Fat embolism syndrome

INTRODUCTION — Fat embolism syndrome (FES) is a rare syndrome that, when severe, is associated with respiratory failure, neurocognitive deficit, and death. It remains a diagnostic challenge for clinicians, but prompt recognition is important so that supportive therapy can be instituted early.

The pathogenesis and etiology, clinical presentation and diagnosis, prevention, treatment, and outcomes of FES are reviewed here. Other embolism syndromes are discussed separately. (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults" and "Amniotic fluid embolism" and "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management" and "Air embolism".)

DEFINITION — Fat embolism is defined by the presence of fat globules in the pulmonary circulation. FES refers to the clinical syndrome that follows an identifiable insult which releases fat into the circulation, resulting in pulmonary and systemic symptoms. (See 'Epidemiology and etiology' below and 'Clinical presentation' below and 'Diagnosis' below.)

EPIDEMIOLOGY AND ETIOLOGY — FES is a rare clinical syndrome that can complicate a wide variety of clinical conditions (table 1), particularly those where fat is manipulated. Almost all cases of FES are due to long bone and pelvic fractures (bone marrow contains a high content of fat). However, some cases are associated with trauma in the absence of orthopedic fractures and rare cases are nontrauma-related.

Orthopedic fractures or trauma — Rates of FES in orthopedic trauma patients vary from <1 percent to >30 percent, with the wide range likely reflecting study population heterogeneity and a lack of standardization for diagnostic criteria [1-3]. As an example, in a matched case-controlled study of the Japan Trauma Data Bank from 2004 to 2017, the incidence of FES in trauma patients was 0.1 percent. However, patients who did not survive >48 hours were excluded such that cases could have been missed [3].

FES is most commonly associated with long bone (especially the femur) and pelvic fractures and less commonly with fractures of other marrow-containing bones (eg, ribs) (table 1) [1,3-5]. The rate of FES is also higher in those with multiple rather than single fractures (1.29 versus 0.17 percent in one series) [1,6] and in patients with open fractures than closed fractures [3]. A delay in the time to reduction of the fracture is also associated with FES [3]. In another retrospective study, hypomagnesemia, hyperphosphatemia, hypoalbuminemia, and blunt traumatic mechanism of injury were identified as risk factors for FES in patients with orthopedic injuries [7].

FES is more common in men than in women and its incidence is highest in those between 10 and 40 years, likely reflecting the incidence of trauma in this age group [1,2].

Although rare, surgical trauma during orthopedic procedures such as total hip or knee arthroplasty (ie, bone marrow needs to be manipulated for hardware placement), intraosseous access or infusions, and bone marrow harvesting and transplant can also result in FES [8-11].

Nonorthopedic trauma — Other trauma-related injury that can be associated with FES include soft tissue injury, particularly injury to adipose tissue (table 1). Rarely, fat embolism can be seen with burns, liposuction, lipoinjection, fat grafting, panniculitis, and cardiopulmonary resuscitation (without rib fracture, some of which may relate to intraosseous access) [12-14]. Rare cases following nonorthopedic surgery (eg, cardiopulmonary bypass, caesarean section), and donor-related FES after lung transplantation, have also been described [14,15].

Nontrauma-related — Rare case reports describe nontrauma-related causes of FES including pancreatitis, sickle or thalassemia-related hemoglobinopathies (especially during a crisis), osteonecrosis, bone marrow necrosis, lipid-based infusions or contrast agents, intramuscular injections of oil for cosmetic purposes, fatty liver disease, renal angiomyolipoma invasion of the inferior vena cava, and others listed in the table (table 1) [8,13,16-29]. Although autopsy data in nontrauma populations report that 63 percent have FES, it is likely that this is an overestimate or represents subclinical disease [6].

PATHOGENESIS — The pathogenesis of fat embolism is unknown. There are two theories: the mechanical theory where fat emboli may be the result of fat globules entering the bloodstream through tissue (usually bone marrow or adipose tissue) that has been disrupted by trauma, and the biochemical theory where inflammation results from the production of toxic intermediaries of circulating fat (eg, chylomicrons, infused lipids, or bone marrow-derived fat). It is feasible that both mechanisms are at play in many cases.

Mechanical theory — This theory proposes that fat from disrupted bone marrow or adipose tissue enters torn venules following trauma. It is supported by the observation that fractures of marrow-containing bone have the highest incidence of FES and cause the largest volume of fat emboli because the disrupted venules in the marrow are tethered open by their osseous attachments, allowing the marrow contents to easily enter the venous circulation. The hypothesis is also supported by the observation that "echogenic material" passes through the right heart during orthopedic and spinal surgery [30,31].

Fat embolism sufficiently explains the respiratory symptoms of FES since fat globules collect and obstruct pulmonary capillaries. In addition, it is thought that circulating fat cells may have prothrombotic potential and may trigger the aggregation of platelets and fibrin resulting in further obstruction of the pulmonary vascular bed, local inflammation, hemorrhage, and edema. When massive, this process may lead to right ventricle failure and obstructive shock. (See "Definition, classification, etiology, and pathophysiology of shock in adults", section on 'Obstructive'.)

Fat emboli may enter the systemic arterial circulation to result in neurologic disease and petechiae associated with FES [32] via one of two mechanisms:

●Paradoxical embolism – Paradoxical embolism occurs when material passes through a patent foramen ovale or other anatomical shunt and into the arterial circulation [30].

●Microembolism – Microembolism occurs when the emboli are so small that they are able to pass from the pulmonary arterial to pulmonary venous circulation through the lungs and eventually to the left side of the heart. This mechanism is supported by the finding of embolized material in the systemic circulation in the absence of a patent foramen ovale.

There are several limitations to the mechanical fat embolism theory: it does not sufficiently explain the 24 to 72 hour interval following the acute insult during which the patient is symptom-free and it does not explain nontraumatic FES.

Biochemical theory — Production of toxic intermediaries of circulating fat is an alternative theory about the mechanism of FES, which may occur instead of or in addition to the mechanical mechanism described above. This theory is based upon the hypothesis that embolized fat degrades into toxic intermediaries with pro-inflammatory effects and is supported by elevated levels of the following:

●Free fatty acids – Circulating free fatty acid levels are moderately elevated in patients with fractures [33,34] and severely elevated (along with circulating lipoprotein lipase) in nontraumatic animal models of FES [35]. Animal studies have found that neutral fat does not injure the lung; however, if it is hydrolyzed over the course of hours to several products, including free fatty acids, it may cause acute respiratory distress syndrome (ARDS). Free fatty acids have been associated with cardiac contractile dysfunction, which may be a feature of FES [36].

●Cytokines – Patients with FES also have been shown to have high levels of phospholipase A2 and inflammatory cytokines, including tumor necrosis factor alpha, interleukin-1, and interleukin-6 [37,38].

●C-reactive protein – C-reactive protein is elevated in patients with FES and appears to be responsible for lipid agglutination, with may obstruct blood flow in the microvasculature. Serum from acutely ill patients has been shown to agglutinate chylomicrons, low density lipoproteins, and the liposomes of nutritional fat emulsions [36].

The production of pro-inflammatory lipid mediators may explain the classic 24 to 72 hour delay from the inciting event to clinically apparent FES. In other words, the onset of symptoms may coincide with the degradation and agglutination of fat. Toxic intermediaries also offer an explanation for nontraumatic FES, although the evidence is largely circumstantial.

CLINICAL PRESENTATION — FES typically manifests 24 to 72 hours after the initial insult, but may rarely occur as early as 12 hours or as late as two weeks after the inciting event [39]. Affected patients develop a classic triad: hypoxemia, neurologic abnormalities, and a petechial rash. None of these features are specific for FES.

Signs and symptoms

Respiratory abnormalities — Pulmonary manifestations are the most common presenting features of FES. Hypoxemia, dyspnea, and tachypnea are the most frequent early findings. In one series, hypoxemia was present in 96 percent of cases [40]. A syndrome indistinguishable from acute respiratory distress syndrome (ARDS) may develop. Approximately one-half of patients with FES caused by long bone fractures develop severe hypoxemia and require mechanical ventilation [41]. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

Neurologic abnormalities — Neurologic abnormalities are also common and typically manifest after respiratory abnormalities, although rare case reports suggest neurological symptoms can occur in isolation [42]. Neurologic manifestations range from the development of an acute confusional state and altered level of consciousness to seizures and focal deficits [40,43]. One study reported that mental status changes occurred in 59 percent of patients with FES [40].

Petechial rash — The characteristic red-brown petechial rash may be the last component of the triad to develop and occurs in only 20 to 50 percent (on average one third) of cases (picture 1) [40,41,44]. It is found most often on the nondependent regions of the body including the head, neck, anterior thorax, axillae, and sub-conjunctiva [45].

Other clinical and laboratory findings — A number of other less common and nonspecific manifestations of FES may also be present. These include [16,40,46]:

●Anemia and thrombocytopenia (one- to two-thirds)

●Retinal scotomata (Purtscher's retinopathy)

●Lipiduria

●Fever

●Coagulation abnormalities, rarely disseminated intravascular coagulation (DIC)

●Myocardial depression

●Right ventricle dysfunction

●Hypotension

●Obstructive shock

Imaging and laboratory findings — Chest and brain imaging are frequently performed to investigate the etiology of respiratory and neurologic abnormalities. Findings are generally nonspecific.

●Chest radiographs are normal in the majority of patients [35]. A minority of chest radiographs reveal air space disease due to edema or alveolar hemorrhage, which tends to be most prominent in the periphery and bases (image 1) [47].

●Computed tomography (CT) of the lung may also be normal but bilateral well-demarcated ground glass opacities or ill-defined centrilobular nodules may be present [48-53]. Less common findings include lobular consolidations, septal or bronchial wall thickening, and areas of crazy paving. The extent of involvement on CT was shown in one study to correlate with severity of the clinical syndrome of FES [53].

●Ventilation perfusion imaging is not helpful but if performed to investigate for the presence of venous thromboembolism, it may demonstrate a mottled pattern of subsegmental perfusion defects with a normal ventilatory pattern [54].

●Acute neurologic abnormalities on magnetic resonance imaging may be associated with a "starfield" pattern of diffuse, punctate, hyperintense lesions on diffusion-weighted imaging, which correlates with the degree of clinical neurologic impairment (image 2 and image 3) [9,55-60]. Other late or severe findings include edema and petechial hemorrhage. Findings on CT of the brain are also nonspecific and may be normal [61].

Similarly, laboratory findings are not specific and may reveal anemia, thrombocytopenia, and coagulation abnormalities including those of DIC. Lipiduria is rare. C-reactive protein is generally elevated in critical illness and lipase is not consistently elevated. No specific biomarker has been validated for clinical use in FES.

DIAGNOSTIC EVALUATION — The main goals are to exclude alternate diagnoses, assess severity of disease, and determine the need for supportive care.

Initial assessment — FES should be suspected in those at risk (table 1) who present with symptoms of respiratory failure. The suspicion should be further increased when neurologic abnormalities and a petechial rash that emerge 24 to 72 hours after an insult (eg, long bone fracture) are present. (See 'Signs and symptoms' above.)

When suspected, chest imaging, typically chest radiography and/or CT, should be performed. CT or magnetic resonance imaging (MRI) of the brain should be performed in those with neurologic symptoms. Routine laboratory studies should be drawn including complete blood count and coagulation studies. Measuring free fatty acid or c-reactive protein levels and examining urine or sputum for the presence of fat are not routinely performed since their diagnostic utility is unclear. (See 'Imaging and laboratory findings' above.)

CT pulmonary angiography is not routinely performed for diagnosis but may help exclude pulmonary thromboembolism as an etiology for hypoxemia. Similarly, microbiology studies and echocardiography may help to rule out competing diagnoses such as pneumonia and heart failure.

Since most experts consider FES a clinical diagnosis [62], further testing is not usually performed. In most cases, this noninvasive approach is considered appropriate since the only therapy that is available for FES is supportive. (See 'Differential diagnosis' below and 'Diagnosis' below.)

Invasive testing — Diagnostic invasive testing is not routinely performed in most patients with suspected FES since there are no definitive therapies for FES and the diagnosis is typically a clinical one. Invasive procedures are usually only performed when a competing diagnosis is suspected, for which available therapies could alter the prognosis. As examples:

●Pulmonary artery catheter – A pulmonary artery catheter (PAC) is not routinely placed for fat analysis from a wedged sample of pulmonary arterial blood since this is neither a sensitive nor specific way to diagnose FES. However, rarely, a sample may be drawn for fat assessment when a PAC is already in place for an alternate reason (eg, shock, pulmonary hypertension). When performed, the clinician should be aware that set diagnostic criteria for fat analysis are not known and the absence of fat does not preclude the diagnosis. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".)

●Bronchoscopy – Similarly, bronchoscopy is not routinely performed. There is some evidence that suggests bronchoalveolar lavage (BAL) can detect fat droplets within alveolar macrophages, as a means of diagnosing fat embolism, but their absence does not rule out FES and the presence of fat globules within pulmonary macrophages is non-specific and can be present in the setting of multi-organ failure and sepsis. Studies done in patients with trauma or the acute chest syndrome of sickle cell disease suggest that BAL may be useful; however, diagnostic criteria vary and lack standardization, and the sensitivity and specificity are unknown (eg, similar findings can be found in lipid aspiration) [17,63-66]. In one study of trauma patients, the presence of FES was associated with a high percentage of alveolar macrophages that contain lipid inclusion bodies (>30 percent) [66]; however, some patients with nontrauma-related acute respiratory distress syndrome (ARDS) also had levels within this range. Thus, we only typically perform lipid analysis in BAL when attempting to concurrently elucidate other etiologies of respiratory failure (eg, infections, tumor). (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Diagnostic'.)

Similarly, there are no data to support the routine use of transbronchial biopsy (TBBX) or video-assisted lung biopsy for the diagnosis of FES. However, fat globules may be found histologically as an incidental finding when tissue biopsy is performed for an alternate reason (eg, tumor embolism). (See 'Diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The major competing diagnoses are other embolization syndromes (thrombus, amniotic fluid, tumor, foreign body, air), acute alveolar filling diseases (eg, heart failure, pneumonia, and acute respiratory distress syndrome [ARDS]), and cutaneous vasculitic disorders (eg, systemic lupus erythematosus [SLE]). The appropriate clinical context of long bone fractures and the appearance of a petechial rash in a patient with hypoxemia and neurologic abnormalities strongly favors a diagnosis of FES; however not every patient presents in this classic fashion such that other conditions need to be considered or ruled out before a diagnosis can be made.

●Pulmonary embolism (PE) – Patients with PE may present in the same time frame (ie, 24 to 72 hours), but neurologic abnormalities and rash are less common and most cases will be distinguished by CT pulmonary angiography (CTPA). (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

●Amniotic fluid embolism syndrome (AFES) – AFES most commonly occurs during labor and delivery, or immediately postpartum or following a first or second trimester abortion, amniocentesis, or abdominal/uterine trauma; rare cases present 48 hours later. Patients are more likely to present with cardiovascular collapse, respiratory failure, and seizures. (See "Amniotic fluid embolism".)

●Tumor embolism – These patients typically present over days to weeks with progressive respiratory symptoms and usually have a known or suspected diagnosis of cancer, although patients with a cancer-related pathologic fracture could theoretically present with FES. (See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management".)

●Foreign body embolism – Embolism of a foreign body (FB) is usually preceded by a history of injection with a FB (eg, silicone) but the presenting symptoms and radiography findings may be similar. (See 'Silicone embolism syndrome' below.)

●Air embolism – Although these patients present with acute respiratory and neurological abnormalities; rash is unusual and the onset of symptoms is usually immediate (ie, occurring at the time of trauma or injury). Air may be detected on echocardiography or brain imaging. (See "Air embolism".)

●Alveolar filling disorders – Most of these disorders (eg, pneumonia, aspiration, pulmonary contusion, heart failure, ARDS) can be distinguished from FES on echocardiography or microbiology sampling, although ARDS is radiologically indistinguishable from and is associated with severe FES. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Heart failure: Clinical manifestations and diagnosis in adults" and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

●Vasculitic disorders – For patients with FES who present with rash, some of the cutaneous vasculitides may also have neurologic and respiratory abnormalities (eg, SLE). However, the rash is often purpuric (not petechial), risk factors for FES are usually not apparent, and many are distinguished by serology and/or biopsy. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

DIAGNOSIS — FES is a clinical diagnosis that can be made when the classic triad of hypoxemia, neurologic abnormalities, and the petechial rash occurs in an appropriate clinical setting (table 1). However, since the presenting manifestations are nonspecific and the rash occurs in fewer than half of cases, the diagnosis of FES is more commonly made when clinical manifestations (eg, hypoxemia plus neurologic impairment) occur in the appropriate clinical setting and no alternative explanation exists (ie, a diagnosis of exclusion). Several diagnostic criteria, such as Gurd's, Schonfeld's, and Lindeque, have been proposed but none has been validated or compared and in general, they are not widely used in practice [18,62,67,68].

When tissue is obtained for other reasons or at autopsy, fat globules can be histologically appreciated by areas of optical clearing and after staining with Oil Red O, and when present may confirm the clinical suspicion for FES. Interestingly, since cases are diagnosed clinically, there are no clinicopathologic correlation studies. However, fat can be seen incidentally, and in patients without the full syndrome, so the clinical significance of fat on histology is uncertain. The presence of a high percentage of alveolar macrophages on bronchoalveolar lavage or high amounts of fat on a wedged pulmonary artery sample may be supportive of the diagnosis but is neither sensitive nor specific for the diagnosis of FES. (See 'Invasive testing' above.)

TREATMENT — There are no definitive treatments for FES, with the exception of individuals with sickle cell disease, who require urgent red blood cell (RBC) exchange transfusion (see 'RBC exchange transfusion in sickle cell disease' below). Therapy is largely supportive while FES resolves spontaneously.

Treatment of the cause — While early correction of fractures may prevent FES, it is unknown whether or not this strategy works as a treatment for those with established FES. Nonetheless, most clinicians advocate for early treatment of the underlying cause as a rational approach to treating FES.

RBC exchange transfusion in sickle cell disease — FES with pulmonary fat embolism can cause acute chest syndrome (ACS) and multiorgan failure syndrome with a high mortality rate. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Pathophysiology' and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Rapidly progressive ACS and multiorgan failure'.)

Consultation with the transfusion medicine service and hematologist for urgent RBC exchange transfusion is essential; details and other aspects of management are discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion' and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Transfusion'.)

Supportive care — With the exception of exchange transfusion for individuals with sickle cell disease, supportive care is the mainstay of therapy for clinically symptomatic FES, while recovery is ongoing. This involves fluid resuscitation, oxygenation, and when indicated, noninvasive or invasive mechanical ventilation. Rarely, patients require intracranial pressure monitoring for massive cerebral involvement, or vasopressors, mechanical cardiac support devices, or extracorporeal membrane oxygenation for refractory shock [55,69,70]. Supportive therapy is continued until FES resolves or death occurs. (See "Evaluation and management of elevated intracranial pressure in adults" and "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit".)

The administration of systemic corticosteroids is controversial. The rationale for the administration of steroids is based upon their anti-inflammatory effects (ie, targeted at one mechanism involved in the pathogenesis (see 'Biochemical theory' above)) as well as evidence that supports their role in preventing FES (see 'Prevention' below). However, most experts do not administer steroids routinely since data report unconvincing benefit in association with a wide range of doses and are limited to case reports/series only; in addition, some suggest harm associated with the increased risk of infection [71-73]. Rarely, for those patients with life-threatening cases of FES, a limited trial (eg, 1 to 5 days) of systemic corticosteroids (eg, hydrocortisone 100 mg three time daily or methylprednisolone 1 to 1.5 mg/kg/day) is appropriate. Its administration should be weighed against the increased risk of steroid-associated infections.

The routine administration of heparin is not advised, although it has been proposed as an agent that may increase the clearance of intravascular lipids. However, the risk of hemorrhage, lack of trials demonstrating benefit and theoretical harm from an increase in free fatty acid production preclude its administration in the absence of a true indication for anticoagulation (eg, venous thromboembolism).

PROGNOSIS — Most patients with FES fully recover spontaneously. In most cases, findings are transient and fully reversible, often within a few days, although features may persist beyond one week when FES is severe [74]. Individual studies have reported mortality rates ranging from 5 to 15 percent [3,4,75]. However, the true mortality is probably lower, as suggested by a meta-analysis that reported only two deaths among the 166 patients with FES who received supportive care alone (1.2 percent) [76]. The etiology of death is typically related to severe respiratory failure, refractory shock, or brain death [42].

PREVENTION

Early immobilization of fractures — Early immobilization of fractures reduces the incidence of FES. The risk is further reduced by operative correction, rather than conservative management (ie, traction alone) [77].

Other potential measures — Additional interventions that may reduce the risk of FES that are used variably by experts include intraosseous pressure limitation and prophylactic systemic steroids.

Intraosseous pressure limitation — Limiting elevation of the intraosseous pressure during orthopedic procedures reduces the intravasation of intramedullary fat and other debris, and may reduce the incidence of FES [78-82]. In a related clinical trial, 40 patients undergoing cemented total hip arthroplasty were randomly assigned to undergo the conventional procedure either with or without the placement of a venting hole [78]. The purpose of the venting hole was to drain the medullary cavity between the greater and the lesser trochanter to limit intraoperative rises in intraosseous pressure. The group in which venting holes had been placed had significantly fewer major embolic events (20 versus 85 percent) as determined by transesophageal echocardiography and clinical monitoring. Other operative refinements may also limit intraosseous pressure, including cementless fixation of hip prostheses and unreamed intramedullary femoral shaft stabilization [79,80].

Prophylactic corticosteroids — The administration of prophylactic corticosteroids is controversial and their administration should only be considered on a case-by-case basis and always weigh the potential benefits of preventing FES against the risk associated with their administration.

Although small randomized trials suggest possible benefit, many surgeons do not use them. This is because most experts consider that FES is too infrequent to justify the routine use of corticosteroids with their associated adverse effects, and that when FES does occur, most patients recover with supportive care alone. In addition, studies that suggested benefit were fundamentally flawed (heterogenous population, small size, inadequately controlled, variable dose and duration), casting doubt over whether or not corticosteroids are associated with a true benefit [18,67,76,83-86]. As an example, in a 2009 meta-analysis of six randomized trials, although corticosteroids resulted in a reduced incidence of FES (relative risk [RR] 0.22, 95% CI 0.08-0.57) and hypoxemia (RR 0.39, 95% CI 0.21-0.71), mortality was not decreased. Another 2012 meta-analysis of seven trials reported similar results [86]. However, in addition to the fundamental flaws in design, most of the trials did not report how many of the long-bone fractures were open or closed, nor did they report the mean duration of fractures until the initial dose of corticosteroids. Thus, a multicenter trial is needed before any definitive conclusion can be drawn regarding the routine administration of corticosteroids in this population.

Although inhaled corticosteroids were shown in one prospective study to reduce the incidence of FES in patients with skeletal injury, further studies are required before such therapy can be routinely administered [87].

SILICONE EMBOLISM SYNDROME — A presentation similar to FES can result following the embolization of silicone to the pulmonary vasculature. Silicone embolism syndrome generally occurs after silicone is injected for cosmetic or therapeutic purposes [88-91]. Common manifestations include hypoxemia, fever, and a petechial rash. A range of pathological changes have been reported, including alveolar hemorrhage and diffuse alveolar damage [92]. Neurologic dysfunction is present in up to one-third of all patients following silicone embolism syndrome, and is associated with rapid clinical deterioration and increased mortality [93]. Management of silicone embolism syndrome is supportive.

Pulmonary foreign body granulomatosis caused by intravenous injection of pulverized pharmaceutical tablets is discussed separately. (See "Foreign body granulomatosis".)

SUMMARY AND RECOMMENDATIONS

●Fat embolism syndrome (FES), a rare clinical syndrome of uncertain pathogenesis, is defined by the presence of fat globules in the pulmonary circulation. FES is most commonly associated with long bone (especially femur) and pelvic fractures. Some cases are associated with trauma in the absence of orthopedic fractures or are nontrauma-related (table 1). (See 'Definition' above and 'Epidemiology and etiology' above and 'Pathogenesis' above.)

●FES typically manifests 24 to 72 hours after the initial insult. The classic triad of findings includes hypoxemia, neurologic abnormalities (eg, confusion, altered consciousness, seizure), and a petechial rash. Less common manifestations include anemia, thrombocytopenia, fever, lipiduria, and coagulation abnormalities; myocardial depression and shock are rare. None of these features are specific for FES. (See 'Clinical presentation' above.)

●When FES is suspected, chest imaging, typically chest radiography and/or CT, should be performed. CT or magnetic resonance imaging (MRI) of the brain should be performed in those with neurologic symptoms. Routine laboratory studies should be drawn including complete blood count and coagulation studies. Measuring free fatty acid or c-reactive protein levels, examining urine or sputum for the presence of fat, and invasive procedures including fat analysis from a wedged sample aspirated from a pulmonary artery catheter, bronchoalveolar lavage fluid, or tissue biopsy are not routinely performed since their diagnostic utility is unclear. (See 'Diagnostic evaluation' above.)

●The differential diagnosis of FES includes other embolization syndromes (thrombus, amniotic fluid, tumor, foreign body, air), acute alveolar filling diseases (eg, heart failure, pneumonia, and acute respiratory distress syndrome) and cutaneous vasculitic disorders (eg, systemic lupus erythematosus). (See 'Differential diagnosis' above.)

●FES is a clinical diagnosis that can be made when the classic triad of hypoxemia, neurologic abnormalities, and the petechial rash occurs in an appropriate clinical setting. However, since the presenting manifestations are nonspecific and the rash occurs in fewer than half of cases, the diagnosis of FES is more commonly made when clinical manifestations occur in the appropriate clinical setting and other relevant diagnoses have been excluded. (See 'Diagnosis' above.)

●FES in individuals with sickle cell disease can cause acute chest syndrome and multiorgan failure that can be fatal. Treatment with urgent red blood cell exchange transfusion is essential. For individuals without sickle cell disease, treatment of FES is largely supportive. Systemic corticosteroids are not routinely administered but may be reserved for severe or refractory cases. (See 'Treatment' above.)

●In those at risk of FES, interventions that have been shown to prevent or reduce the incidence and/or severity of FES are early immobilization of fractures, operative correction rather than conservative management (ie, traction alone), and limitation of the intraosseous pressure during orthopedic procedures. We do not advocate for the routine administration of prophylactic postoperative systemic corticosteroid therapy since most cases resolve spontaneously, FES is relatively uncommon, and data to support their use are fundamentally flawed. (See 'Prevention' above.)

●Most patients with FES fully recover spontaneously. In most cases, symptoms are transient and fully reversible, often within a few days, although features may persist beyond one week when FES is severe. Although reported mortality rates range from 5 to 15 percent, the true mortality is probably lower. (See 'Prognosis' above.)