The first reported case of death due to fat embolism syndrome (FES) was documented by Zenker in 1862 [1]. Modern liposuction was first developed in the early 1980s [2], and subsequently, in 1983, Hunter et al. [3] reported on “Pulmonary complications following abdominal lipectomy,” which is considered the earliest report of FES associated with cosmetic surgery. Since then, numerous cases of FES related to cosmetic procedures have been documented, suggesting a significant correlation between the increasing prevalence of cosmetic surgeries and the incidence of FES.

FES is a potential complication that can arise from procedures such as liposuction, fat grafting, or even fractures, and in some cases, it can be life-threatening.

In adults, the diameter of adipocytes typically ranges from 20 to 200 μm, while the diameter of fat particles obtained through standard aspiration cannulas can exceed 1 mm. High-pressure injection, large-volume fat grafting, and liposuction present significant risks for developing FES [4].

In this article, we aim to provide a comprehensive overview of FES, with a focused review on the three most representative and critical forms of this condition.

Fat, the causative agent of FES can be classified into two types within the human body. One type is the mobile fat present in the bloodstream, and the other is the fat stored outside the blood vessels. Mobile fat exists in the form of chylomicrons bound to apolipoproteins. Stored fat accumulates as triglycerides (TG) within adipocytes. TG can be hydrolyzed into free fatty acids (FFAs) by lipase, and these FFAs can bind to albumin and be transported through the bloodstream to other tissues [5].

FFAs are considered toxic substances. They bind with calcium ions in the blood, disrupting the junctions between endothelial cells. This results in damage to the endothelial surface of capillaries, increasing vascular permeability and leading to hemorrhage and edema [6].

The progression from asymptomatic fat embolism to severe FES can be explained by two mechanisms. One is the mechanical obstruction theory, which posits that when adipose tissue is damaged, peripheral vessels are mechanically obstructed by fat emboli, leading to ischemia and severe dysfunction of distal organs [7]. This condition is known as fulminant acute FES. Rapidly progressing clinical symptoms require a significant amount of fat emboli (Fig. 1). However, FES resulting from mechanical obstruction is rare. The other theory is the chemical theory, which suggests that FFAs damage organs and cause subacute FES [6]. Subacute FES is the most common clinical type and typically occurs 12 to 48 hours post-injury (Fig. 2).

Peltier [8] was the first to explain these two theories through animal experiments. He discovered that when chemically pure triolein, a type of TG, was injected into the veins of rabbits, the LD50 (lethal dose for 50%) was relatively high at 900 mg/kg. Through gross and microscopic examination, he observed right ventricular hypertrophy and ischemic changes in the lungs, providing evidence for the mechanical obstruction theory. Additionally, he injected three types of FFAs (oleic acid, linoleic acid, and linolenic acid), finding LD50 values of 250 mg/kg, 225 mg/kg, and 200 mg/kg, respectively. These are relatively low doses. Autopsy results showed no right ventricular hypertrophy, but there was diffuse hemorrhage in the lungs, suggesting the biochemical toxicity of FFAs. These findings laid the foundation for our understanding of the pathogenesis of FES.

In FES, the fat emboli entering the circulatory system are primarily in the form of adipocytes and/or liquid fat in the form of TG from destroyed adipocytes. Therefore, the two main theories of FES (mechanical obstruction and biochemical mechanisms) are likely interconnected and do not operate independently [9]. That is, if the amount of fat entering the bloodstream is insufficient to cause fulminant FES, the TG fat emboli are hydrolyzed into FFAs. This conversion leads to a transition from mechanical obstruction to a biochemical phase, resulting in subacute FES [9-11].

There is a common misconception that FES only occurs due to the liquid component of fat. However, research indicates that not only liquid fat, but also fat cells can act as embolic material [12]. Fat cells can cause occlusion on their own, and they can also trigger inflammatory responses that promote thrombus formation, leading to mechanical occlusion [13,14]. Additionally, based on the results of the rabbit experiment with a 700 mg/kg intravenous injection of triolein, liquid TG can also act as emboli, initially presenting macroscopic pathological symptoms like occlusion and immediate organ ischemia, and over time, microscopic pathological changes resulting from chemical reactions lead to bleeding and typical symptoms of FES [9].

Unlike other embolisms, a significant characteristic of FES is the transition from ischemic symptoms to hemorrhagic symptoms as time progresses [9-11]. The precise mechanism by which FES induces bleeding remains unclear. One theory suggests that the lipoprotein lipase acts on intravascular fat, generating FFAs that induce chemokine-derived cell infiltration, thereby damaging cell-capillary walls [15]. Another theory posits a response of the lung to release lipase. This enzyme hydrolyzes fat particles, releasing FFAs and glycerol into the circulation, significantly increasing capillary permeability. This can disrupt cellular structure and lead to edema and bleeding [16,17].

One mechanism underlying iatrogenic FES that we wish to elucidate in this article is the injection of fat into the bloodstream. Therefore, the quantity and pressure of injection are crucial. The volume required to generate this reflux does not need to be high. Injecting 3 mL of saline solution containing isotopes rapidly into the radial artery was sufficient to be detected at the carotid-subclavian junction [17]. Khan et al. [18] demonstrated that even injecting less than 0.1 mL of saline solution into the supratrochlear artery of the forehead was sufficient to reach bifurcation at the orbital apex. Moreover, with sufficient pressure to overcome the blood pressure of punctured small arteries, retrograde flow can be generated, potentially affecting other distal organs [19].

Understanding these basic mechanisms is crucial for identifying specific complications associated with FES. Among them, the most severe and clinically significant manifestations are pulmonary fat embolism (PFE), cerebral fat embolism (CFE), and vision loss due to fat embolism. If these conditions are not promptly recognized and treated, they can be life-threatening or lead to serious sequelae.

FES is primarily a diagnosis of exclusion. Various criteria aiding diagnosis have been proposed by Gurd and Wilson [28], Schonfeld [29], and Lindeque [30] (Table 1). According to Gurd and Wilson's diagnostic criteria, the presence of at least two major signs or one major sign along with four minor signs is required for a diagnosis of FES. Using Schonfeld's criteria, a score of 5 or more is sufficient for diagnosis, while Lindeque's criteria allow for a diagnosis if even one criterion is met. However, from a broader perspective, respiratory dysfunction, neurological symptoms, and petechial rash are the primary indicators of FES. Petechial rash typically appears within 3 days of symptom onset and is considered the only pathognomonic feature of FES. Nevertheless, the absence of petechial rash should not exclude the diagnosis of FES.

All patients require conservative treatment based on their symptoms. This includes oxygen therapy, monitoring of vital signs, intravenous fluid therapy, glucocorticoid pulse anti-inflammatory treatment, reduction of intracranial or intraocular pressure, vasodilators to improve circulation, nutritional and neuroprotective therapy. If infection is evident, anti-inflammatory and antibiotic treatments are necessary. While hyaluronidase is known to be effective for vascular embolism caused by hyaluronic acid injections, there is no evidence to support its efficacy in treating FES [44]. Patients with skin necrosis should undergo debridement of the affected area and treatment with tissue growth factors. For patients with cerebral infarction, free radical scavengers may be administered to protect brain cells [26]. Administration of albumin appears to be beneficial, likely due to its ability to bind FFAs [45,46].

The high mortality rate and the lack of effective treatments for fat embolism emphasize the necessity for preventions. To minimize the occurrence of life-threatening complications associated with liposuction and fat grafting, the following actions are recommended. Patients should be informed that vision loss, respiratory dysfunction, and neurological impairment can occur within the first 4 days post-procedure, and immediate medical support is crucial. Therefore, patients should not be left alone on the first day after the procedure [16]. Surgeries should adhere strictly to standardized protocols, with careful monitoring of the patient's vital signs and neurological symptoms. Local anesthesia is preferred over general or intravenous anesthesia when possible. Physicians must have a thorough understanding of facial vascular anatomy to avoid inadvertent intravascular fat injection. Injection sites must be selected with meticulous care. Although grafted fat tissue tends to survive better in highly vascular areas, this increases the risk of vascular injury [24]. Ultrasound-guided injections or the use of epinephrine before surgery can reduce vascular damage [16]. Kadouch et al. [56] demonstrated the enhanced safety of temporal fat grafting using duplex-ultrasound guidance. For gluteal augmentation, fat tissue should be placed in the subcutaneous space above the deep muscle plane and gluteal fascia plane using ultrasound guidance [47,57,58]. Some authors suggest that using blunt-tipped, large-diameter cannulas instead of needles may be preferable to avoid puncturing small branch vessels [22,59,60]. Fat particles should be injected slowly at low pressure while retracting the syringe [18,61]. Applying digital pressure proximal to the vessel during injections in high-risk areas can prevent the retrograde flow of fat into the bloodstream [62]. Injecting smaller volumes than those required to reach the ophthalmic artery or ICA can reduce complications [18]. For safety, a 1 mL multi-channel syringe can be utilized, and injections should be administered very slowly, especially in high-risk areas, with the syringe withdrawn at low pressure [15,63]. Currently, no medications have been proven to prevent the occurrence of fat embolism or alleviate its symptoms.

Treatment failure in fat embolism can stem from three main reasons. Firstly, there is confusion due to the generalized diagnosis of FES without further differentiation. Fat embolism resulting from fractures is sometimes referred to as bone marrow embolism. This implies the presence of various embolic materials, including not only liquid fat but also fat cells, hematopoietic cells, and others [64]. Unlike air embolism or thrombotic or septic embolism [65,66], which occur due to a single substance or mechanism, fat embolism involves diverse embolic materials and mechanisms. In other words, the embolic material in fat embolism can be either fat cells themselves or in the form of liquid fat, and the mechanisms of occurrence can involve mechanical occlusion or chemical action. These distinctions need to be accurately identified to enable proper comparison of diagnosis, treatment, and outcomes, etc. and to facilitate the development of new treatments. Secondly, there are inherent limitations of thrombectomy materials [24]. Currently available stents are primarily designed with open or coil like closed-loop structures, which can effectively capture solid thrombi but are less efficient in capturing liquid emboli. Thirdly, very small, disseminated fat emboli can induce microcirculatory disturbances, reducing the potential benefits of embolectomy. Additionally, while hyaluronic acid fillers contain hyaluronidase as a solvent, there is no solvent in fat cells or liquid fat. Moreover, TG naturally break down to form FFAs, which can lead to secondary vascular damage and bleeding [9].

Effective treatment for FES demands clear differentiation between liquid fat and fat cell emboli. Liquid fat FES requires chemical treatments, with drugs like albumin targeting FFAs showing promise. Thrombolytics, such as urokinase, should be used cautiously, as they can exacerbate bleeding in non-thrombotic cases. Fat cell-related FES needs physical removal and often coexists with liquid fat emboli. Developing advanced devices for safely extracting emboli from delicate vessels, like the central retinal and ophthalmic arteries, is essential.