflex. In 1867, von Bezold proposed the theory of cardiac depressor reflex, which was later completed by Jarisch. The essential point of the Bezold-Jarisch reflex is an activation of mechanoreceptors located in the left ventricle. In acute pulmonary thrombo-embolism, when an embolus lodges in a large branch of the PA, it may trigger a hyper-adrenergic state, resulting in an increase in the LV contractility with restriction of the diastolic filling. This could stimulate the ventricular mechanoreceptors (type C afferent fibers) involved in the Bezold-Jarisch reflex and lead to an increase in the efferent vagal response, causing a decrease in heart rate, a delay in AV conduction and a decrease in sympathetic tonus, resulting in peripheral vasodilation, and finally syncope.

• A third possible explanation is heart arrhythmias and conduction disturbances due to RV overload.

A history of syncope in patients with suspected PE should be considered as a possible criterion for the high risk of fatal complications during an in-hospital period.

Complete AV block with idioventricular rhythm can be the initial manifestation of an APE sometimes together with syncope.

In the presence of syncope during pulmonary thromboembolism due to massive embolism and Bezold-Jarisch reflex (as previously mentioned), various degrees of AV block may occur. However, complete AV block is possible in the presence of preexisting complete left bundle-branch block. In fact, in this subset of patients, complete AV-block is known to be due to the development of acute right bundle-branch block, resulting in syncope. The development of right bundle-branch block is linked to its anatomic position; in fact, the right branch of the His bundle is particularly exposed due to its superficial sub-endocardial trajectory on the RV face of the septum, and it is therefore very sensitive to a sudden distension of the right cavities.

PE is often under-diagnosed for a long time because of its atypical symptoms, and the diagnosis is made only when the clinical picture is complicated by the onset of an arrhythmia that forces the patient to go to hospital. In this case the physician finds himself faced with an arrhythmia that is the consequence of another problem that may be unrecognized,92) which is the case with AF, atrial flutter, atrial tachycardia, and PSVT.

In PE patients, clinical signs and symptoms suggesting thrombophlebitis are present in 32% of cases. However, DVT is present in 79% of cases, and if it is not present, it could mean that it has already embolized. In most patients with DVT, the clots are localized proximally with 40–50% of cases having a more complex clinical picture in which PE is present, but very often silent. Silent PE is frequent in the post-surgery phase, above all in patients without prophylaxis. APE develops 3–7 days after DVT and in 10% of cases can be fatal within 1 hour of the onset of symptoms.93)

Platypnea-orthodeoxia is a syndrome of dyspnea and hypoxia in an upright posture (desaturation SO₂), relieved by recumbence. Platypnea-orthodeoxia is also associated with PFOs with and without PE and with or without paradoxical embolism. Two conditions must coexist to cause this syndrome: an anatomical component in the form of an interatrial communication, and a functional component that produces a deformity in the atrial septum resulting in a redirection of shunt flow with the assumption of an upright posture. The former may be an atrial septal defect, a PFO, or a fenestrated ASA. The latter may be cardiac, such as pericardial effusion or constrictive pericarditis; pulmonary, such as emphysema, arteriovenous malformation, pneumonectomy, or amiodarone toxicity; abdominal, such as cirrhosis or ileus; or vascular, such as aortic aneurysm or elongation. Platypnea-orthodeoxia could be explained on the basis of positional modification of abnormal shunting. The upright position could stretch the interatrial communication (a PFO, atrial septal defect or a fenestrated ASA) allowing more streaming of venous blood from the inferior vena cava through the defect, whether or not a persistent Eustachian valve coexists. In the case of a PFO, the occurrence of PE creates higher left atrial pressure that may be one of the elements to explain the shunt and the platypnea orthodeoxia.94)

It is well known that a number of patients affected by hemodynamic stable PE are admitted to the ED presenting chest pain without further symptoms of PE, but in a few cases, the presenting symptoms are even more unusual: in fact, 2 cases of PE in young men evaluated in the ED for acute pain in the upper abdomen and showing basal pulmonary abnormalities consistent with PE92) have been described in litetrature.

Delirium, an acute confusional state, is a common, complex medical disorder associated with substantial morbidity and mortality among patients of 65 years and older. This potentially reversible cognitive disturbance is increasingly recognized as a sign of serious underlying illness. Hypoxia is a well-known precipitating factor for delirium and that PE is a common cause of hypoxia.

Therefore delirium may complicate PE in patients with other evidence of the disease. Delirium in the elderly should be regarded as an atypical presentation of PE related to the hypoxemia picture, acute ventricular impairment, hypotension, and/or paradoxical embolism that could explain this “lung-brain connection,” but the full mechanisms remain unknown.93)95)