Fat Embolism

Etiology

Traumatic Causes

Traumatic causes of FES are more common than nontraumatic causes. Trauma-related FES can occur from long bone fractures, such as femur and tibia fractures, as well as pelvic fractures. Surgical procedures such as pelvic or knee arthroplasty, intramedullary nailing, and reaming can cause FES. Intramedullary nail insertion techniques that can increase the likelihood of FES development include increased reaming velocity, overzealous nailing of the medullary cavity, and a widened gap between the nail and the bone cortex.

Other rare traumatic conditions that can cause FES include the following:

• Massive soft tissue damage
• Crush injury
• Prolonged cardiopulmonary resuscitation
• Severe burn involving more than 50% of body surface area
• Bone marrow transplant
• Liposuction
• Median sternotomy

Nontraumatic Causes

Cases of nontraumatic FES are very rare and include the following:

• Fatty Liver
• Acute or chronic pancreatitis
• Therapy with corticosteroid
• Infusion of fat emulsion
• Lymphography
• Hemoglobinopathies
• Sickle cell disease
• Thalassemia

Several risk factors are associated with the development of FES. The following conditions increase the risk of developing FES:

• Young age
• Closed fractures
• Multiple fractures
• Prolonged conservative treatment of long bone fracture

Epidemiology

Variable data on the incidence of fat embolism and FES have been reported. Clinical diagnosis of small fat embolism or mild cases of FES may be missed. Results from 1 study showed that approximately 67% of patients with orthopedic trauma had fat globules in their blood. If the blood sample is taken from a site near the fracture, the incidence is closer to 95%. Fat embolism and FES can also occur intraoperatively while repairing a long bone fracture. Transesophageal echocardiography detected fat embolism in nearly 41% of patients. Fat embolism has a higher incidence than FES. Results from the landmark study carried out by Gurd, using the established clinical criteria, showed a 19% incidence of FES in a group of trauma patients. Since early open reduction and internal fixation has become the standard of care for repairing long bone fractures, the incidence of fat embolism and FES has gradually decreased. Results from most recent studies showed an incidence of about 1% to 11%.

Pathophysiology

Fat particles or globules are released from the organs of primary origin and enter the microcirculation, causing damage to the capillary beds. The disruption affects microcirculatory homeostasis in the brain, skin, eyes, and heart. Two main theories attempt to explain the development of FES: mechanical and biochemical.

Mechanical Theory

Gassling et al postulated that large fat droplets are released into the venous system. Elevation of the intramedullary pressure from trauma or surgical procedures leads to the release of fat into the venous sinusoids. From the venous system, these fat globules are deposited in the pulmonary capillary bed, where they travel to the brain through the arteriovenous shunt. Initially, no valid explanation existed for the development of FES in patients without a patent foramen ovale, but the presence of an arteriovenous shunt clarifies the mechanism. Additionally, intravascular fat droplets are deformable, which explains their ability to traverse the pulmonary vasculature. The pathophysiologic changes produced by fat droplets include the following:

• Elevated pulmonary artery pressure
• Impairment of oxygen exchange from ventilation-perfusion mismatch
• Systemic effects on end organs such as the brain, kidneys, and skin

The deposition of fat droplets in the brain produces a cascade of reactions. Disruption of microcirculation leads to systemic inflammatory response syndrome, local inflammation, and ischemia. The release of inflammatory mediators and vasoactive amines, such as histamine and serotonin, increases vascular permeability and vasodilation, leading to hypotension and hypoperfusion.

Biochemical Theory

Baker et al proposed this theory to explain the development of FES. According to this theory, the precipitating event, whether traumatic or nontraumatic, triggers a hormonal change in the body. This change leads to the release of free fatty acids (FFAs) and chylomicrons. The presence of acute-phase reactants, such as C-reactive protein, causes the chylomicrons to coalesce and migrate. Baker et al attributed the development of FES to FFAs. Pneumocyte hydrolysis of fat particles generates FFAs, which migrate to other organs, causing multiple organ dysfunction syndrome. The biochemical theory helps explain the development of FES in patients without trauma.

Histopathology

The pathogenesis of FES is poorly understood, and evaluating the progression of histopathologic changes in patients is not practical. Animal model studies have included injecting triolein, a form of fat found in bone marrow, into the caudal veins of rats and monitoring lung changes over an 11-day period. The subsequent histopathologic examination of the lung tissues included staining for fat, collagen, and smooth muscle actin. The most notable change was a decrease in arterial and arteriolar patency over the first 96 h. However, arterial and arteriolar patency returned to normal toward the end of the observation period, on day 11. Significant inflammation and fibrosis around the blood vessels were also observed. These changes were noticeable within the first couple of hours after infusion and persisted throughout the study. Although results from a rat model provided insight into the changes that can occur in patients with fat embolism or FES, direct extrapolation to patients remains limited.

History and Physical

A fat embolism can travel to most organs in the body. Fat embolism and FES are multiorgan disorders that can damage the kidneys, heart, skin, brain, and lungs. Fat embolism typically manifests 24 to 72 hours after the initial insult.

History

The history should elicit the time of symptom onset. Additionally, because most cases of fat embolism and FES are related to orthopedic trauma, the time and mechanism of the trauma and intraoperative maneuvers should be noted in the history. For example, sickle cell disease and other hemoglobinopathies can precipitate FES. Patients should be asked about a family history of sickle cell disease and any complications, such as acute chest syndrome, vaso-occlusive crises, or avascular necrosis of the long bones. The history of drug ingestion or alcohol use that can trigger pancreatitis leading to FES should also be clarified. The symptoms of fat embolism and FES are nonspecific. Patients might report the following:

• Pain related to bone fracture
• Nausea
• General weakness
• Malaise
• Difficulty breathing
• Headache

Signs and Symptoms

Clinical manifestations include but are not limited to the following:

Respiratory:

• Tachypnea
• Tachycardia
• Diaphoresis

Central nervous system:

• Agitation from hypoxia
• Restlessness
• Change in mental status
• Seizure
• Coma
• Skin
• Petechial rash
• Eye

Retinal hemorrhage

Physical ExaminationThe examination of a patient with FES should be very thorough. Particular attention should be paid to the patient's general appearance.

General appearance: Most patients with FES are anxious, agitated, and ill-appearing.

Respiratory system: Assess for abnormal breath sounds, work of breathing, and evidence of respiratory distress or impending respiratory failure.

Cardiovascular: Blood pressure and heart rate may initially be high, but patients may develop cardiovascular collapse with ensuing hypotension.

Central nervous system: A Glasgow Coma Scale score of less than 8 indicates that the airway should be secured and the patient should receive mechanical ventilation. Symptoms involving the central nervous system in FES are thought to arise from cerebral edema rather than cerebral ischemia.

Skin: Usually, a petechial rash on the skin, along with the above risk factors, should alert the clinician to possible FES.

Eye: A fundoscopic examination is necessary to check for retinal hemorrhage.

Evaluation

Diagnosis of FES can be very challenging because the signs and symptoms can be vague. No universally accepted diagnostic criteria exist. Based on experience and research, several authors have proposed diagnostic criteria for FES.[3][4][5] Gurd et al in 1970 and later Wilson in 1974 put forward the following diagnostic criteria: 2 major criteria or at least one major criterion and 4 minor criteria.

Major Criteria

• Petechial rash
• Respiratory insufficiency
• Cerebral involvement in patients without head injury

Minor Criteria

• Fever greater than 38.5 °C
• Tachycardia with heart rate greater than 110 bpm
• Retinal involvement
• Jaundice
• Renal signs
• Anemia
• Thrombocytopenia
• High erythrocyte sedimentation rate
• Fat macroglobulinemia

Schoenfeld Criteria

Results from another report by Schoenfeld et al proposed a quantitative means for diagnosing FES. A cumulative score greater than 5 is required for the diagnosis.

• 5 points: Petechiae rash 
• 4 points: Diffuse infiltrate on chest radiography
• 3 points: Hypoxemia
• 1 point (for each): Fever, tachycardia, and confusion

Lindeque Criteria

Lastly, Lindegue et al suggested using respiratory symptoms alone as the diagnostic criteria for FES. This criterion has not gained worldwide acceptance compared with the Gurd, Wilson, and Schoenfeld criteria.

• Sustained PaO2 less than 8 kPa
• Sustained PCO2 greater than 7.3 kPa
• Sustained respiratory rate greater than 35 bpm despite sedation
• Dyspnea, increased work of breathing, anxiety, and tachycardia

Ancillary Studies

Apart from the aforementioned diagnostic criteria, other ancillary studies are needed to aid in the diagnostic workup, including the following:

Complete blood count: Anemia and thrombocytopenia are very common in FES.

Comprehensive metabolic panel: Metabolic acidosis, elevated blood urea nitrogen (BUN), and elevated creatinine levels are common in patients with FES.

Arterial blood gas:

Ventilation-perfusion mismatch is a hallmark of FES. The arterial blood gas analysis usually shows a low partial pressure of oxygen, resulting in hypoxemia. An increased alveolar-arterial (A-a) gradient is common in FES. The A-a gradient is the difference between the partial pressure of oxygen in the alveolus and the partial pressure of oxygen in the pulmonary artery. In FES, the pulmonary blood vessels are occluded, causing perfusion impairment with normal ventilation. This process results in ventilation-perfusion mismatch.

To calculate the A-a gradient, use the formula:

A-a Gradient = PAO2 − PaO2,

PaO2 is the partial pressure of oxygen in the pulmonary artery.PAO2 is the partial pressure of oxygen in the alveolar sac.

To calculate the PAO2 and PaO2, use the following equations:

PAO2 = FiO2 (Atmospheric Pressure − Water Vapor Pressure) − (PCO2 / R),

PaO2 = Partial Pressure of Oxygen in the pulmonary artery.

PaO2 in arterial blood gas can be used as follows:

FiO2 is the concentration of inspired oxygen expressed as a fraction. FiO2 is around 0.21 in room air.

Atmospheric pressure is the barometric pressure (760 mm Hg at sea level). Water vapor pressure is 48 mm Hg at 37 °C. PaCO2 is the partial pressure of alveolar carbon dioxide. If approximated, PaCO2 is presumed to be equal to arterial PCO2. PACO2 is presumed to be equal to 40 mm Hg.

R is the respiratory quotient, equating to about 0.8 on a regular diet. The normal alveolar partial pressure of oxygen is calculated as follows:

PAO2 = Alveolar Partial Pressure of Oxygen = FiO2 × (Atmospheric Pressure − Water Vapor Pressure) − (PCO2 / R)

0.21 × (760 − 48) − (40 / 0.8) = 150 − 50 = 100 mm Hg,

The normal partial pressure of oxygen in arterial blood is 75 to 100 mm Hg.

PAO2 − PaO2 = 100 mm Hg − 75 mm Hg = 25 mm HgPAO2 − PaO2 = 100 mm Hg − 100 mm Hg = 0 mm Hg

These calculations imply that the A-a gradient can range from 0 to 25 mm Hg. The normal A-a gradient is usually less than 10 mm Hg. However, ventilation-perfusion mismatch can significantly increase the A-a gradient in FES.

Bronchoalveolar Lavage

tool for FES. Lipid inclusions in macrophages might suggest FES but are not specific, as these findings can be seen in other clinical conditions. Moreover, the procedure is time-consuming and invasive, and it might not yield the best diagnostic yield. Attempts to develop biological markers for FES have been disappointing due to low specificity. Results from studies have demonstrated elevated lipase, free fatty acid, and phospholipase A2 levels in FES, but these findings are also observed in other lung diseases. Blood, urine, and sputum analysis might show the presence of fat globules. Again, this finding is nonspecific in fat embolism and FES.

Imaging Studies

Chest radiography:

The chest radiography reveals the presence of the following:

• Diffuse interstitial marking
• Pulmonary edema
• Lung infiltrate
• Flake-like pulmonary marking (snowstorm appearance)

CT scan of the chest:

• Areas of  increased vascular congestion
• Pulmonary edema

Imaging of the brain:

CT is not a very sensitive imaging study of the brain in FES. However, CT can be used to exclude other causes of altered mental status, such as epidural, subdural, or subarachnoid bleeding. MRI is the most sensitive test for demonstrating brain changes related to FES. Takahashi et al categorized these changes into the following 4 grades based on the size and distribution of the lesions on T2-weighted imaging:

• Grade 0: Normal
• Grade 1: Mild
• Grade 2: Moderate
• Grade 3: Severe

Lesions seen in FES are distributed in the following areas of the brain:

• Centrum semiovale
• Subcortical white matter
• Ganglionic regions
• Thalamus

Results from their study demonstrated that the resolution of these lesions correlates well with clinical recovery from FES. Some of these lesions develop as a result of vasogenic edema from free fatty acids (FFAs), which are potentially neurotoxic. Transesophageal echocardiography may be used intraoperatively to monitor the release of fat globules or bone marrow materials into the bloodstream during intramedullary nailing and reaming. Fat emboli in the pulmonary artery can increase the pulmonary artery wedge pressure and right ventricular afterload.

Treatment / Management

Pharmacotherapy

No specific treatment exists for fat embolism or FES. Based on experimental studies, an attempt was made to use dextrose infusion to decrease FFA mobilization. Ethanol was also used as an agent to inhibit lipolysis. In clinical practice, neither intervention has proven benefits.[6][7][8] Results from experimental use of heparin in an animal model showed benefit, but it is no longer used in clinical practice due to the risk of bleeding. No proven clinical benefit with heparin in FES has been demonstrated. Corticosteroid therapy has been proposed for the treatment of FES based on the following effects:(B2)

• Inhibition of complement-activated leucocyte aggregation
• Limiting FFA level
• Membrane stabilization

Results from a meta-analysis of 7 randomized controlled trials using corticosteroid prophylaxis showed a nearly 77% reduction in the risk of FES in patients with long bone fractures. However, no differences were found in mortality, infection, or avascular necrosis between the treatment and control groups. For this reason, the use of corticosteroids remains very controversial.

Inferior Vena Cava Filter

Inferior vena cava filter placement has been proposed as a measure to prevent the showering of fat emboli. However, inferior vena cava filter placement has not been studied sufficiently as a prophylactic treatment for FES.

Operative Measures

Early open reduction and internal fixation of long-bone fractures is highly recommended. The incidence of FES is higher in patients with long bone fractures treated conservatively. Using internal fixation devices in the treatment of long bone fractures significantly reduces the incidence of FES. During operative fixation of long bone fractures, care must be taken to limit intramedullary pressure, because high pressure is associated with increased fat emboli entering the systemic circulation. Some techniques used in orthopedic surgical procedures to reduce embolization include:

• Lavage of bone marrow before fixation
• Venting of the femoral bone
• Drilling of small holes in the cortex of the bone to lower intramedullary pressure

None of these maneuvers has been shown to reduce FES.

Supportive Care

Once a patient develops FES, supportive care is the mainstay treatment. Supportive care is geared toward ensuring adequate oxygenation of the end organs.

Goals of supportive care:

• Provision of adequate oxygenation and ventilation
• Maintenance of adequate hemodynamic stability
• Transfusion of packed red blood cells to improve oxygen delivery if indicated
• Prophylaxis of deep venous thrombosis with a sequential compression device
• Adequate nutrition and hydration

Supplemental oxygen might be required, and if the patient develops fulminant acute respiratory distress syndrome, intubation and mechanical ventilation might be required.

Albumin:

Albumin is recommended as part of the resuscitation tools for hypovolemia. This binding restores intravascular volume and helps to bind free fatty acids. This prevents the systemic dissemination of fat globules.

Indications for intubation:

• Altered mental status with Glasgow Coma Scale score of less than 8
• Moderate to severe respiratory distress with no improvement with noninvasive support

FES might also cause pulmonary hypertension with right ventricular failure. Inotropic support with dobutamine or a phosphodiesterase inhibitor such as milrinone might be required. Cerebral edema, if present, might require treatment with the following:

• Mannitol
• Hypertonic saline
• Intracranial pressure monitors

Differential Diagnosis

The differential diagnosis of fat embolism and FES is related to each system that this disease affects

Respiratory

FES and fat embolism should be distinguished from pulmonary contusion, pulmonary edema, aspiration pneumonia, and pulmonary thromboembolism. CT of the chest can aid in distinguishing FES from other lung pathologies. Pulmonary contusion typically develops about 6 to 10 hours after a chest injury. On CT of the chest, pulmonary contusion appears as localized ground-glass opacification in the lung. In pulmonary edema, CT findings include symmetric vascular engorgement, pleural effusion, and ground-glass opacification. The gold standard for diagnosing thromboembolism is chest CT angiography, which classically shows a filling defect.

Central Nervous System

Clinical conditions affecting the central nervous system that should be considered in the differential diagnosis:

• Meningitis
• Encephalitis
• Brain tumor
• Epidural hemorrhage
• Subdural hemorrhage
• Subarachnoid hemorrhage

All of the conditions listed above can cause altered mental status with a change in the Glasgow Coma Scale score, mimicking FES. CT of the brain can help delineate hemorrhage or a tumor. Meningitis and encephalitis can be ruled out with a lumbar puncture and cerebrospinal fluid analysis.

Skin Rash

The following conditions can present with petechial skin rashes

• Idiopathic thrombocytopenic purpura
• Thrombotic thrombocytopenic purpura
• Leukemia

All these blood disorders should be considered in the presence of skin rash and other associated clinical signs and symptoms. Consultation with a hematologist-oncologist and dermatologist can help establish the clinical diagnosis.

Prognosis

In patients with traumatic FES, the prognosis depends on early open reduction and internal fixation of the long bone fracture. Most patients with adequate supportive therapy can recover from the neurologic, respiratory, and retinal changes associated with FES. Results from the most recent studies showed mortality of 7% to 10%. The most common causes of morbidity and mortality include acute respiratory distress syndrome and cerebral edema.