Fat Embolism

Background

For those who manage major trauma victims, the topic of fat embolism weighs heavily on the mind. The incidence of this problem can approach 90% in patients who have sustained major injuries. If it progresses to the rare clinical entity known as fat embolism syndrome (FES),^[1] a systemic inflammatory cascade affecting multiple organ systems, morbidity and mortality are high. Accordingly, swift diagnosis and treatment of fat embolism are paramount for ensuring the survival of this patient population.^[2]

Ernst Von Bergmann, in 1873, was the first person credited with making a clinical diagnosis of fat embolism. He did this on the basis of knowledge gathered from experiments with cats 10 years previously, in which he injected them with intravenous oils. Von Bergmann later described a patient who fell off a roof and sustained a comminuted fracture of the distal femur; 60 hours after the injury, the patient developed dyspnea, cyanosis, and coma.^[2]

The diagnosis of FES is mainly a clinical one. It is dependent on clinical identification of dyspnea, petechiae, and cognitive dysfunction in the first few days following trauma, long bone fracture, or intramedullary surgery. Various laboratory studies and imaging modalities exist to aid in its discovery (see Presentation and Workup). Supportive measures are the mainstay of treatment; thus, efforts are targeted at prevention, early diagnosis, and symptom management (see Treatment).

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Pathophysiology

The exact mechanism of fat embolism and its evolution to the entity known as FES has not been fully elucidated, but a number of experimental models have been proposed. Asymptomatic fat embolism to the pulmonary circulation almost always occurs with major trauma, including elective surgical procedures such as intramedullary nailing of long bones, which has been demonstrated with echocardiography. The development of FES is rare, occurring in 0.5-11% of cases.^{[3, 4]}

Although poorly understood, the development of FES is attributed to a series of biochemical cascades resulting from the mechanical insult sustained in major trauma. Release of fat emboli leads to occlusion of the microvasculature, triggering an inflammatory response that is clinically manifested by dermatologic, pulmonary, and neurologic dysfunction.^{[5, 6]} (See the images below.)

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Frozen section of lung stained with oil red O showing multiple orange red fat globules of varying sizes in septal vasculature. Image courtesy of Dr AV....

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Hematoxylin-eosin stain of section of lungs showing blood vessel with fibrinoid material and optical empty space indicative of presence of lipid disso....

Pulmonary consequences of FES are clinically similar to those of acute respiratory distress syndrome (ARDS) and almost always occur. They are usually the initial manifestation of FES, typically appearing within 24 hours after the traumatic insult. They result from injury to the pulmonary capillary endothelium caused by free fatty acids that were hydrolyzed by lipoprotein lipase, releasing local toxic mediators. These mediators cause increased vascular permeability, resulting in alveolar hemorrhage and edema and causing respiratory failure and ARDS.^{[7, 8]}

Approximately 20-30% of the population have a patent foramen ovale; this may explain how fat emboli that pass through the pulmonary circulation end up with systemic manifestations of FES, particularly involving the brain and kidneys. As a result of the occluded cerebral vasculature, patients exhibit gross encephalopathy, localized cerebral edema, and white-matter changes.^{[7, 9, 10]}

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Etiology

Causes of FES include the following:

• Blunt trauma (associated with 90% of all cases)^{[11, 12]}
• Acute pancreatitis
• Diabetes mellitus
• Burns
• Joint reconstruction
• Liposuction
• Cardiopulmonary bypass
• Decompression sickness
• Parenteral lipid infusion
• Sickle cell crisis^{[13, 14, 15]}
• Pathologic fractures

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Epidemiology and Prognosis

Fat embolism occurs in up to 90% of all trauma patients.^{[16, 12]}  FES accounts for only 2-5% of patients who have long-bone fractures.^[9]

The duration of FES is difficult to predict because the syndrome is often subclinical or overshadowed by other illnesses or injuries. Increased alveolar-to-arterial oxygen gradient and neurologic deficits, including coma, may last days or weeks. Hematologic aberrations due to FES frequently are indistinguishable from those due to other causes common in these patients.

As in ARDS, pulmonary sequelae usually resolve almost completely within 1 year. Residual subclinical diffusion capacity deficits may exist. FES alone has not been reported to cause global anoxic injury, but it may contribute in conjunction with other cerebral insults. Residual neurologic deficits may range from nonexistent to subtle personality changes to memory and cognitive dysfunction to long-term focal deficits.

Outcomes in patients who develop FES are bleak if the syndrome is not identified early and aggressive supportive measures are not initiated. When action is taken early in the disease course, the prognosis is generally favorable, with a mortality of less than 10%.^[2]

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History

The history of a patient with fat embolism may include the following:

• Major blunt trauma, usually resulting in long-bone fractures, pelvic fractures, or both
• Elective long-bone orthopedic procedures or cardiothoracic procedures
• Parenteral lipid infusion
• Recent corticosteroid administration

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Physical Examination

Gurd and Wilson outlined an approach to diagnosing fat embolism syndrome (FES) on the basis of major and minor criteria.^[17] One major criterion, four minor criteria, and the presence of macroglobulinemia are required for the diagnosis.

Major criteria for diagnosing FES are as follows:

• Symptoms and radiologic evidence of respiratory insufficiency
• Cerebral sequelae unrelated to head injury or other conditions
• Petechial rash

Minor criteria are as follows:

• Tachycardia (heart rate >110 beats/min)
• Pyrexia (temperature >38.5° C)
• Retinal changes of fat or petechiae
• Renal dysfunction
• Jaundice
• Acute drop in hemoglobin level
• Sudden thrombocytopenia
• Elevated erythrocyte sedimentation rate
• Fat microglobulinemia

Early signs of the systemic inflammatory response syndrome (SIRS) may herald the onset of FES. Tachypnea, dyspnea, and hypoxia appear as a result of ventilation-perfusion abnormalities 12-72 hours after injury.

Alert clinicians may notice reddish-brown nonpalpable petechiae developing over the upper body, particularly in the axillae, within 24-36 hours of insult or injury. These petechiae occur in 20-50% of patients and resolve quickly, but they are virtually diagnostic in the right clinical setting. Subconjunctival and oral hemorrhages and petechiae can also appear.^[9]

Central nervous system dysfunction initially manifests as agitation or delirium but may progress to stupor, seizures, or coma and is frequently unresponsive to correction of hypoxia.^[18] Retinal hemorrhages with intra-arterial fat globules are visible upon funduscopic examination.

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Laboratory Studies

An otherwise unexplained increase in pulmonary shunt fraction alveolar-to-arterial oxygen tension difference, especially if it occurs within 24-48 hours of a sentinel event associated with fat embolism syndrome (FES), is strongly suggestive of the syndrome. Thrombocytopenia, anemia, and hypofibrinogenemia are indicative of FES; however, they are nonspecific.

Urinary fat stains are not considered to be sensitive or specific enough for diagnosing FES or for determining the risk of it. Fat globules in the urine are common after trauma.^[11]

Preliminary investigations of the cytology of pulmonary capillary blood obtained from a wedged pulmonary artery catheter revealed fat globules in patients with FES and showed that this method may be beneficial in early detection of patients at risk.

In the future, genotyping for polymorphisms associated with increased susceptibility to inflammatory stimuli may help identify those at risk for FES. Specific antibody therapy targeting inflammatory molecules has not been useful.

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Radiography and Computed Tomography

Serial chest radiographs reveal increasing diffuse bilateral pulmonary infiltrates within 24-48 hours of the onset of clinical findings.

Findings from noncontrast computed tomography (CT) of the head performed because of alterations in mental status may be normal or may reveal diffuse white-matter petechial hemorrhages consistent with microvascular injury.

Because the embolic particles are lodged in the capillary beds, helical CT findings may be normal. Parenchymal changes consistent with lung contusion, acute lung injury, or acute respiratory distress syndrome (ARDS) may be evident, depending on the burden of secondary lung injury.

Nodular or ground-glass opacities in the setting of trauma suggest fat embolism.^[20]  In one retrospective review, ground-glass opacities in the setting of trauma were the most common findingings on helical chest CT; 67% of all FES subjects enrolled had ground-glass opacities.^[21] The presence of ground-glass opacities involving more than 75% of lung parenchyma with the concomitant presence of consolidation correlates with disease severity.^{[21, 19]}

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Ultrasonography

In a small case study, five patients with trauma were monitored with intracranial Doppler ultrasonography, two during intraoperative nailing of long-bone fractures.^[22] Cerebral microembolic signals were detected as long as 4 days after injury.

Transesophageal echocardiography (TEE) may be of use in evaluating the intraoperative release of marrow contents into the bloodstream during intramedullary reaming and nailing. The density of the echogenic material passing through the right side of the heart correlates with the degree of reduction in arterial oxygen saturation.

Repeated showers of emboli on TEE have been noted to increase right heart and pulmonary artery pressures. Embolization of marrow contents through a patent foramen ovale also has been noted. However, evidence of embolization obtained by means of TEE is not correlated with the actual development of FES.

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Other Imaging Studies

Scant data exist regarding magnetic resonance imaging (MRI) findings in patients with FES; however, in one small patient group, multiple nonconfluent, hyperintense lesions were seen on proton-density– and T2-weighted images.^[23]

Nuclear ventilation-perfusion imaging of the lungs may be performed when pulmonary embolism is suspected. The findings from this scan may be normal or may demonstrate subsegmental perfusion defects.

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Bronchoalveolar Lavage With Staining for Fat

Bronchoalveolar lavage (BAL) specimens have been evaluated in trauma patients and sickle-cell patients with acute chest syndrome, and the results have been mixed.^{[24, 25]}

Lipid inclusions commonly appear in patients with traumatic and nontraumatic respiratory failure; the standard cutoff in the BAL studies—5% fat-containing macrophages—results in a low specificity for the test. To improve specificity, some authors suggest raising the cutoff to 30%. At present, using BAL to aid in the diagnosis of FES or to predict its likelihood is controversial.

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Supportive Medical Care

Specific medical therapy for fat embolism and fat embolism syndrome (FES) does not exist at this time, and supportive measures have not been tested in adequate randomized, controlled trials. Treatments such as heparin, dextran, and steroids have not been shown to help reduce morbidity and mortality, but methylprednisolone given prophylactically may have beneficial effects.^[26]

Current care of patients with fat embolism is aimed at supporting physiologic derangements and includes the following:

• Maintenance of adequate oxygenation and ventilation with open lung strategies such as the use of airway pressure release ventilation (APRV)
• Maintenance of hemodynamic stability
• Administration of blood products as clinically indicated
• Hydration
• Prophylaxis of deep venous thrombosis and stress-related gastrointestinal bleeding
• Nutrition

Judicious use of crystalloids, colloids, and diuretics is necessary; volume depletion may precipitate shock and organ dysfunction, but volume overload may worsen the hypoxia.

Continuous pulse oximetry monitoring in at-risk patients (eg, patients with long-bone fractures and multiple trauma), may facilitate early detection of desaturation, allowing prophylactic administration of oxygen and possibly steroids, thereby decreasing the chances of hypoxic injury and systemic complications of FES.^[27]

At-risk patients should be placed in a monitored setting, and appropriate services should be consulted. If a patient has sustained major traumatic injuries, transfer to the nearest trauma center with 24-hour in-house surgical intensive care is essential.

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Surgical Management

Early stabilization of long-bone fractures is recommended to minimize bone marrow embolization into the venous system.^[28] Rigid fixation within 24 hours has been shown to yield a fivefold reduction in the incidence of FES.^[9]

Appropriate surgical technique, particularly in reaming or nailing the marrow, may help reduce the volume of fat embolization. Utilization of a vacuum or venting during reaming has been shown to decrease the incidence of fat embolization.^[9]

Prophylactic placement of inferior vena cava filters may help reduce the volume of fat that reaches the heart in at-risk patients.

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Prevention

Several studies performed in the late 1970s attempted to show that use of methylprednisolone as a “membrane stabilizer” would reduce the incidence of FES, but follow-up work has yet to reproduce these findings.^{[29, 30]}

A meta-analysis of randomized trials studying corticosteroid use as a preventive adjunct in patients with long-bone fractures uncovered 104 studies, of which only seven met the authors' eligibility criteria for analysis.^[31] Although the pooled analysis of 389 patients found that corticosteroids reduced the risk of FES by 78%, the authors warned that these studies were of poor quality and held to standards of the 1970s.^{[31, 32]}

The use of heparin has been shown to reduce the degree of pulmonary comprise and intravascular coagulation despite the risk of hemorrhage and intravascular lipolysis; however, this practice has not been shown to yield a statistically significant benefit.

Ethanol (which decreases lipolysis) and dextrose (which decreases free fatty acid mobilization) have been used as prevention modalities, but at present, there is little to no evidence to support the use of these agents in FES.^[32]

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Medication Summary

The goals of pharmacotherapy for fat embolism syndrome (FES) are to reduce morbidity and prevent complications. Corticosteroids may be used in certain cases. The best dosing protocol for corticosteroids in the prophylaxis of FES has not been established, and currently, there is no treatment regimen.

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Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol, A-Methapred)

• Dosing, Interactions, etc.

Clinical Context:  Methylprednisolone is most often used for the prophylaxis of FES in at-risk patients. Currently, there are no good data to support the use of this agent over the use of any other steroids.

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Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli.

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Normal saline (NS, 0.9% NaCl)

Clinical Context:  NS restores interstitial and intravascular volume. It is used in initial volume resuscitation.

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Lactated Ringer

Clinical Context:  LR solution restores interstitial and intravascular volume. It is used in initial volume resuscitation.

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Class Summary

Isotonic sodium chloride solution (normal saline [NS]) and lactated Ringer (LR) solution are isotonic crystalloids, the standard intravenous (IV) fluids used for initial volume resuscitation. They expand the intravascular and interstitial fluid spaces. Typically, about 30% of administered isotonic fluid stays intravascular; therefore, large quantities may be required to maintain adequate circulating volume.

Both fluids are isotonic, and they have equivalent volume-restorative properties. Whereas some differences exist between the metabolic changes observed with the administration of large quantities of one fluid and those observed with high-volume administration of the other, for practical purposes and in most situations, these differences are clinically irrelevant. No demonstrable difference in hemodynamic effect, morbidity, or mortality exists between resuscitation with NS and resuscitation with LR solution.

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Albumin (Buminate, Albuminar-5, Albuminar-25, Plasbumin-5, Plasbumin-25)

• Dosing, Interactions, etc.

Clinical Context:  Albumin has been recommended for volume resuscitation. It is useful for plasma volume expansion and maintenance of cardiac output. It also binds with the fatty acids and may thus decrease the extent of lung injury. Five-percent solutions are indicated to expand plasma volume, whereas 25% solutions are indicated to raise oncotic pressure.

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Class Summary

Colloids are used to provide oncotic expansion of plasma volume. They expand plasma volume to a greater degree than isotonic crystalloids and reduce the tendency of pulmonary and cerebral edema. About 50% of the administered colloid stays intravascular.

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