Версия для печати Bocharov S.N., Lebed M.L., Kirpichenko M.G.

NEW VIEW OF PATHOGENESIS OF FAT EMBOLISM SYNDROME

Irkutsk Scientific Center of Surgery and Traumatology,

Irkutsk State Medical University, Irkutsk, Russia

 

More than 150 years have gone after the first allusion of fat embolism syndrome (FES). However the problem is far from the solution.

Currently, the pathogenesis of fat embolia is a topic of discussions [1]. There is not any uniform concept explaining all pathophysiological links of fat embolism syndrome. There are two main processes: mechanical obstruction and biochemical injury. The mechanical theory means that fat globules, which enter the venous system through venous sinuses, cause multisystem dysfunction because of physical obstruction of the vessels [1, 2, 3]. Fat cells have the anti-inflammatory and anticlotting potential, cause rapid aggregation of platelets and stimulate formation of fibrin, with sedimentation in the circulatory bed of the lungs [1]. Obstruction of lung capillaries causes hemorrhage, interstitial edema, alveolar collapsing, reactive hypoxemic vasoconstriction [1]. Massive fat embolia leads to microcirculatory obstruction and shock [4].

On the other part, the biochemical theory considers severe vasculitis and its secondary histotoxic effects of FES in relation to excessive mobilization of free fatty acids [1, 3, 5]. Bone marrow fat is decomposed by tissue lipase leading to increase in levels of glycerol and toxic free fatty acids [11]. Injury to the endothelium of pulmonary capillaries initiates the cascade of anti-inflammatory cytokines and leads to development of acute respiratory distress syndrome (ARDS) [4]. The biochemical concept is confirmed by increase in levels of plasma phospholipase A2, anti-inflammatory cytokines and free radicals in patients with FES [6, 7].       

Most cases of FES are associated with combination of the mechanic and biochemical processes. Manifestations of FES are conditioned by embolia in venous and arterial bed. Petechial skin rash appears because of postobstructive bleeding at the capillary level, but also can be a result of systemic inflammatory response and prothrombotic state. The symptomatology of the disorders in central nervous system (CNS) varies from local deficiency to encephalopathy. It also confirms the multifactorial pathogenesis of FES [1].

According to the results of the experimental studies we found the decrease in the level of cholesterol and HDL. It indirectly shows the early development of functional hepatic insufficiency, because more than 80 % of cholesterol is synthesized by hepatocytes. Moreover, they are non-specific antioxidants, and decrease in their level testifies the reduction of antioxidant potential of the plasma and activation of the processes of free radical oxidation. Single-step increase in the level of chylomicronemia indicates the inhibition of lypolytic activity of the hepatocytes [8, 9, 10, 11].

These circumstances were the incentive for indepth researching of the features of lipid metabolism and its significance for fat hyperglobulemia.        

 

MATERIALS AND METHODS

The study included 85 patients with various pathologies of the hip joint. The patients received total hip joint replacement. Pharmaceutical prevention of fat embolia was conducted with presurgical intravenous introduction of Essentiale H (20 ml). During the early postsurgical period it was used several times with the dosage of 40 ml. The presence of fat globulemia was realized with staged collection of the blood: before surgery, during preparation of the spinal canal, in the end of surgery, on the days 1, 2, 3 after surgery. Identification and calculation of fat globules was realized with optical microscopy of venous blood plasma smear stained with cerasine red [12]. The positive result was identification of globules with the size > 6 µm. Lipid fractions (VLDL, LDL, HDL) were measured with electrophoresis with gel plates and the diagnostic sets from Cormay (Poland). The measurement devices were the semiautomatic biochemical analyzer Humalyzer 2000 (Germany), the densitometer Sebia (Cormay, Poland). The level of cholesterol was estimated with the diagnostic set Vital (Saint Petersburg) with the fermentation method (the reference: 3.62-8.03 mmol/l). The level of triglycerides was measured with the fermentation colorimetric method with use of the test system from Human GmbH (Germany) (the reference: 0.6-2.2 mmol/l). The levels of apolipoprotein A (the reference: 94-178 mg/dl) and apolipoprotein B (the reference: 63-133 mg/dl) were measured with the immunoturbidimetric method and the test sets from ByoSystems (COD 31095, 31098) (Spain). The activity of plasma lipoprotein lipase was measured with the enzymatic kinetic method and the test sets from Biocon (COD 9162) (Germany) (the reference: 190 IU/l).

The results of the performed examinations were analyzed with Statistica software [13].

 

RESULTS AND DISCUSSION

It was found that fat hyperglobulemia develops in 79 % of cases during total hip replacement. Within the first 24 hours after surgery the number of cases of globulemia demonstrates two-fold decrease. On the second day its probability decreases, but still remains significant. And only by the moment of the third day the chance of development of fat globulemia significantly decreases as compared with the intrasurgical stage (the table 1).   

Table 1
Frequency of fat globulinemia (FG) in intraoperative period of total hip replacement
Parameters	Before surgery	After surgery	1st day	2nd day	3rd day
	0 (85)	68 (17)	31 (54)	15 (70)	4 (81)
NFG (Nw/out FG)
	0	0.79	0.35	0.16	0.04
Probability
	0.0	3.76	0.54	0.2	0.04
Odd

          

The examination of lipid metabolism identified the significant decrease in the level of cholesterol immediately after the surgery. This decrease persisted within the first 24 hours after the surgery, with simultaneous increase in the level of triglycerides (the table 2). 

Table 2				P
Changes in lipid metabolism at fat globulinemia in perioperative period of total hip replacement (Friedman ANOVA), n = 85
Parameters	Before surgery	After surgery	1st day
	5.3 (3.7; 6.2)	3.5 (3.3; 4.1)*	3.1(2.9; 3.1)*	0
Cholesterol (mmol/L)
	1.7 (0.9; 2.2)	2.4 (1.8; 2.7)*	2.3(1.3; 2.7)*	0
Triglycerides (mmol/L)
	202 (194; 213)	207 (164; 214)	215 (218; 215)	0.49
Lipase (mg/dL)
Apo A (mg/dl) Note: * – р < 0.05 (Wilcoxon criteriawith Bonferroni correction).	214 (191; 214)	208 (168; 216)	215 (213; 216)	0.56

One should mention the reliable decrease in the level of apoprotein B after the surgery. It persisted within the first 24 hours after the surgery.

The significant changes were identified in the ratios of plasma lipoproteins (the table 3).

Table 3
Changes in plasma lipoprotein composition in fat globulinemia in perioperative period of total hip replacement (Friedman ANOVA), n = 85
Parameter	Before surgery	After surgery	1st day	P
	0 (0; 0)	1.7 (0; 7.35)*	0 (0; 3.6)*	0.004
Chylomicronemia
	17.9 (10.1; 21.9)	36.6 (21.3; 46.8)*	34.2 (17.3; 48.9)*	0.01
VLDL
	42.7 (42.5; 62.7)	56 (41.5; 57.2)	45.8 (43.4; 48.7)	0.8
LDL
	37.4 (22.4; 37.9)	12.7 (8.3; 23.7)*	23.5 (11.4; 29.7)*	0.001
HDL
Note: * – ð < 0.05 (Wilcoxon test with Bonferroni correction).

The level of chylomicronemia significantly increased after the surgery and persisted at this level within the first 24 hours after it. The level of LDL also increased. But we found the decrease in HDL, with the level significantly lower than the basic one.

The study of lipid metabolism at the background of hyperglobulinemia identified some serious disorders. The increase in the blood levels of triglycerides was associated both with delivery of extravascular fat into the blood and with increasing energy deficiency as result of surgical intervention. Hypertriglyceridemia reflects the activation of the processes of free radical oxidation.

The decreasing level of cholesterol testifies the acute development of functional insufficiency of the hepatocyte. It is confirmed by disorder in the ratio between lipopolysaccharide fractions: intense decrease in HDL and increase in VLDL. Despite the constant level of lipase activity (like as the level of apoprotein A), significant postsurgical reduction in apoprotein B testifies the significant consumption for VLDL synthesis. At the same time, the constant blood level of LDL at the background of increasing VLDL means decreasing synthesis in plasma, because of deficiency. It is known that hepatocytes demonstrate the quick response to the increasing blood levels of triglycerides by means of apoprotein B synthesis. The time for its synthesis is 14 minutes. The sharp decrease in its substrate at the background of fat hyperglobulinemia testifies both the deficiency of consumption and decrease in its formation in hepatocytes.

Therefore, the results of the studies confirmed the patterns of changes in lipid metabolism in hip joint replacement caused by functional hepatic insufficiency, and allowed to develop the own scheme of the syndrome of fat hyperglobulinemia/embolia which one can see on the image.

In concordance with the above mentioned scheme, the development of fat embolia syndrome can be formulated as follows. Distribution of fat after its entrance into the vascular bed leads to various degrees of embolization of vessels in the lungs and the organs of systemic circulation. We believe that emboli penetrate the vessels of lesser and greater circulation simultaneously. But the biggest fat globuli stay in the pulmonary vessels. Elasticity of fat globuli allows their easy deformation and easy penetration through the system of pulmonary arterial branches (considering their size of 15-20 mc). The simultaneous appearance of fat globuli in the vessels of lesser and greater circulation is confirmed by their identification in the blood from the subclavian vein and the peripheral vein during preparation of the spinal canal during hip joint replacement. The simultaneous appearance of fat in the vessels of lesser and greater circulation is also confirmed by the following early symptoms of fat embolia syndrome: hyperthermia, petechia, hepatic and renal dysfunction, icterus and changes in retina which are not caused by only fat embolia.

Embolization of the vessels of the lungs and other organs leads to disarrangement of microcirculation, and hypoxia with initiation of the processes leading to development of multiple organ dysfunction syndrome (MODS). First of all, the liver and the lungs suffer. The insufficiency of these organs develops. At this stage the protection mechanism is activation of lipoideretic function of the body. In this process the most important role is taken by the lungs and the liver. The lipoideretic function consists in activation of various groups of lipases, phagocytic activity, which may lead to pathologic patterns and vicious circle (if some provoking factors are not removed), when intense consumption of protein substrates and their depletion happens as result of emulsification of fat. It results in disorder of fat systemic metabolism, disarrangement of emulsion stability of plasma lipids and accumulation of toxic products of disordered lipid metabolism. The result of these processes is intravascular formation of fat globuli, their circulation in the blood and further embolization of the vessels of lesser and greater circulation.

Therefore, the outcome of formation of fat embolia syndrome is development of functional incapacity of the liver, which is the key link.