Fat embolism: the hidden murder for trauma patients!

ABSTRACT Introduction: fat embolism syndrome (FES) is an acute respiratory disorder that occurs when an inflammatory response causes the embolization of fat and marrow particles into the bloodstream. The exact incidence of FES is not well defined due to the difficulty of diagnosis. FES is mostly associated with isolated long bone trauma, and it is usually misdiagnosed in other trauma cases. The scope of this study was to identify and search the current literature for cases of FES in nonorthopedic trauma patients with the aim of defining the etiology, incidence, and main clinical manifestations. Methods: we perform a literature search via the PubMed journal to find, summarize, and incorporate reports of fat embolisms in patients presenting with non-orthopedic trauma. Results: the final literature search yielded 23 papers of patients presenting with fat embolism/FES due to non-orthopedic trauma. The presentation and etiology of these fat embolisms is varied and complex, differing from patient to patient. In this review, we highlight the importance of maintaining a clinical suspicion of FES within the trauma and critical care community. Conclusion: to help trauma surgeons and clinicians identify FES cases in trauma patients who do not present with long bone fracture, we also present the main clinical signs of FES as well as the possible treatment and prevention options.


INTRODUCTION
F at embolism was first described by Zenker in 1862 and later clinically diagnosed by Von Bergmann in 1873 1 .It is a complex phenomenon defined by the existence of fat particles in the microcirculation 2,3 .Fat embolism syndrome (FES), on the other hand, refers to the many possible clinical manifestations occurring due to fat embolism 4 .Fat embolism frequently occurs among trauma patients, more specifically, orthopedic trauma patients 2,4,5 .However, fat embolism has also been described in a variety of nonorthopedic-related trauma cases, such as burns, lung transplants, and liposuction 6,7 .
The presentation and diagnosis of FES are not yet well understood, and there are challenges in detecting the syndrome and precisely determining the related complications 6 .The diagnosis of fat embolism can be relatively difficult, as there are no all-inclusive criteria for its diagnosis; therefore, its diagnosis is usually one of exclusion 6,8 .Given the nature of circulating fat globules in the microcirculation, a diagnosis of fat embolism can be and is routinely performed during autopsy 6,9 .The underdiagnosis of fat embolism is highlighted by the fact that the clinical incidence was detected to be less than 1%, while postmortem incidence was evaluated to be 20% 10,11 .FES can involve multiple organs and is considered a lethal complication among trauma patients 12 .FES can lead to complications such as severe respiratory failure or brain death 13 .The mortality rate associated with FE and FES was estimated to range between 5% and 15% 14,15 .
Therefore, due to the fatality of FES in trauma patients, it is important to maintain a high clinical suspicion of FES 16 .
According to the findings in the literature, the pathophysiologic mechanism behind fat embolism in cases without any fractures might be attributed to two factors: first, the acute rise in pressure at the site of trauma, and second, the changes in the emulsification of blood lipids during shock 20,21 .FES is acknowledged as a fatal consequence of trauma, but with prompt identification and timely intervention, a positive prognosis is possible 12 .The aim of this paper is to highlight the importance of always suspecting fat embolism in trauma cases, including those that are not exclusively orthopedic cases.We will discuss the challenges of diagnosing this complication and the ways to treat it and reduce the mortality related to FES.

METHODS
A literature search was conducted using the PubMed database.The PubMed search was conducted using the terms fat embolism and fat embolism syndrome (MeSH).This initial search produced 4175 papers.
We narrowed the search to case reports published from September 1 st , 2013, to September 1 st , 2023.This yielded 289 case reports.
We further investigated these papers and excluded all papers of patients presenting with a fat embolism or FES due to orthopedic-related trauma.When we categorized the related medical conditions, we defined orthopedic trauma as fractures and interventions such as total hip replacement, knee arthroplasty, internal fixation, and spinal instrumentation.Additionally, any bone fracture due to blunt force trauma, falls, and motor collisions was classified as orthopedic trauma.On the other hand, non-orthopedic trauma encompassed procedures such as liposuction or fat injection, as well as medical conditions such as burns, bone marrow harvesting and transplant, and soft tissue injuries, as indicated in Table 1.The final number of case reports relevant to the study was found to be 21.
Additionally, papers of patients from other search engines, such as Google Scholar, were found and added to the total number of relevant papers.This brought the total number of relevant papers of patients presenting with a fat embolism or FES due to non-orthopedic-related trauma to be 23 papers.For the clinical presentation, we referred to respiratory abnormalities as the presence of tachypnea, hypoxemia, dyspnea, chest pain, hemoptysis, and/or cyanosis.Neurological abnormalities were characterized by the presence of disturbance of consciousness, restlessness, seizures, limb weakness, paralysis, aphasia, sensory disturbance, headache, and/or dizziness, Cardiovascular abnormalities were identified by the presence of tachycardia, hypotension, cardiac arrest, bradycardia, and/or angina, as presented in Table 2.

RESULTS
In our search, several case reports were identified to have fat embolism or FES in patients experiencing non-orthopedic-related trauma.We identified 23 papers discussing case presentations of fat embolism from patients presenting with conditions such as soft tissue injury with no fracture and liposuction.The main findings related to the cases in this review are presented in Table 3.Among all the cases we found, there was a diverse range of clinical presentations, risk factors, and ages of incidence.In our search, the most common cause of non-orthopedic trauma-related patients was cosmetic procedures such as liposuction.We present our findings in Table 3.

Rev Col Bras Cir 51:e20243690
Bentaleb Fat embolism: the hidden murder for trauma patients!An additional tool to aid in the diagnosis of FES is the use of imaging.Common radiological imaging tools and their expected clinical picture within FES are summarized in Table 7.
The large variance among these diagnostic criteria, as seen in Tables 3-5, may lead to irregularity in the diagnosis of FES.A patient fulfilling one of the criteria (e.g., Gurd) may not fulfill one of the other criteria (e.g., Schonfeld) despite presenting with a fat embolism.

Pathophysiology
Several theories exist that attempt to explain the full pathophysiology of FES; however, they inadequately encompass all presentations associated with FES 47 .The current pathophysiological understanding of fat embolism is dominated by two differing theories: biochemical theory and mechanical theory.The biochemical theory is built on the understanding that clinical manifestations of fat embolism occur due to a proinflammatory environment 4 .
The biochemical theory speculates that trauma causes an inflammatory response in the body that leads to the release of fat cells from the marrow of the bone into the venous system 2 .Neutral fat found in the bone marrow does not normally cause acute lung injury; however, it could be metabolized over several hours into intermediates such as free fatty acids that could cause damage and lead to clinically relevant sequelae such as acute respiratory distress syndrome (ARDS), as was seen in animal models 48 .Free fatty acids could also potentially lead to complications such as dysfunction of cardiac muscle 48 .The biochemical theory could potentially explain delays in the clinical manifestations of FES 9 .The other predominant theory is the mechanical theory.The mechanical theory states that an increase in intramedullary pressure due to trauma can cause the release of fat into the venous system via open venous sinusoids 2 .The biochemical theory assists in explaining FES for nontraumatic reasons 4 .The FES seen in most patients is most likely due to a combination of both biochemical and mechanical theories 4 .

Bentaleb Fat embolism: the hidden murder for trauma patients!
To understand the basis of FES conception, a further scrutiny of the biochemical and mechanical theories is needed to correlate what occurs at the cellular level and what is observed clinically.The biochemical theory (or the Sedimentation theory) puts forward that an increase in catecholamine levels and plasma lipase allows lipids from fat stores in the body to mobilize, eventually forming fat droplets within the circulation 44,49 .
The biochemical theory may be summarized in the following manner: any form of trauma to the body triggers a pro-inflammatory response which aims to advance cellular repair and to promote readiness for potential further traumatic insults.Following this, the body may sometimes form an exaggerated response to subsequent ensuing trauma such as a fat embolism.This amplified response is theorized to add additional endothelial cellular injury leading to possible multi organ damage as seen in FES 7 .Patchy ground-glass opacities 46 Small Bilateral Pleural Effusions 46 Cerebral MRI (For Cerebral Fat Embolism) Bright Spots on a Dark Background (Starfield Pattern) and microbleeding 36 The mechanical theory postulates that fat stored in the bone marrow obtains access to the circulation via venous sinusoids in the presence of trauma 4 .These fat particles then travel into the vasculature and embolize causing the symptoms of FES 44 .The mechanical theory does not explain the full series of manifestations seen in FES 44 .It fails to explain the temporal separation of events seen typically 24-72 hours after a fat embolism such as a petechial rash 7 .
In addition to the biochemical theory and the mechanical theory, the coagulation theory has also been proposed to elucidate the pathophysiology of FES.The coagulation theory states that tissue thromboplastin that is released by the marrow activates both the complement system and the extrinsic coagulation cascade 10 .This is done by direct activation of Factor VII which causes intravascular coagulation to occur 10 .The coagulation theory proposes that the circulating fat causes an inflammatory environment 7 .
The presence of hypovolemia that is typically seen after trauma, endothelial damage, and the aforementioned inflammatory environment lead to the activation of the clotting cascade, which may potentially increase the size of the fat embolism thereby intensifying obstruction in the circulation 7 .
In conclusion, the three proposed theories for fat embolism explain, by different means, the possible sequence of events leading to the clinical manifestations seen in FES.It becomes clear that no singular theory may account for all the manifestations seen in FES, and that it is more likely an amalgamation of all three theories that work synergistically resulting in the clinical phenomena seen in FES.

Incidence
The exact incidence of fat embolism remains unknown 50 .It varies significantly in the literature depending on the cause and the diagnostic criteria used.
The incidence was reported to be as low as less than 1% in some studies 51 and as high as 20% in others 11,52 .Most of the studies explore the incidence of FES in orthopedic patients and not in patients presenting with FES due to non-orthopedic-related trauma.He et al. reported in their pooled analysis from PubMed and Web Science the incidence of FES in nonfracture trauma-related cases 19 .
A total of 11.8% of FES cases were associated with liposuction or autologous fat injection, 2.2% of cases were associated with fat-soluble injections, and 0.7% were associated with multiple soft tissue injuries 19 .
Non-orthopedic fat embolism has been associated with cosmetic procedures such liposuctions and fat grafting, and it happens most commonly in the lungs.It can be explained by the generation of lipid fragments that enter the venous circulation following damage to adipose tissue and small blood vessels, which results in lung injury 53 .The survival rate for patients with multiple soft tissue injuries was reported to be zero in this paper 19 .
While the incidence of FES is significantly low in cases of multiple soft tissue injuries, the fatality is very high, which is why it is important for physicians to be alert about the presentation of FES.

Imaging and Clinical Investigations
Adjunct to clinical assessment, investigations and diagnostic tests can support the diagnosis of FES.
Arterial blood analysis (ABG) with Pa02 of less than 60mmHg and hypocapnia demonstrating an increase in pulmonary shunt fraction and an A-a gradient increase strongly suggest FES 50 .Additionally, a decrease in hematocrit 24 to 48 hours post trauma is also suggestive of FES, as it can be due to intra-alveolar hemorrhage 50 .
Cytological examination of urine showing fat globules is not specific 50 .However, a study showed that cytological examination of pulmonary capillary blood from a wedged pulmonary artery catheter can be useful for the early detection of FES 54 .
Imaging can also be helpful in confirming FES diagnosis.Chest CT with ground-glass opacities is the most common finding in FES patients 19 .A chest X-ray with patchy infiltrative shadow or low transmittance can also suggest FES 19 .However, a normal initial chest CT or chest X ray does not rule out FES diagnosis, and it is important to keep in mind the risks associated with repeated radiological exposure when considering a second CT scan 16 .A more telling imaging test is a cerebral MRI revealing dispersed hyperintense lesions on T2 images 16 .It has been demonstrated to be sensitive in FES patients with cerebral manifestations, including those with normal chest CT results 10,55 .It has also been reported in the literature that cerebral fat embolism presents with microbleeds exhibiting a characteristic patten described as "walnut kernel", which can be helpful in diagnosing difficult cases of FES 56 .The use of bronchoalveolar lavage (BAL) to support FES diagnosis remains controversial.Although the detection of fat droplets in alveolar macrophages can enable early and rapid diagnosis of FES 57 , it is not specific, as fat droplets in alveolar macrophages can also be associated with lipid infusions, sepsis, or hyperlipidemia 50 .

Diagnostic Criteria
Diagnosing FES is still very challenging and relies mainly on a combination of clinical symptoms and imaging and laboratory findings 58,59 .There are multiple diagnosis criteria for FES: Gurd and Wilson criteria, Modified Gurd criteria, Schonfeld criteria, and Lindeque criteria, summarized in Tables 3-5 16 .Most of these criteria have been criticized in the literature due to their low specificity 55 .They are all rooted in the classical triad of progressive respiratory insufficiency, petechial rash, and mental deterioration that manifest 24-48 hours post trauma 16 .However, studies report that the presentation of the three triad criteria simultaneously is very low 16,55,60  Cutaneous manifestations, such as petechial rash, are less commonly observed 19 .Additionally, studies have shown that the petechial rash does not appear until 3-5 days after the onset of respiratory insufficiency 10,46 .Therefore, the combination of respiratory insufficiency and neurological disturbances can be sufficient to suspect FES and diagnose it, which is indicated by the Gurd and Wilson criteria as well as the modified Gurd criteria 16 .Aggarwal et al. recommend suspecting FES and referring patients to the ICU when they present with neurological disturbances and hypoxemia along with long bone fractures 12 .Future areas of research focusing on FES should involve enhancing our comprehension of FES to allow for a more accurate diagnosis 58 .

Treatment and Management
The treatment and management course for anticoagulation therapy for patients with FES 4 .However, the use of heparin to treat FES carries serious potential complications, such as bleeding, that must be taken into account and could possibly be a dangerous addition to the treatment regimen of FES 47,62 .Another potential preventative treatment for fat embolism is the use of early internal fixation devices for patients with long bone fractures, which could potentially reduce the incidence of FES 3 .The delayed stabilization of fractures has been associated with an increased risk of pulmonary insults such as fat embolism 63 .
Supportive care continues to be the key pillar in the management of FES.A key aspect to the management of fat embolism is ensuring sufficient arterial oxygenation 50 .
Patients need to be provided oxygen to maintain the PaO 2 of oxygen at 90mmHg or higher 64 .If the hypoxemia is severe and approaches dangerous levels, endotracheal intubation and additional mechanical ventilation support are given 64 .Several case studies have been presented with patients presenting with FES due to non-orthopedic trauma-related reasons who have successfully been treated due to a combination of therapeutic strategies that include mechanical and pharmacological interventions.
One case report of a 29-year-old woman presenting with FES while undergoing liposuction was successfully treated with no long-term complications due to a combination of several therapeutic interventions, including ventilation, a low dose course of corticosteroids, human albumin, and low-weight molecular heparin 65 .The use of venovenous extracorporeal membrane oxygenation (VV-ECMO) was recently proven to be successful in managing patients with acute respiratory distress caused by FES 66,67 .
However, data and information encompassing the use of these therapeutic techniques in non-orthopedic traumarelated FES cases are sparse and demand more attention to fully understand effective treatments.

R E S U M O R E S U M O
fat embolism has not been well established and remains chiefly supportive in nature.Therapeutic interventions made specifically for tackling FES have mostly been ineffective 2 .Corticosteroids, which work via several mechanisms, such as potentially decreasing the levels of free fatty acids, may aid in the treatment of FES 2 .There has been some evidence that corticosteroids may be effective in the prevention of FES in patients with long bone fractures 61 .However, the use of corticosteroids in the management and treatment of fat embolism remains a controversial topic.Additional proposed pharmacological interventions include the use of systemic

Firstly, the prevalence
and small sample size of the searched papers may affect the generalizability of the findings.Since the study is based on a limited number of papers, it may not capture the full spectrum of the condition or accurately represent the population at large.Additionally, due to the lack of specific treatment options, the study may not provide clear guidance on managing the condition effectively.Moreover, the reliance on case reports in the published literature suggests that there is a significant number of misdiagnosis patients, which may further influence the validity and reliability of the findings.It is important to take these limitations into consideration when interpreting the results and applying them to clinical practice.CONCLUSION FES remains undiagnosed in many trauma cases and the related fatality is very high.In many cases, FES is only discovered as the cause of death on postmortem autopsy.Treatment remains limited and continues to be mainly supportive, and interventions such as maintaining sufficient oxygen levels are crucial for patient survival.Therefore, it is important to be clinically alert and suspect of FES when a trauma patient presents with respiratory insufficiency and neurological disturbances.

Table 1 -
Non-orthopedic diagnosis and procedures with potential for fat embolism.

Table 2 -
Main clinical signs and symptoms related to FES.

Table 3 -
Summary of case report findings with their respective clinical signs, diagnostic criteria, treatment, and outcomes.

Table 4 -
Key Distinct Components for Diagnosing a Fat Embolism based on the Gurd criteria.

Table 5 -
Schonfeld Classification System for Fat Embolism Syndrome

Table 6 -
Summary of Linedgue Diagnostic Criteria for Fat Embolism Syndrome

Table 7 -
Summary of Common Radiological Imaging Findings in Fat Embolism Syndrome.
. He et al. reported that the two most