Nonthrombotic Pulmonary Embolism (Air, Amniotic Fluid, Fat, Tumor)
What every physician needs to know
- Are you sure your patient has NTPE? What should you expect to find?
Beware: there are other diseases that can mimic NTPE.
- How and/or why did the patient develop NTPE?
- Which individuals are at greatest risk of developing NTPE?
- What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
- What imaging studies will be helpful in making or excluding the diagnosis of NTPE?
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of NTPE?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of NTPE?
- What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of NTPE?
- If you decide the patient has NTPE, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
- What other considerations exist for patients with NTPE?
What’s the evidence?
What every physician needs to know
Nonthrombotic pulmonary embolism (NTPE) is embolization to the pulmonary circulation of different cell subtypes (adipocytes, hematopoietic, amniotic, trophoblastic or tumor), bacteria, fungi, foreign material, or gas. It is less common than pulmonary thromboembolism (
Nonthrombotic pulmonary embolism (NTPE) is characterized as embolization to the pulmonary circulation of different cell types (adipocytes, haematopoietic, amniotic, trophoblastic or tumor), bacteria, fungi, foreign material or gas. (Reprinted with permission from Jorens PG et al. 2009; 34: 452-474.)
NTPEs, which are carried in the blood, embolize to the pulmonary circulation. The clinical effects and pathogenesis of NTPEs are more complex than the "simple" mechanical obstruction that occurs with pulmonary thromboembolism. Depending on the specific type of NTPE, some nonthrombotic emboli may cause severe inflammatory reactions in both the systemic and pulmonary circulation as well as in the lung itself.
NTPE presents a diagnostic challenge, as it often presents with very uncharacteristic but distinctive clinical features that are frequently overlooked. The clinical signs range from dramatic acute presentations, such as the acute respiratory distress syndrome after fat and amniotic embolism, to signs observed late in the course of the disease, such as after-tumor emboli. Paradoxical non-thrombotic emboli may also cause cerebral signs and symptoms.
NTPEs can be associated with specific imaging findings, and familiarity with these features should facilitate the diagnosis. On thin-section CT of the lungs, peculiar radiographic findings, such as a feeding vessel, the tree-in-bud pattern, or the appearance of micronodules distributed at the termination of bronchovascular bundles, may be seen in certain forms.
Pathological observations play a key role in the diagnosis, as sometimes carefully aspirated blood from the pulmonary artery (PA) or specific staining of cells recovered from bronchoalveolar (BAL) fluid are helpful in the diagnosis. Frequently, lung biopsies that reveal the severe granulomatous reaction of unfortunate post-mortem pathological investigations of pulmonary tissue are necessary to confirm the diagnosis.
Acute and chronic nonthrombotic pulmonary embolism is an underestimated cause of acute and chronic pulmonary hypertension.
NTPE frequently requires peculiar treatment options. Despite the detailed descriptions of several forms of NTPE, well-designed trials have not been performed to evaluate therapy in these patients.
Non-thrombotic pulmonary embolism (NTPE) is characterized as embolization to the pulmonary circulation of different cell types (adipocytes, hematopoietic, amniotic, thophoblastic, or tumor), bacteria, fungi, foreign material, or gas (
Fat embolism (FE)
Fat embolism is characterized by the release of fat into the systemic circulation. Fat embolism syndrome (FES) is a rare clinical consequence of FE characterized by pulmonary distress, mental status changes, and a petechial rash.
Amniotic fluid embolism (AFE)
The embolism of amniotic fluid (AF), a mixture of maternal extracellular fluid and fetal urine, squamous cells, lanugo hairs, vernix caseosa, mucin, and sometimes meconium, leads to an idiosyncratic response. The severity of symptoms of this so-called "anaphylactoid syndrome of pregnancy" is related to the host reaction to the antigenic components of the AF.
Pulmonary tumor embolism (PTUE), characterized by the occlusion of pulmonary vessels by tumor cells, is different from a true metastasis, as there is no tendency for the tumor emboli to invade the arterial wall.
Gestational trophoblastic disease (GTD)
The pathogenesis is unique because the tumor arises from fetal, not maternal, tissue.
Septic pulmonary emboli reach the lung from many sources, including thrombophlebitis and infected heart valves, catheters, and pacemaker wires.
Cystic hydatid disease
Cystic hydatid disease, or echinococcosis, is a parasitic infection caused by the larval or cyst stage of the tapeworm Echinococcus granulosus affecting the liver (75%) and lungs (15%). Embolism is caused by vesicles or cysts that mechanically obstruct the blood flow.
Particulate/foreign material embolism
Embolic particles may reach the lung after injection of foreign materials as occurs with intravenous injection of illicit drugs.
Gas embolism (venous of arterial)
Gas embolism (GE) is mainly air embolism (AE), although other gases, such as carbon dioxide, nitrous oxide, helium, and nitrogen, can also provoke these symptoms.
Are you sure your patient has NTPE? What should you expect to find?
NTPE presents a diagnostic challenge, as the condition often presents with uncharacteristic clinical signs that are frequently overlooked. These range from dramatic presentations, such as acute respiratory distress syndrome after fat and amniotic embolism, to signs observed late in the course of the disease, such as after-tumor emboli. Moreover, paradoxal embolization may cause cerebral signs and symptoms.
Fat embolism (FE) syndrome (FES)
The clinical diagnosis of FES is one of exclusion supported by laboratory and radiological investigations.
Gurd and Wilson proposed that its diagnosis could be based on the presence of at least one of three major symptoms, four of eight minor symptoms, and fat macroglobulinemia. The major signs are respiratory distress, cerebral involvement unrelated to head injury, and a petechial rash on the anterior surfaces of the neck, thorax, and mucous membranes. The minor features are tachycardia, pyrexia, retinal and urinary changes (anuria, oliguria, or fat globules), and the laboratory features anemia, thrombocytopenia, or a high erythrocyte sedimentation rate.
Sixty percent of FES cases present with major symptoms within twenty-four hours after the acute cause with a symptom-free period of at between six and twelve hours.
Three-quarters of patients develop pulmonary signs, which are frequently mild, Hypoxia, tachypnea, hemoptysis, and chest pain can be observed, and rales and ronchi may be heard. FE is one of the indirect causes of acute respiratory distress syndrome (ARDS).
Petechiae that may be observed in the axillae, the trunk, the conjuctiva, the neck, or the oropharyngeal mucosa resolve in a few days.
Central nervous system signs range from encephalopathy to coma, do not improve after correction of hypoxemia, and may even occur without pulmonary signs. The neurological signs are generally reversible.
Fundoscopic evaluation may reveal macular edema and retinal hemorrhages, and fat droplets may occasionally be detected in the retinal vessels.
Amniotic fluid embolism
The condition can neither be predicted nor prevented.
The best diagnostic criteria are: 1) currently pregnant or within 48 hours of delivery; 2) one or more of the following observations a) hypotension, b) respiratory distress, c) DIC, or d) coma and/or seizures; and 3) absence of other medical explanations for the acute and dramatic clinical course.
The presentation of AFE can vary widely: sudden onset of hypoxemia and cardiovascular collapse, the main symptoms, are often preceded by agitation, nausea, or seizures.
In 51 percent of the cases, the initial symptom is respiratory distress; in the remainder, the first signal is hypotension (27%), coagulopathy (12%), or seizures (10%). Some patients are diagnosed with pulmonary edema and ARDS later in the course of the disease.
Global encephalopathy is not uncommon, but focal cerebral ischemia rarely occurs. A majority of AFE patients develop seizures and permanent neurological dysfunction because of impaired cerebral oxygen delivery.
The most common symptom is progressive dyspnea, which occurs over a period of weeks to months, as well as pleuritic chest pain, cough, hemoptysis, and weight loss.
A typical profile includes a documented or suspected underlying malignancy, acute to subacute onset of dyspnea, and signs of cor pulmonale.
Only 8 percent of patients with pathological evidence for PTUE have documented morbidity or mortality attributable to the emboli, and the "classic" signs of right heart failure are only reported in 15-20 percent of patients.
Metastases to other organs are usually documented prior to the onset of respiratory symptoms. However, PTUE as the initial manifestation of underlying malignancy has been reported in a few cases.
Gestational trophoblastic disease (GTD)
Because of the routine use today of ultrasound and beta-hCG in the workup of early gestational abnormalities, complete molar pregnancy (the cause of GTD) rarely presents with the traditional signs.
Vaginal bleeding is the most frequent symptom.
Self-limited respiratory distress arises in 3-10 percent of patients following molar evacuation, with the number rising to 25 percent when the uterus is larger than normal based on gestational timing and the human chorionic gonadotropin level is markedly elevated.
The acute illness usually lasts 24-48 hours, typically followed by a rapid and profound clinical improvement over the following 48-96 hours.
Pulmonary trophoblastic embolism has been reported to cause sudden death.
The characteristic features are a febrile illness, cough, hemoptysis, and lung infiltrates associated with an active focus of an extrapulmonary infection.
Cystic hydatid disease
The major complication is rupture of the cyst into the pericardium, which can lead to anaphylactic shock or tamponade.
Hemoptysis is the most frequent sign, but it is, of course, aspecific.
Classification is based according to the clinical presentation: (a) acute fatal cases; (b) subacute pulmonary hypertension with death in less than a year; and (c) chronic pulmonary hypertension.
The majority of cases follow a course of prolonged pulmonary hypertension punctuated by acute embolic episodes.
In this case, the condition is caused by the intravenous (IV) injection of illicit drugs, drugs intended for oral administration, or other foreign material.
Most patients with talcum emboli (mostly in IV heroin users) are asymptomatic, although slowly progressive dyspnea, persistent cough, non-specific chest pain, anorexia, weight loss, fever, and night sweats may occur.
Lung sounds are usually normal, or they have minimal bibasal crepitations.
Embolization of the material used during therapeutic cerebral arteriovenous malformation may cause respiratory distress.
Cellulose granulomatosis can cause sudden death.
The clinical findings described in silicone embolism syndrome are very similar to those observed in FES.
Retained catheter fragments have been associated with a high rate of complications, such as arrhythmias, perforation, infection, and thrombus formation observed days to weeks after embolization.
Embolization of periprostatic seed implants after brachytherapy may be underestimated because there are usually no symptoms.
Clinical features appear to be dose-related and may progress even after drug injections have been stopped.
Multiple episodes of injection may elicit intractable pulmonary hypertension.
Gas embolism (GE)
The best diagnostic criterion is the patient's history.
The entry into the bloodstream requires a pressure gradient: when venous pressure is negative, as during spontaneous inspiration, or when the vein is located higher than the heart, gas is forced under pressure.
Venous GE presents as cough, dyspnea, tachypnea, and a hypoxemic "gasp" reflex when a substantial number of the pulmonary vessels are occluded. Arrhythmia, pulmonary hypertension, right ventricular strain, and arterial AE can develop related to shunting.
In venous embolism, the mill-wheel murmur, a splashing auscultatory sound caused by the presence of gas in the cardiac chambers and great vessels, can be auscultated.
Arterial GE causes ischemia. Hypoxemia caused by obstruction of the coronary of cerebral arteries (cerebral arterial gas embolism, or CAE) may lead to death.
Arterial embolization into the coronary arteries induces a specific drum-like or "mill-wheel" murmur and electrocardiographic changes of ischemia. Arrhythmias, cardiac failure, and arrest are all possible.
About half of patients also have some history of (temporary) altered consciousness. The absolute quantity of gas and the areas of the brain that are affected determine the wide variety of symptoms. Impaired breathing may be seen.
A delayed recovery from general anesthesia may indicate the presence of CAE.
Marbling of the skin may occur, especially in superiorly located body parts because of air buoyancy.
Defection of gas bubbles in retinal vessels and the occurrence of sharply defined areas of pallor on the tongue have been described.
Beware: there are other diseases that can mimic NTPE.
NTPE presents a formidable diagnostic challenge, as the condition often presents with unusual and peculiar clinical signs that are frequently overlooked. They range from dramatic, acute presentations, such as ARDS, to signs observed late in the course of the disease. It resembles other causes of acute and right heart failure, such as thrombotic pulmonary embolism and right cardiac infarction.
Because of similarities, the presence of both thrombotic and non-thrombotic pulmonary embolism should be suspected in patients who complain of unexplained dyspnea and who develop acute or chronic cor pulmonale.
Amniotic fluid embolism is the only subtype that mimics left heart failure.
How and/or why did the patient develop NTPE?
Embolization of bone debris and fat globules probably occurs in most patients after a pelvic or long-bone fracture, an endomedullary nailing of long-bone fractures, or placement of a knee or hip prosthesis. From 0.25 percent to 11 percent of the patients who sustain a single long-bone fracture meet the criteria of FE, and the incidence of FES is higher after several fractures. FES occurs after bone fractures of the lower extremities, less frequently with upper extremity fractures, and rarely with vertebral or rib fractures.
FE is also the leading cause of respiratory dysfunction in victims of blasts and blunt trauma.
The finding of fat cells in the pulmonary vessels at autopsy in cases of natural death is caused by resuscitative measures (
The finding of fat cells in the pulmonary vessels at autopsy in cases of natural death is caused by resuscitative measures.
Other causes of FE include hemoglobinopathies, especially sickle cell disease (SCD). Bone marrow necrosis after vessel occlusion and activation of the clotting system, which may cause FE in SCD and even severe respiratory failure, accounts for 33 percent of sudden deaths in SCD patients with lung problems.
FE has been described rarely after procedures. Both pulmonary thromboemboli and FE have been found in lethal cases after liposuction, and accidental or intentional IV lipid overdose has been described after IV injection of preparations intended for intramuscular use only and that are frequently formulated with vegetable oils.
Amniotic fluid embolism
The incidence of AFE ranges between 1 in 6,000 to 1 in 120,000 pregnancies. AFE occurs during labor but before delivery in the majority of cases and during Caesarean section in 19 percent of cases.
AFE accounts for 12 percent of all maternal deaths related to legally induced abortion, with a death-to-case rate of two per one million abortions.
AFE is not well associated with (surgical) manipulation during Caesarean section, curettage, cervical suture removal, repair of an incompetent cervix, or trans-abdominal amniocentesis, or after car or motor vehicle accidents.
In twenty-four well-documented cases of AFE occurring following (surgical) trauma, at least thirteen of these patients died directly related to AFE.
Macroscopic PTUE has been reported in many tumor types, including sarcomas and hepatocellular, breast, and renal cell carcinomas. Microscopic PTUE was found predominantly in gastric, hepatocellular, and pancreatic carcinomas and choriocarcinomas. It has also been described in patients with lung, prostate, thymic, gallbladder, bladder, colorectal, skin, or cervical cancer.
Gestational trophoblastic disease (GTD)
Trophoblastic embolism may be subclinical in normal pregnancy and more pronounced in eclampsia.
It may also occur within hours following abdominal hysterectomy for invasive moles (abnormal proliferation of trophoblastic epithelium of the placenta) and molar evacuation and as a side effect of chemotherapy for choriocarcinoma.
Septic pulmonary emboli reach the lung from many extrapulmonary sources, including infected heart valves, pacemaker wires, and septic thrombophlebitis from such sources as the tonsils; the jugular, dental or pelvic region; and infected central venous catheters.
The increasing use of catheters and prosthetic vascular devices and increasing numbers of immunocompromised patients have changed the epidemiology. SPE is currently becoming an uncommon complication of IV drug use, presumably because of improved hygiene. In children too, soft tissue infection, osteomyelitis, and IV catheters are the main risk factors.
In a series of post-mortem examinations, fungal emboli were found more frequently than bacterial emboli in patients with (hematological) malignancies.
A peculiar subtype is Lemierre's syndrome (postanginal sepsis), an anaerobic thrombophlebitis of the internal jugular vein. In cases of tonsillopharyngitis' odontogenic infection, mastoiditis, or sinusitis, the causative organisms include the anaerobic gram-negative Fusobacterium species. Lung abscesses and empyema have been reported frequently in these patients.
Cystic hydatid disease
The parasite can reach any part of the body, although the liver (75%) and lungs (15%) are the organs most commonly affected.
Hydatic PE occurs when a hydatid cyst ruptures into the right ventricle or atrium, or occasionally because of hemotogenous dissemination from a hepatic focus.
A great variety of exogenously injected or implanted materials can embolize. Some medications intended for oral administration are ground, mixed in liquid, and injected intravenously. Other substances, including talcum, starch, cellulose and cotton, may be seen in individuals who engage in IV drug abuse or parenteral injection of tablets. Similar emboli can also occur when cotton fibers remain on angiographic guide wires or catheters after they have been wiped with cotton gauze.
Catheter emboli are rare iatrogenic complications, as they usually develop after an attempt to withdraw a catheter through an introducing needle with the result that the distal potion is sheared off. Embolization of needle fragments has also been reported in IV drug abusers.
Pulmonary emboli caused by accidental or intentional IV injection of metallic mercury have been reported.
Liquid silicone, an inert material used during illegal cosmetic procedures in women and transsexual men, may embolize.
Patients with an arterio-venous malformation (AVM) who undergo endovascular treatment with any of several materials may develop pulmonary symptoms within 48 hours of the procedure because of embolization of the material.
Percutaneous vertrebroplasty is usually safe, but symptomatic pulmonary embolization of cement used during this procedure has been described.
Radioactive seed implants may detach during their guided placement in the prostate and periprostatic tissues (prostate brachytherapy and migrate into the pulmonary circulation.
The two subtypes of GE, venous and arterial, can be distinguished by the mechanism of entry and the site where the emboli lodge.
Preconditions for venous AE include a hydrostatic gradient that favors the entry of air in vessels and the incising of non-collapsed veins. Venous AE is also an iatrogenic problem during the manipulation of a central venous and hemodialysis catheter, where it has a high mortality rate.
AE is a rare complication of ventricular assist device pump dissection, ventilation-induced lung trauma, and laparoscopy that can lead to air, argon, or CO 2 embolism. Other causes include pleural lavage, the intraoperative use of hydrogen peroxide, and insufflation of air during endoscopy, laser therapy, arthroscopy, thoracotomy, non-invasive ventilation, carotid endarteriectomy, or prostatectomy.
The entry of gas into the pulmonary veins or the systemic arteries as a result of overexpansion of the lung by decompression barotrauma or a paradoxical embolism causes arterial embolism. Microbubbles that originate in extracorporeal devices but that are endogenous in cases of decompression sickness or mechanical heart valves may also cause arterial GE.
Which individuals are at greatest risk of developing NTPE?
NTPE is highly unpredictable: there are no individual risk factors.
The pathophysiology of FES remains unclear. Bone particles and fat globules are capable of physically blocking capillaries of the lung. The increase in bone marrow canal pressure during intramedullary instrumentation (e.g., nailing) can lead bone contents into the venous circulation. The use of conventional cementing techniques is associated with echocardiographic evidence of embolism in many patients.
Intraoperative prophylactic measures that limit the rise of intramedullary pressure reduce the incidence of postoperative FE.
Small fat droplets may even pass through lung capillaries and enter the systemic circulation through pulmonary or arteriovenous shunts (a patent foramen ovale).
Paradoxal cerebral FE by obstruction of brain capillaries must be considered in the diagnosis of an altered mental status after fractures or joint replacement.
Amniotic fluid embolism
Previously suggested predisposing factors, such as a large fetal size, use of oxytocics, advanced gestational age, amnioinfusion, complicated labor, or multiparity, cannot be identified conclusively.
Logistic regression has identified advanced maternal age, placental pathologies, and Caesarean deliveries in one large population-based cohort study.
What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
There are no pathognomonic laboratory tests for NTPE.
Diagnosis is facilitated by the presence of hematological and biochemical abnormalities.
An increase in the serum level of lipids is not specific, as such an increase is seen relatively often in critically ill patients, although particularly in patients who have received IV lipid emulsions (e.g., propofol, total parenteral nutrition). Hypercapnia and combined respiratory and metabolic acidosis can also be observed.
Amniotic fluid embolism
Disturbances of coagulation ranging from mild thrombocytopenia with disseminated intravascular coagulation (DIC) to isolated DIC with or without cardiopulmonary instability have been described. Isolated DIC may even be the first indication of AFE, so the Trombelastograph® test may be useful in assessing coagulopathy and guiding therapy during or after AFE.
Arterial blood gas measurements show hypoxia, hypocapnia, or an increased alveolar-arterial oxygen gradient.
Blood cultures are invaluable when evaluating a patient with suspected SPE.
Cystic hydatid disease
Serologic tests, though more specific than imaging techniques, are less sensitive, but they are useful confirmatory tests.
BAL typically reveals lymphocytosis with a predominance of CD8 lymphocytes.
The coagulation system, complement and kinines, are activated by "bubbles," but coagulopathies, which are common in animal models, are rarely observed in humans.
Possibly as a consequence of the extravascular shift of fluid into injured tissues, Hemoconcentration has been reported.
What imaging studies will be helpful in making or excluding the diagnosis of NTPE?
Thin-section CT of the lungs may show peculiar radiographic findings.
Lesions located at the end of vessels (the so-called feeding vessel-sign) have been reported in uncomplicated pulmonary emboli and pulmonary metastases but also in several subtypes of NTPE, such as septic emboli. Such lesions simply indicate the hemotogenous origin of the parenchymal nodule. Multi-detector CT is superior to the classical CT technology for detection of this feeding sign (
Two typical signs on CT for (septic) nonthrombotic embolism: cavitated subpleural nodule (white arrow) with feeding vessel in a patient with staphylococcal endocarditis (See also Figures 6 and 7.) (Reprinted with permission from Jorens PG et al. Eur Resp J 2009; 34: 452-474)
The tree-in-bud pattern consists of small centrilobular nodules of soft tissue attenuation. They are connected to multiple branching linear structures of small caliber that originate from a single stalk and are distributed at the termination of bronchovascular bundle. Originally described in cases of endobronchial spread of Mycobacterium tuberculosis, this pattern is also recognized as a radiological sign of NTPE, such as in tumor or foreign material (cellulose) emboli. These micronodules represent intra-arteriolar accumulation of the embolus with an adjacent inflammatory mostly granulomatous reaction.
Ill-defined centrilobular and subpleural (micro) nodules distributed at the termination of bronchovascular bundles may be observed in certain subtypes such as FES and septic emboli (
Hemorrhagic nodules have a characteristic, although non-specific, CT appearance that consists of a central area of soft tissue attenuation surrounded by a halo of ground glass attenuation, named the CT "halo" sign. This sign, which can be caused by several pathological processes, is found in hemorrhagic pulmonary nodules, in non-hemorrhagic inflammatory lesions, and in septic emboli.
In cerebral fat embolism, the lesions in watershed areas appear on MRI diffusion-weighted images as bright spots on a dark background, known as the "Starfield Pattern."
In the early stage, atypical, usually bilateral lung infiltrates (chest X-ray) or consolidation and ground glass opacities (CT scan) are seen.
A high incidence of relatively small (< 1 cm), ill-defined centrilobular and subpleural nodules on a CT scan have been described in the acute phase of FES. These nodules represent ischemia, alveolar edema, and microhemorrhages by the deposition of free fatty acids (FFAs). These ill-defined centrilobular nodules indicate deposition of hemosiderin-laden macrophages.
Diffuse lung calcifications located in the branches of the pulmonary arteries are described after the FES.
In patients with SCD, areas of ground-glass opacity are identified as segments with hypoperfusion. Matching defects are seen on ventilation/perfusion.
MRI and MR-spectroscopy are the most sensitive imaging techniques for cerebral emboli. MRI-T2 weighted findings show non-confluent areas of high intensity in watershed areas. On the diffusion-weighted images, these lesions appear as bright spots on a dark background, known as the "Starfield Pattern."
Cerebral microembolism can be monitored by detecting microembolic signals with transcranial Doppler.
Amniotic fluid embolism
The chest radiography can reveal diffuse bilateral homogeneous opacities. Because AFE is characterized by the absence of frank pulmonary vessel obstruction, obstruction of branches of the PA during angiography is seen only rarely. Transoesophageal echocardiography may reveal enlargement of the right ventricle and main pulmonary trunk, consistent with acute right ventricular pressure overload and failure, but also left ventricular failure in view of the depression of the left ventricular function by AF.
A normal chest radiograph with hypoxemia in a patient with a malignancy might even suggest the presence of PTUE: only one in eight patients have a parenchymal abnormality on a plain radiograph. Cardiomegaly and prominent pulmonary vasculature, the radiographic changes associated with elevated pulmonary pressures, are seen in less than half of the cases.
Subsegmental, mismatched peripheral defects can be seen on a ventilation-perfusion scan in patients with exclusively microvascular disease.
Tumor emboli are usually located in small or medium-sized arteries, so angiography, the standard for thromboembolic disease, has poor sensitivity and specificity. Pulmonary angiographic findings include delayed filling of the segmental arteries and tortuosity of the third- to fifth-order vessels.
The CT findings further include multifocal dilatation of the peripheral subsegmental arteries and signs of pulmonary infarction.
The tree-in bud pattern is commonly seen on thin-section CT of the lungs.
Gestational trophoblastic disease
Pulmonary involvement occurs in up to 80 percent of women with metastatic GTD. Radiographic findings may include alveolar, nodular, and miliary patterns; pleural effusion; and signs of pulmonary arterial occlusion.
Cystic hydatid disease
A cardiac hydatid cyst can cause complete occlusion of the PA. Rarely, an interventricular cyst ruptures via the pulmonary veins, resulting in multifocal cystic lesions of the lung.
Clinical and radiologic features at presentation are non-specific.
A chest CT and echocardiography are invaluable when evaluating a patient with suspected SPE.
TEE provides greater spatial resolution than transthoracic imaging does and is a superior method for imaging vegetations of cardiac valves, abscesses, and leaflet perforations.
Typical radiographic features include patchy air space lesions that simulate non-specific bronchopneumonia, multiple ill-defined round or wedge-shaped densities of varying sizes located peripherally, and the feeding vessel sign.
Rapid progression of the lesions to cavities or abscess formations can occur.
One study has reported that the size of the nodules in gram-positive septic emboli was larger than those in gram-negative septic emboli. Cavitation and air bronchogram in the nodules were seen more frequently in the gram-positive emboli, while a ground-glass attenuation halo around a nodule and a feeding vessel sign were more commonly observed in gram-negative emboli.
Pulmonary infarction is frequent when distal arteries are occluded. Peripheral parenchymal consolidation (wedge-shaped lesions) is then partially caused by pulmonary hemorrhage from the extravasations for the bronchial arterial flow.
Cystic hydatid disease
The diagnosis is difficult in the absence of typical clinical and radiological findings. Guided by echocardiographic findings, diagnosis is largely based on the arteriogram, which reveals segmental or lobar perfusion defects. A combined contrast-enhanced spiral CT, MRI and pulmonary magnetic resonance angiography (MRA) of the chest can be useful in evaluating complicated cardiac hydatid cysts. On enhanced CT, an intra-arterial cyst has a typical hypodense appearance.
Initially, imaging reveals several small (1 mm) nodular and reticular opacities or interstitial nodules, some of which occur in a centrilobular distribution throughout the lungs after talcum or cellulose granulomatosis. Later, homogeneous upper lobe opacities resembling massive fibrosis may be identified.
Gallium lung scans may show diffuse bilateral uptake in talcum granulomatosis. Cellulose granulomatosis has also been described as a cause of the tree-in-bud appearance on high-resolution CT (micronodules distributed at the termination of bronchovascular bundles).
In mercury embolism, chest radiographic findings show permanent or gradually resolving multiple small metallic spherules. In catheter emboli, radiographs may reveal a catheter fragment overlying an unexpected portion of the lung, mediastinum, or heart. Angiography or CT findings can confirm the position of the catheter fragment.
No imaging technique alone has sufficient accuracy, so diagnosis should be made on clinical suspicion.
In venous embolism, the chest radiograph findings include normal findings, radiolucency in the vessels, edema, enlarged central pulmonary arteries, and dilatation of the superior vena cava. Air in the distal PA may appear in a bell shape, and CT may reveal air in the vessels or heart.
Precordial Doppler ultrasonography, a sensitive technique to detect intracardiac air, is often used during surgical procedures. An even more sensitive method is echocardiography, which may detect a patent foramen ovale and/or small air bubbles as white reflections.
Abnormalities on brain MRI may range from no abnormalities to local edema.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of NTPE?
Amniotic fluid embolism
Several reports confirm the possibility of severe left ventricular failure. PA catheter readings in human AFE cases frequently show low cardiac output and an elevated pulmonary capillary wedge pressure. In eighteen well-documented cases of left ventricular failure after AFE, ventricular failure contributed to the fatal course in five cases.
Respiratory function tests generally show a persistent hypoxemia and a reduction of carbon monoxide diffusion.
ETCO2 measurement is the intraoperative standard, and the magnitude and duration of the ETCO2 decrease correlate with the volume of embolized air. A decrease in the end-tidal carbon dioxide (ETCO2) levels, as determined by capnography, suggest a change in the relationship between ventilation and perfusion. Arterial saturation, as measured by pulse oximetry, cannot detect AE as readily as ETCO2 can.
What diagnostic procedures will be helpful in making or excluding the diagnosis of NTPE?
The clinical manifestations are non-specific, so clinical suspicion of NTPE requires testing to confirm the diagnosis.
A chest X-ray may demonstrate diffuse alveolar infiltrates or more specific findings, such as metallic spherules or catheter fragments, in patients with foreign material emboli.
A high-resolution CT scan may demonstrate a feeding vessel sign, the tree-in-bud pattern, or ill-defined centrilobular and/or subpleural (micro) nodules. The CT "halo" sign suggests the presence of septic emboli.
A CT angiogram may demonstrate an obstructed pulmonary artery when large emboli obstruct flow, as can occur in patients with hydatid cysts. However, this finding is less common than it is with thrombotic pulmonary emboli.
An MRI of the brain may show the "Starfield Pattern" in patients with fat embolism, and echocardiography may show right ventricular overload and failure. Left ventricular failure can occur in patients with amniotic fluid embolism.
A gallium scan may reveal diffuse bilateral uptake in patients with talc granulomatosis.
Peripheral blood has low invasiveness but is usually nonspecific.
Hypoxemia occurs in all types of NTPE.
There is evidence of DIC with amniotic fluid embolism.
Hyperlipidemia may be present with fat embolism.
Antibody titres (serology) may help to diagnose hydatid cystic disease.
Hemoconcentration is sometimes observed in gas embolism.
BAL is invasive and has some risk, but it is usually nonspecific. Indicative findings are:
CD8 lymphocytes with foreign material
Fat droplets in macrophages with fat embolism
Fetal cells with amniotic fluid embolism
Talcum crystals as foreign material
Induced sputum is a safe procedure. Fat globules may be seen in fat embolism.
Pulmonary microvascular cytology via Swan-Ganz catheter is invasive and carries risk, but it has a high diagnostic yield. It may reveal fat emboli with fat embolism in patients who are not receiving high amounts of lipids IV, fetal cells with amniotic fluid embolism, and tumor cells with tumor embolism.
Open lung biopsy is invasive and carries risk. It can reveal a granulomatous reaction by polarized microscopy for some foreign material emboli and specific cell types in embolic particles in a range of NTPE conditions.
Fundoscopy carries minimal risk but requires an experienced ophthalmologist. It may reveal fat droplets and hemorrhages in fat embolism, talcum deposits in foreign material embolism, and gas bubbles in gas embolism.
Monitoring shows ETCO2 decrease with gas embolism.
What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of NTPE?
Consider taking blood from the PA through a Swan-Ganz catheter after large emboli are excluded in the right atrium, the ventricle, and the pulmonary artery, and the clinical condition allows the safe placement of a Swan-Ganz catheter. Blood should be collected as described by Masson. A representative sample can be obtained if blood is drawn from the distal lumen of a wedged PA catheter. After discarding the first 10 ml, draw an additional 10ml and heparinize and analyze it utilizing several staining mechanisms, such as Papanicolaou's method (fetal amniotic cells? tumor cells?) or a staining method for fat (fat embolism?).
Fat globules can be found in the blood, urine, sputum, and the bronchoalveolar (BAL) or even cerebrospinal fluid. To identify FFAs and fat, cells may be stained with the Oil Red O, Nile Blue, or Sudan Black staining techniques (
Fat emboli (Oil Red O Staining), showing as red dots in induced sputum in a massive fat embolism syndrome after bilateral hip surgery.
Blood drawn from the femoral vein and examined cytopathologically may yield necrotic bone elements mixed with fat.
Pulmonary microvascular cytology, consisting of analysis of blood sampled while a Swan-Ganz catheter is in the wedge position, has proven to be useful in diagnosing FE(S). Induced sputum analysis is also a safe and non-invasive test to detect FE in SCD (
However, BAL Oil Red O-positive macrophages are frequently observed in the BAL fluid of trauma patients irrespective of the presence of FES, in aspiration pneumonia, and when the patient has received lipid infusions. To define FES, some authors have reported a cut-off of more than 5 percent of alveolar macrophages containing fat droplets, ranging from 10-100 percent (median value 46%), in cases with proven or probable FE. Others have proposed a threshold of 30 percent.
Amniotic fluid embolism
Again, pulmonary microvascular cytology (fetal cells?) consisting of analysis of blood sampled while a Swan-Ganz catheter is in the wedge position has proven to be useful in diagnosing AFE (
Papanicolaou staining showing fetal keratinocytes surrounded by inflammatory cells in the pulmonary arterial blood taken from a Swan Ganz in wedged position (Reprinted with permission from Huybrechts et al. Acta Cardiol 2006; 61:643-646)
Fetal sqaumae in the bronchoaveolar lavage fluid of a patient with massive amniotic fluid embolism (Reprinted with permission from Pluymakers et al. Resuscitation 2007; 72: 324-332)
TKH-2 immunostaining is a more sensitive method than Alcian blue staining for detection of AF-derived mucin in lung sections.
Tumor macroembolism is clinically indistinguishable from thromboembolism, so the diagnosis is achieved mostly through autopsy.
Obtaining a suitable sample of blood from the pulmonary capillary bed for tumor cells again requires that blood be aspirated from the distal port while the catheter is in the wedged position to avoid malignant cells from "upstream" (e.g., the liver) contaminating the sample. Blood is subsequently either filtered or spun down, and the remaining cells stained using the Papanicolaou method. The interpretation of such samples proves to be challenging, as megakaryocytes and endothelial cells may mimic malignant cells.
Tumor macroembolism is also reported in sudden death and requires medicolegal investigation. It should be distinguished from primary tumors arising from the intima of the PA.
Gestation trophoblastic disease
Some authors have demonstrated syncytiotrophoblast and multinucleated trophoblast giant cells in pulmonary arterial blood sampled during molar evacuation.
Pathological observations play a key role in the exact diagnosis, and carefully aspirated blood from the pulmonary artery or specific staining of cells recovered from BAL-fluid may be helpful. Frequently, lung biopsies that reveal severe granulomatous reaction or unfortunate post-mortem pathological investigations of pulmonary tissue confirm the diagnosis (
Crystals of unknown composition in a patient who injected an unknown chemical substance intravenously. Abundantly present crystals obstruct the pulmonary arteries (open lung biopsy).
BAL typically reveals lymphocytosis with a predominance of CD8 lymphocytes, and talcum crystals can occasionally be detected.
A diagnosis can be obtained by examining transbronchial or open-lung biopsy specimens, which may show macrophages with intracellular talc crystals. Definitive diagnosis is often achieved only at autopsy.
Micro-embolic foreign material generally elicits a granulomatous reaction.
Identification of the particulates may require the use of ultrastructural analysis by analytical electron microscopy techniques, including selected area diffraction and X-ray energy-dispersive analysis. Polarization microscopy is an ideal means of detecting foreign material like intravascular deposits and aspirated foreign material. Talcum is distinguished readily by its appearance under polarized light because it exhibits a birefringent appearance with sharp, elongated fibers. Cellulose particles are longer, mod-shaped, birefringent material. Crospovidone appears as basophilic particles within arteries and extravascular granulomas. Organic starch stains positively with PAS.
If you decide the patient has NTPE, how should the patient be managed?
Current treatments for NTPE are usually supportive.
Achieve adequate oxygenation following the principles of management of ARDS, as well as hemodynamic stability. Transfusions and bronchodilators may improve oxygenation. Most patients, even those who have severe respiratory failure, recover with treatment.
Several agents have been used to attempt to reduce the levels of circulating, fat but these are not currently recommended. In addition, the beneficial effect of corticosteroids, either before or after the development of symptoms, has not been proven.
However, the successful use of veno-venous (V-V) extra-corporeal membrane oxygenation (ECMO) has been reported.
If a persistent foramen ovale is present, its closure before surgical manipulation of the fracture is feasible.
Amniotic fluid embolism (AFE)
AFE can be neither predicted nor prevented, so randomized controlled trials are not possible.
The maternal and fetal outcome is unpredictable, but the majority of patients will require ICU admission. Management is directed towards the maintenance of oxygenation and circulatory support. Mechanical ventilation can be necessary to maintain oxygen supply and invasive monitoring may be necessary to guide the use of inotropic agents and fluid.
Volume expansion in hypotension and inotropic support is indicated if (left) heart failure is observed.
In some cases, after-load reduction may be beneficial in restoring cardiac output, providing pre-load is adequately preserved. ECMO and intro-aortic balloon counterpulsation may be considered in left ventricular failure that is unresponsive to medical therapy. Diuretics are useful in mobilizing pulmonary edema.
In 65 percent of AFE cases, delivery had not yet occurred. Immediate delivery of the fetus by Caesarean section is mandatory to prevent fetal hypoxic damage and to facilitate resuscitation. Case reports have highlighted the importance of displacing the uterus laterally to avoid compressing large vessels and even performing an emergency Caesarean section during resuscitation.
Correction of the coagulopathy involves the administration of blood components. Cryoprecipitate is rich in fibronectin, which aids the reticulo-endothelial system in the filtration of antigenic AF. The successful use of activated recombinant factor Vlla in the management of severe hemorrhage secondary to AFE has been reported.
Leukocyte depletion filtering of cell-salvaged blood obtained from Caesarean section may reduce particulate contaminants. Several studies have revealed no increased risk of complications after autologous blood autotransfusion during Caesarean section. Successful hemorrhage management may be further optimized by uterine artery embolization, thereby avoiding hysterectomy.
Plasma exchange transfusion, continuous hemofiltration, and aprotinin administration have been attempted, as has the inhalation of nitric oxide, to treat hypoxemia.
In light of the similarities to anaphylaxis, corticosteroids and epinephrine have been suggested as useful therapeutic adjuvants. The successful treatment of a moribund patient with cardiopulmonary bypass and PA thromboembolectomy has also been shown.
The prognosis is poor; the median survival is only a few weeks, so interventions to cure or slow the progressive deterioration are rarely performed. However, surgical cure by resection of the primary tumor has been reported in patients with atrial myxoma, renal cell carcinoma, and choriocarcinoma. Chemotherapy is rarely indicated, although favorable results have also been reported in patients with choriocarcinoma and breast cancer.
Gestational trophoblastic material
Management of trophoblastic embolization is no different from that of other causes of hypoxemia and NTPE. Infusions of fluid and blood tend to cause pulmonary edema, which may precipitate heart failure. Preferred therapy consists of diuretics and ventilatory support. Emergency pulmonary embolectomy under cardiopulmonary bypass has been reported for an embolism of malignant trophoblastic material.
Septic patients are also at risk of thrombotic pulmonary embolism. Although the deployment of inferior venal caval filters is of theoretical benefit, the uncertainly of their potential adverse event profile has limited their use. Vena caval filters should not be implanted in a patient with a risk of septic embolism.
Improved outcomes for patients with SPE are attributable to earlier diagnosis, administration of broad-spectrum antibiotics, and improvements in surgical care (
Destroyed tricuspidal valve in a patient with endocarditis and septic pulmonary emboli
Gram staining of this destroyed triscupidal valve shows abundantly present bacteria.
Cystic hydatid disease
When a right-sided cardiac hydatid cyst is diagnosed, early surgical treatment should be performed under open-heart surgery conditions. Median sternotomy and the use of extracorporeal circulation must be the surgical approach of choice when cysts are present in the cardiac chambers. Embolectomy by removing multiple fragments of a ruptured andocyst of the PA, followed by surgical closure of the cardiac cyst cavity, can be performed. Surgical intervention can be complicated by rupture of the artery and/or the cyst.
Surgical treatment combined with chemotherapy may improve the prognosis, but medical therapy is advocated for patients with recurrent hydatidosis or in those where surgical intervention involves a high risk.
Given the high complication rate associated with embolic catheter fragments, effort should be made to recover these foreign bodies prior to central embolization. Many non-surgical techniques have been developed to remove catheter material from vessels.
Talcum granulomatosis and embolization of other foreign materials may cause pulmonary hypertension and fibrosis. Treatment with corticosteroids has been attempted, with gradual or temporary improvement, although there is a risk of relapse after cessation. Recurrent and ongoing IV drug abuse, leading to a histiocytic reaction in the transplanted lung, should raise substantial concerns on performing lung transplantation.
Aggressive treatment is essential. For venous GE, the mainstays of treatment are the prevention of further entry of gas, volume expansion, administration of 100 percent oxygen, and cardiopulmonary resuscitation, if necessary. In a somnolent patient, resuscitation and intubation should be performed to maintain oxygenation. Administration of up to 100 percent oxygen can decrease bubble size by favoring the elimination of gas from the bubbles.
The patient should be placed in the left lateral decubitus position to prevent right ventricular outflow obstruction. Evacuation of air from the right ventricle with the use of a multi-orifice central venous or pulmonary arterial catheter is recommended. Occasionally removal of up to half of the entrained gas can be achieved, with optimal placement of the catheter tip 2 cm below the junction of the superior vena cava and the right atrium.
Patients with arterial GE should be placed in the flat, supine position. The buoyancy of gas bubbles is not sufficient to counteract blood flow, so such bubbles are propelled toward the head even when the patient is in a head-down position. In addition, the head-down position may aggravate cerebral edema.
A short period of hypertension that occurs following a bubble's lodging in the cerebral circulation is therapeutic because it facilitates bubble redistribution to the capillaries and veins. The treatment goal is to maintain at least normal blood pressure and to prevent hypotension. Seizures should be suppressed with barbiturates, which also reduces cerebral oxygen consumption.
For arterial GE, hyperbaric oxygen (HB0) is the treatment of choice as soon as stabilization has been achieved. The hyperoxia produces diffusion gradients for oxygen into and nitrogen out of the bubble. HBO decreases cerebral edema, improves oxygenation, and diminishes the activation of leukocytes. Delayed treatment (up to 48 hours) may ameliorate the patient's condition.
As hemoconcentration leads to an increased blood viscosity, normovolemia should be achieved by the administration of colloid solutions.
What is the prognosis for patients managed in the recommended ways?
Increased awareness of NTPE as an underestimated cause of acute and chronic embolism that may result in acute and chronic pulmonary hypertension is needed.
Fat embolism syndrome
FES is largely self-limiting and is usually associated with a good outcome. Treatment of FE should focus on prevention. Early immobilization, open reduction, internal fixation of fractures, and methods to reduce intramedullary pressure during total hip arthroplasty have reduced the incidence of FE.
When fracture stabilization is delayed in patients with multiple injuries, the incidence of ARDS, FE, and pneumonia; the costs of hospital care; and the number of days in the intensive-care unit (ICU) increases. The exact method of fracture fixation, as opposed to the moment of fixation, plays a minor role in the development of pulmonary dysfunction.
Amniotic fluid embolism
The reported case fatality rate continues to be high, accounting for as much as 10 percent of all maternal deaths in the US. The mortality ranges from 21.6 percent to 86 percent. Although there is still significant maternal and neonatal morbidity, the vast majority of women survive. However, among the survivors in a large registry, only 15 percent were neurologically intact.
The prognosis is poor; the median survival from diagnosis is only a few weeks. In view of these patients' likely prognosis, interventions to cure or slow down the progressive deterioration are rarely performed.
The prognosis varies widely: for patients with mercury emboli, the prognosis is good, although death has been reported. The clinical findings described in silicone embolism syndrome are similar to those observed in FES. A mortality rate as high as 24 percent has been reported.
Massive venous and arterial gas embolism is characterized by a high mortality rate. When over 50 ml of gas is injected abruptly in human veins, acute cor pulmonale, asystoly or both can occur. The lethal volume of injected air in humans is estimated to range from 100 ml to 500 ml.
What other considerations exist for patients with NTPE?
The complex pathogenesis of different subtypes of NTPE is more complex than "simple" mechanical obstruction, such as that seen after vascular thrombi. Nonthrombotic emboli also lead to severe inflammatory reactions.
Fat emboli initiate a biochemical and inflammatory cascade: trapped in pulmonary vessels, they may be metabolized to free fatty acids (FFAs) and glycerol by lipase. FFAs induce cellular damage, capillary leads, and clot formation. It is unclear why this cascade occurs in some patients and not others.
In childen, the fat content of the bone marrow is lower than it is in adults, and the composition (less of the toxic oleic acid) is different. These differences may at least partially explain the lower incidence of FE in younger people.
Amniotic fluid embolism
The severity of symptoms is driven by the antigenic potential of abnormal AF. finding epithelial squames from the fetal skin in the PA alone is not pathognomonic: the combination of symptoms with detection of these cells is required. Tumor emboli have an unusual level of resistance to recannulation, so they are more likely than other types of emboli to lead to irreversible obstruction.
Gestational trophoblastic disease
The pathogenesis is unique because the tumor arises from fetal, not maternal, tissue. Therefore, trophoblastic embolization sufficient to cause severe pulmonary compromise is rare.
Cystic hydatid disease
Cystic hydatid disease, or echinococcosis, is a parasitic infection caused by the larval or cyst stage of the tapeworm Echinococcus granulosus. Echinococcosis is mostly endemic in sheep-farming areas of the Middle East, South America, and Oceania, and along the Mediterranean coast. Autopsy findings indicate that embolism is caused by vesicles or cysts that act purely mechanically by obstructing the blood flow.
Is talcum-induced pulmonary granulomatosis caused by an immunologic mechanism of delayed hypersensitivity? Birefringent material, such as that seen in talcum PE, is often, but not exclusively, demonstrated introcellularly in lung tissue (94%).
Various volatile anesthetic agents diminish the ability of the pulmonary circulation to filter out gas.
What’s the evidence?
Bernard, GR, Artigas, A, Brigham, KL, Carlet, J, Falke, K, Hudson, L. "The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.". Am J Respir Crit Care Med . vol. 149. 1994. pp. 818-824.(The acute respiratory distress syndrome (ARDS), a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries high morbidity and mortality rates. The American-European Consensus Committee on ARDS was formed to focus on the definition and on the pathophysiologic mechanisms of this most severe form of acute lung injury. Nonthrombotic embolism, particularly fat embolism, is one of the “extra-pulmonary” external causes of ARDS.)
Chastre, J, Fagon, JY, Soler, P, Fichelle, A, Dombret, MC, Huten, D. "Bronchoalveolar lavage for rapid diagnosis of the fat embolism syndrome in trauma patients.". Ann Intern Med. vol. 113. 1990. pp. 583-588.(The identification of large intracellular fat droplets in a high percentage of alveolar macrophages recovered by bronchoalveolar lavage in trauma patients is a rapid and specific method for establishing the diagnosis of the fat embolism syndrome.)
Clark, SL, Hankins, GD, Dudley, DA, Dildy, GA, Porter, TF. "Amniotic fluid embolism: analysis of the national registry.". Am J Obstet Gynecol . vol. 172. 1995. pp. 1158-1167.(A retrospective review of the medical records on amniotic fluid embolism in a national registry. Amniotic fluid embolism occurred during labor in 70 percent of the women. Maternal mortality was 61 percent, with neurologically intact survival seen in only 15 percent of women. Clinical and hemodynamic manifestations seem to be similar to those seen in anaphylaxis and septic shock.)
Goldhaber, SZ, Visani, L, De Rosa, M. "Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).". Lancet. vol. 353. 1999. pp. 1386-1389.(A large trial exploring the clinical outcome after thrombotic pulmonary embolism: Pulmonary embolism remains an important clinical problem with a high mortality rate.)
Gurd, AR, Wilson, RI. "The fat embolism syndrome.". J Bone Joint Surg Br. vol. 56B. 1974. pp. 408-416..(Outlines the diagnostic classical criteria for the fat embolism syndrome based on a number of major and minor signs.)
Han, D, Lee, KS, Franquet, T, Muller, NL, Kim, TS, Kim, H. "Thrombotic and nonthrombotic pulmonary arterial embolism: spectrum of imaging findings.". Radiographics. vol. 23. 2003. pp. 1521-1539.(Along with clinical examination and laboratory tests, imaging plays a key role in the diagnosis of pulmonary embolism. An illustrative series of the imaging findings found in patients with nonthrombotic embolism: knowledge of appropriate imaging methods and familiarity with the specific imaging features should facilitate prompt and effective diagnosis.)
Hansell, DM. "Small-vessel diseases of the lung: CT-pathologic correlates.". Radiology. vol. 225. 2002. pp. 639-653.(Diseases that primarily affect the small vessels of the lung are difficult to diagnose. This excellent review highlights some of the less obvious imaging manifestations of occlusive and inflammatory diseases of the small pulmonary vessels, including those found after some subtypes of nonthrombotic pulmonary embolism.)
Harnett, MJ, Hepner, DL, Datta, S, Kodali, BS. "Effect of amniotic fluid on coagulation and platelet function in pregnancy: an evaluation using thromboelastography.". Anaesthesia. vol. 60. 2005. pp. 1068-1072.(This study nicely substantiates the hypothesis that coagulation profile changes are invariable accompaniments of amniotic fluid embolism.)
Huybrechts, W, Jorens, PG, Jacquemyn, Y, Colpaert, C, Vrints, C, Conraads, V. "Amniotic fluid embolism: a rare cause of acute left-sided heart failure.". Acta Cardiol. vol. 61. 2006. pp. 643-649.(Data are provided that do not support obstruction of the pulmonary vasculature by amniotic fluid as the only primary pathophysiological event in amniotic fluid embolism. Several reports suggest the presence of severe left ventricular failure. This review describes the hemodynamic data of all well documented cases of left ventricular failure after AFE, confirming the clinical picture of cardiogenic pulmonary edema.)
Jorens, PG, Van Marck, E, Snoeckx, A, Parizel, P. "Nonthrombotic pulmonary embolism.". Eur Resp J. vol. 34. 2009. pp. 452-472.(The most extensive review ever published on all aspects (the pathophysiology, incidence, diagnosis, prognosis, and treatment) of all causes of non-thrombotic pulmonary embolism.)
Kwon, WJ, Jeong, YJ, Kim, KI, Lee, IS, Jeon, UB, Lee, SH. "Computed tomographic features of pulmonary septic emboli: comparison of causative microorganisms.". J Comput Assist Tomogr . vol. 31. 2007. pp. 390-394.(Are the size and pulmonary distribution of nodules in gram-positive septic emboli different from gram-negative? According to this study, the detailed CT characteristics of peripheral nodules in pulmonary septic emboli may be able to differentiate the causative microorganisms and to provide additional information regarding treatment plans in patients with sepsis.)
Masson, RG, Ruggieri, J. "Pulmonary microvascular cytology: a new diagnostic application of the pulmonary artery catheter.". Chest . vol. 88. 1985. pp. 908-914.(The authors hypothesize and demonstrate that withdrawal of blood from a pulmonary artery catheter, particularly in the wedge position, can recover diagnostic cells and debris in patients with nonthrombotic embolism. The blood sample from the pulmonary artery should be collected as described in this leading paper.)
Muth, CM, Shank, ES. "Gas embolism.". New Engl J Med. vol. 342. 2000. pp. 476-482.(An in-depth review of venous and arterial gas embolism.)
Pluymakers, C, De Weerdt, A, Jacquemyn, Y, Colpaert, C, Van de Poel, E, Jorens, PG. "Amniotic fluid embolism after surgical trauma: two case reports and review of the literature.". Resuscitation. vol. 72. 2007. pp. 324-332.(Can trauma really cause amniotic fluid ambolism? A review of all well-documented cases of trauma-related amniotic fluid embolism.)
Rossi, SE, Franquet, T, Volpacchio, M, Gimenez, A, Aguilar, G. "Tree-in-bud pattern at thin-section CT of the lungs: radiologic-pathologic overview.". Radiographics. vol. 25. 2005. pp. 789-801.(The tree-in-bud pattern on CT consists of small, centrilobular nodules of soft-tissue attenuation connected to multiple branching linear structures of similar caliber that originate from a single stalk. This pattern is now recognized as a CT manifestation of many diverse entities, including nonthrombotic pulmonary embolism.)
Rossi, SE, Goodman, PC, Franquet, T. "Nonthrombotic pulmonary emboli.". AJR Am J Roentgenol . vol. 174. 2000. pp. 1499-1508.(A concise overview of the clinical and radiographic features of nonthrombotic pulmonary emboli.)
Sakuma, M, Sugimura, K, Nakamura, M, Takahashi, T, Kitamukai, O, Yazu, T. "Unusual pulmonary embolism: septic pulmonary embolism and amniotic fluid embolism.". Circ J. vol. 71. 2007. pp. 772-775.(Characterization of the etiology of thrombotic and non-thrombotic embolism in a huge series of autopsies. Fungal septic emboli were found more frequently than bacterial, an observation that does not correlate with our daily clinical practice.)
Van den Brande, FG, Hellemans, S, De Schepper, A, De Paep, R, Op De Beeck, B, De Raeve, HR. "Post-traumatic severe fat embolism syndrome with uncommon CT findings.". Anaesth Intensive Care . vol. 34. 2006. pp. 102-106.(Although the diagnosis of fat embolism syndrome is usually based on clinical findings, this case report and review describe the ill-defined centrilobular and subpleural nodules in addition to ground-glass opacities and consolidation on a computed tomography scan. The nodules presumably represent alveolar edema, microhemorrhage, and an inflammatory response secondary to ischemia and cytotoxic emboli.)
Vichinsky, EP, Neumayr, LD, Earles, AN, Williams, R, Lennette, ET, Dean, D. "Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group.". New Engl J Med. vol. 342. 2000. pp. 1855-1865.(This study shows that, among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by infection, but it is also precipitated by fat embolism.)
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