Continuing Education Activity

Fat embolism (FE) and fat embolism syndrome (FES) are clinical phenomena characterized by the systemic dissemination of fat emboli within the systemic circulation. The dissipation of fat emboli disrupts the capillary bed and affects microcirculation, causing a systemic inflammatory response syndrome. This activity reviews the pathophysiology, diagnosis, and presentation of fat embolism syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the difficulty in making a diagnosis of fat embolism syndrome.

• Evaluate the presentation of fat embolism syndrome.

• Interpret the treatment of fat embolism syndrome.

• Communicate the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by fat embolism syndrome.

Introduction

 Fat embolism and fat embolism syndrome (FES) are clinical phenomena characterized by the systemic dissemination of fat emboli within the systemic circulation. The dissipation of fat emboli disrupts the capillary bed and affects microcirculation, causing a systemic inflammatory response syndrome.[1][2][3][4] End-organ manifestation typically involves the skin, the central nervous system, the lungs, and the retina. FES is most common in patients with orthopedic trauma. It also can occur in nontraumatic conditions such as acute or chronic pancreatitis, bone marrow transplant, or liposuction.

In most instances, diagnosis is usually established during the autopsy. Fat embolism is the presence of fat globules in microcirculation, whereas FES is a systemic manifestation of the dissemination of fat molecules or globules in microcirculation. FES is a continuum of fat embolism. Zenker first described the clinical presentation of FES in 1863 in a patient suffering from a crush injury. In 1873, Von Bergmann clinically diagnosed the condition for the first time. Since the initial description by Zenker and Von Bergmann, several articles and studies have been published on this disease entity. In the early 1970s, Gurd proposed a clinical criterion for diagnosing FES. This was later modified by Wilson in 1974 in conjunction with Gurd and is the most commonly used clinical criteria for diagnosis. Since the majority of reported cases of fat embolism are seen in patients with orthopedic trauma, most research on this condition is in orthopedic patients. Even though the clinical criteria proposed by Gurd et al and Wilson can help or aid in the diagnosis, FES still poses a major diagnostic challenge to most clinicians.[1][2]

Etiology

Traumatic Causes

Traumatic causes of FES are more common than nontraumatic causes. Trauma as a cause of FES can occur from the fracture of the long bones, such as the femur and tibia, and also the pelvis. Operations such as pelvis or knee arthroplasty and intramedullary nailing and reaming can cause FES. The technique of inserting the intramedullary nails that can increase the likelihood of development of FES includes increased velocity in reaming, overzealousness in the nailing of the medullary cavity, and the widened gap between the nail and the cortex of the bone

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 transplantation
• 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 management 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 and go unnoticed. In 1 study, about 67% of orthopedic trauma patients have fat globules in their blood. If the blood sample was taken from a site close to the area of the fracture, the incidence is closer to 95%. Fat embolism and FES can also occur intraoperatively while repairing a long bone fracture. A transesophageal echocardiogram detected fat embolism in nearly 41% of patients. Fat embolism has a higher incidence than FES. In the landmark study carried out by Gurd, using the established clinical criteria, an incidence of 19% of FES was reported in a group of trauma patients. Since early open reduction and internal fixation have become the standard of care for repairing fractures of long bones, the incidence of fat embolism and FES has gradually decreased. Most recent studies show 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 the microcirculatory hemostasis in the brain, skin, eyes, and heart. Two main theories try 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 from trauma or surgery 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 via the arteriovenous shunt into the brain. Initially, there was no valid explanation for the development of FES in patients with no patent foramen ovale, but the presence of an arteriovenous shunt clarifies this. Also, intravascular fat droplets are deformable, hence their ability to transverse the pulmonary vasculature. The pathophysiological changes produced by fat droplets include the following:

• Elevated pulmonary artery pressure
• Impairment of oxygen exchange from ventilation-perfusion mismatch
• Systemic effects on end-organisms such as the brain, kidney, 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 like histamine and serotonin increases vascular permeability and vasodilation, with ensuing hypotension and hypoperfusion.

Biochemical Theory

Baker et al proposed this theory for the development of FES. According to this theory, the precipitating event, whether traumatic or nontraumatic, triggers a hormonal change in the body system. This leads to the release of free fatty acid (FFA) and chylomicrons. The presence of acute phase reactants, such as C-reactive protein, causes the chylomicron to coalesce and migrate. Baker et al attribute the development of FES to FFA. Pneumocyte hydrolysis of fat particles generates FFA, which migrates to other organs, causing multiple organ dysfunction syndromes. The biochemical theory helps to explain the development of FES in nontraumatic patients.

Histopathology

The pathogenesis of FES is poorly understood, and evaluation of the progression of histopathological changes in patients is not very practical. Animal model studies included injecting Tirolean, a form of fat found in bone marrow, into the caudal veins of rats and monitoring changes in the lungs over an 11-day period. The subsequent histopathological examination of the lung tissues included staining for the smooth muscle's fat, collagen, and actin. The most notable change was a decrease in the patency of the arteries and arterioles over the first 96 hours. Still, there was a return to normal patency towards the end of the observation period, the 11th day. There was also significant inflammation and fibrosis around the blood vessels. These changes were noticeable within the first couple of hours of infusion and persisted for the time frame for which the study was conducted. Although the results of a rat model give insight into the changes that can occur in patients with fat embolism or FES.

History and Physical

A fat embolism can travel to most of the body's organs. Fat embolism and FES are multiorgan diseases 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 and onset of symptoms. Also, since 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.

Sickle cell disease and other forms of hemoglobinopathy can precipitate FES. Patients should be asked about the history of sickle cell disease in family members and any complications of sickle cell disease like acute chest syndrome, vaso-occlusive crises, or avascular necrosis of long bones. The history of drug ingestion or alcoholism that can trigger pancreatitis leading to FES should also be clarified. The symptoms of fat embolism and FES are nonspecific. Patients might complain of the following:

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

Signs and Symptoms

These 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 Examination

The 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-looking.

Respiratory system 

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

Cardiovascular

The blood pressure and heart rate might be high in the beginning, but patients might suffer a cardiovascular collapse with ensuing hypotension

Central nervous system 

A Glasgow Coma Scale assessment of less than 8 indicates that the airway should be secured and the patient placed on 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 with all the risk above factors should alert the clinician about FES.

Eye 

A fundoscopic examination is necessary to check for the presence of retinal hemorrhage.

Evaluation

Diagnosis of FES can be very challenging because the signs and symptoms can be vague. There are no universally accepted diagnostic criteria. 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 criteria and 4 minor criteria.

Major Criteria

• Petechial rash
• Respiratory insufficiency
• Cerebral involvement in non-head injury patients

Minor Criteria

• Fever greater than 38.5 C
• Tachycardia heart rate greater than 110 beats per minute
• Retinal involvement
• Jaundice
• Renal signs
• Anemia
• Thrombocytopenia
• High erythrocyte sedimentation rate
• Fat macroglobulinemia

Schoenfeld Criteria

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 x-ray
• 3 points - hypoxemia
• 1 point (for each) - fever, tachycardia, 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 to the Gurd, Wilson, and Schoenfeld criteria.

• Sustained Pa02 less than 8 kilopascal 
• Sustained PC02 greater than 7.3 kilopascal
• Sustained respiratory rate greater than 35 breaths per minute despite sedation
• Dyspnea, increased work of breathing, anxiety, 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, increased levels of BUN, and creatinine can be seen in patients with FES.

Arterial blood gas

Ventilation-perfusion mismatch is a hallmark of FES. The arterial blood gas analysis usually has a low partial pressure of oxygen, causing 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. The result of this in FES is a ventilation-perfusion mismatch.

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

A-a gradient = PA02 - Pa02

• Pa02 is the partial pressure of oxygen in the pulmonary artery
• PA02 is the partial pressure of oxygen in the alveolar sac

To calculate the PAO2 and Pa02 

• PAO2 = FiO2 (P atmospheric - P water vapor) – (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.

This is around 0.21 at room air.

• P atmospheric is the barometric pressure (760 mmHg at sea level).
• P water vapor is the water vapor pressure (48 mmHg at 37 C).
• PaCO2 is the partial pressure of alveolar carbon dioxide.

If approximated, this is presumed to be equal to arterial PCO2. PACO2 is presumed to be equal to 40 mmHg

• R is the respiratory quotient, equating to about 0.8 on a regular diet.

The normal alveolar partial pressure of oxygen is as follows: 

• PA02 = alveolar partial pressure of O2 = FiO2 × (patmospheric - P water vapor) - (PCO2/R).
• 0.21 × (760 - 48) - (40/0.8) = 150-50 = 100 mmHg

The normal partial pressure of oxygen in arterial blood is between 75 to 100mmHg.

• PA02 - Pa02 = 100 mmHg - 75 mm = 25 mmHg
• PA02-Pa02 =100 mmHg -100 mmHg = 0 mmHg

This implies that the A-a gradient can have values that range from 0 to 25 mmHg

The normal A-a gradient is usually less than 10 mmHg. However, a ventilation-perfusion mismatch can significantly increase FES.

Bronchoalveolar Lavage

Bronchoalveolar lavage has been extensively researched as a diagnostic tool for FES. Lipid inclusion in the macrophages might point to a diagnosis of FES but is not specific, as this can be seen in other clinical conditions. Moreover, the procedure is time-consuming and invasive and might not give the best diagnostic yield.

Attempts at developing biological markers for FES have been disappointing because of low specificity. Lipase, free fatty acid, and phospholipase A2 have been demonstrated to be elevated in FES, but this also can be seen in other disease conditions of the lung

Blood, urine, and sputum analysis might show the presence of fat globules. Again, this is nonspecific in fat embolism and FES.

Imaging Studies

Chest X-ray

The chest X-ray reveals the presence of the following:

• Diffuse interstitial marking
• Pulmonary edema
• Lung infiltrate
• Flake-like pulmonary marking (snowstorm appearance)31

CAT scan of the Chest

• Area of  increased vascular congestion
• Pulmonary edema

Imaging of the Brain

CT scan is not a very sensitive imaging study of the brain in FES. Still, it can be used to exclude other causes of altered mental status, such as epidural, subdural, or subarachnoid bleeding. MRI is the most sensitive test that can be used to demonstrate changes in the brain related to FES. Takahashi et al categorized these changes into the following 4 grades based on the size and distribution of the lesions in 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 semi vale
• Subcortical white matter
• Ganglionic regions
• Thalamus

The authors 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 FFA, which is potentially neurotoxic. Transesophageal echocardiography may be utilized 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

There is no specific treatment for fat embolism or FES. Based on experimental studies, an attempt was made to use dextrose infusion to decrease FFA mobilization. Ethanol also was used as an agent to inhibit lipolysis. In clinical practice, there were no proven benefits.[6][7][8] Experimental use of heparin in an animal model was found to be beneficial but is no longer used in clinical practice because of the potential risk of bleeding. There has not been a proven clinical benefit with heparin in FES. Therapy with corticosteroids has been proposed for the treatment of FES based on the following effects:

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

A meta-analysis of 7 randomized control trials using corticosteroid prophylaxis showed a close to 77% reduction in the risk for FES in a patient with a long bone fracture. However, there is no difference in mortality, infection, or avascular necrosis between the treatment group and the control group. For this reason, the use of corticosteroids is still very controversial.

Inferior Vena Cava Filter

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

Operative Measures

It is highly recommended that early open reduction and internal fixation of long bone fractures be started. The incidence of FES is higher in a patient with long bone fractures who are managed conservatively. Using internal fixation devices in managing long bone fractures significantly reduces the incidence of FES. During operative fixation of the long bone fracture, care must be taken to limit the intramedullary pressure, as high pressure is associated with increased fat emboli entering the systemic circulation. Some techniques utilized in orthopedic surgery 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, this is the mainstay treatment. Supportive care is geared toward adequately oxygenating 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. It 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 score of less than 8
• Moderate to several respiratory distresses with no improvement in noninvasive support

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

• Mannitol
• Hypertonic saline
• Intracranial pressure monitors

Differential Diagnosis

The differential diagnosis of fat embolism and FES are related to each system that this system 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 pathologies of the lung. Pulmonary contusion typically develops after about 6 to 10 hours of a chest injury. On CT of the chest, there is a localized ground glass opacification on the lung. In pulmonary edema, there is symmetrical vascular engorgement with pleural effusion and ground-glass opacification. The gold standard for diagnosis of thromboembolism is a CT angiogram of the chest where, classically, a filling defect is present.

Central Nervous System

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

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

All the conditions listed above can cause altered mental status with a change in the Glasgow Coma Scale mimicking FES. CAT scan of the brain can help delineate a bleed or 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 in 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 support therapy can recover from the neurological, respiratory, and retinal changes associated with FES. The most recent studies approximate mortality between 7% to 10%. The most common causes of morbidity or mortality include acute respiratory distress syndrome, ARDS, and cerebral edema.

Enhancing Healthcare Team Outcomes

An interprofessional team is best able to diagnose and manage fat embolism. The diagnosis is not always simple, and there is no specific treatment for the disorder. The key is keeping the patient hydrated and promptly immobilizing or fixing the fractured limb. Many agents have been recommended for treating fat embolism, but none have proven reliable or consistently effective. A meta-analysis of seven randomized control trials using corticosteroid prophylaxis showed a close to 77% reduction in the risk for FES in a patient with a long bone fracture. There is, however, no difference in mortality, infection, or avascular necrosis between the treatment group and the control group. For this reason, the use of corticosteroids is still very controversial. The prognosis of patients with fat embolism depends on early open reduction and internal fixation of the long bone fracture. Most patients with adequate support therapy can recover from the neurological, respiratory, and retinal changes associated with FES. Delays in treatment can lead to ARDs, cerebral edema, and a mortality rate that averages 7%.[9][10]