The Fat Embolism Syndrome
Diagnostic Radiology
1
Frieda Feldman, M.D., Kent Ellis, M.D., and William M. Green, M.D. The " shock lung syndrome," whenever associated with trauma, is probably in part the consequence of fat emboli, though aspiration, disseminated intravascular coagulation, microatelectasis, pulmonary edema, and hemorrhage due to other lung insults may be important in the etiology of man y cases. When lung injury is due to fat emboli, there is an interval between the time of trauma and the onsetof clinical symptoms and chest radiographic findings. The radiographic picture is that of a diffuse alveolar and interstitial lung density. In severe cases marked respiratory embarrassment requires the use of both oxygen therapy andmechanical respirators for survival. INDEX TERMS :
Embolism. pulmonary. Respiratory Tract, insufficiency' Trauma
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T
IS IMPORTANT for the radiologist to recognize the fat embolism syndrome as a serious complic ation of skeletal injury. Ear ly recognition and appropriate respiratory care may save a life . Although involving all age groups, the syndrome is most typ ically seen in otherwise healthy young adults (or even in children (67 )) who have experienced severe trauma-usually secondary to automobile accidents . It has been suggested that " the diagnosis of fat embolism syndrome is made on the basis of the clinical picture of pulmonary and cerebral dysfunction in a patient, who , most commonly, after long-bone fractures. manifests fever , abnormal arterial blood gases, and at least one other manifestation such as abnormality on a chest roentgenogram, petechiae, fat in the retinal vessels on funduscopy , fat on cryostat frozen section of clotted blood, or fat in the urine " (16 ).
I
INCIDENCE AND PATHOPHYSIOLOGY
Although fat emboli have been known to be associated with trauma for more than a century (5), their sour ce and mode of action are still disputed. Probably som e pulmonary fat embolization follows virtually every fracture or severe traumatic injury (38, 39 , 44, 49 , 54 , 56 , 59-61 ). A cross-table lateral film of the knee taken with a horizontal beam in the region of a distal femoral fracture site (Fig . 1) commonly reveals a fat-blood interface without any evidence of skin laceration . This is not surprising to surgeons who frequently aspirate fat from traumatized knee joints. Nor are fat and marrow aggregates in the lung (Fig . 2.A) unusual findings for pathologists who also frequently note fat emboli in the kidney, retina , and brain (Fig. 2,8). Obviously . the severity and extent of the fat embolization vary widely (3. 18,26,42, 45-47. 53, 62) . The full-blown clinical fat embolism syn drome, however. is relatively rare even among pat ients
Fig. 1. Note the extensive fat-fluid interface. This indicates a large amount of liquid fat released into the knee joint following trauma. Embolization of such fat to the lungs is a major mechanism in the fat embolization syndrome. Table I: Fa t Embolism Incidence Per No. of Cent Cases
Autopsy Batt lefield WW II (Mallory) Korea (Scully) Civilian Fuchsig
65 93 16
60 110 5265
Major Cau se of Death
5%
Palrn ovrc
Clinical
Immediately after death 80 969 6 hours aft er death 96 12 hours after death 100 Range 0 . 8-6% Fat l mbohsrn Syndrom e
4. 2%
with major fractures (3 % or less) (TABLE I). Note that in Palmovic 's series (43). patients surviving a number of hours after severe trauma had a greater incidence of fat emboli than those dying immediately. Prevailing opinion is that the fat emboli originate as
, From the Department of Radiology (F. F., Professor; K. E., Professor), College of Physicians and Surgeons, Columbia University, Columbia-Presbyterian Medical Center, New York , N. Y. Presented at the Fifty-ninth Scientific Assembly and Annual Meeting, Chicago, III., Nov. 253~ 1973. ah 535
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neutral fat released from disrupted adipose tissues mainly in the marrow spaces, and that they reach the lungs after direct entry into the vascular system via severed veins in the injured region and to a less extent via the lymphatic system (23, 45-47). These fat emboli mainly affect the small vessels of the lungs, though some of the fat traverses the pulmonary vascular bed and goes on to embolize the organs supplied by systemic arteries and so to produce the other features of the clinical syndrome, especially cerebral, skin, retinal, and renal manifestations. The major modes of action of these fat emboli are: 1. Mechanical Occlusion of Small Vessels: Even though the lung microvasculature is the primary target of fat emboli, acute cor pulmonale produced by fat emboli is a great rarity. Apparently very large amounts of embolized fat are necessary to have this effect. 2. Chemical Injury to the Small-Vessel Walls: Hydrolysis of the neutral fat produces chemically toxic fatty acids, which are known to cause local damage to the microvasculature. Such neutral-fat breakdown in the lung by action of lung lipase is a cause of local edema, hemorrhage, and loss of surfactant with secondary microatelectasis. The relevance of this mechanism of injury is supported by the known activation of lung lipase after fat embolization, by the injurious effects of certain free fatty acids on small blood vessels in experimental models (31), and also by the usual delay between the injury and gross clinical evidence of lung dysfunction in the syndrome (11-14, 20). 3. Aggregation of Blood Platelets and Stimulation of Intravascular Coagulation: Fat globules are known to induce platelet as well as erythrocyte aggregation on the basis of experimental studies (4, 18). Secondary local release of serotonin, histamine, and various other agents including kinins can cause local edema, hemorrhage, intravascular clotting, and vessel disruption. Each of the three mechanisms just outlined probably contributes to the lung dysfunction which is the most serious problem in the fat embolism syndrome. Similar actions on the small blood vessels of the brain, the retina, and the skin may cause the cerebral dysfunction, the funduscopic changes, and the typical skin petechiae which are so characteristic of the syndrome. Fat evidently traverses the glomeruli to reach the urine in about 50% of cases. In many, however, the cerebral dysfunction is probably more the consequence of hypoxia due to respiratory failure than of fat emboli in the brain (64). The major alternate theory for the pathogenesis of fat embolism is a metabolic one. The occurrence of fat embolization in nontraumatic conditions and the slow absorption of radioiodinated 3 11) triolein from traumatized bone ends of experimental animals (63) has led to the contention that the injured site per se is not the sole source of embolic fat and that a sizable contribution stems from body fat depots (33). Free fatty acids are normally mobilized and released into the blood in sub-
e
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stantial amounts as the consequence of many types of stress (7). These fatty acids may in some instances be aggregated and/or esterified in the blood stream into fat globules of sufficient size to cause substantial fat emboli (28). While such a mechanism for production of fat emboli is generally thought to be of minor importance, this may be the explanation for the occasional presence of fat emboli in the absence of conventional types of trauma (33). Other causes of this syndrome reported, which are not associated with conventional trauma, include burns, infections, diabetes mellitus, liver injury, fatty liver, pancreatitis, sickle-cell disease, blood transfusions, inhalation anesthesia, cardiac massage, lymphangiography, renal transplant and/or infarction, cardiopulmonary disease, childbirth, some cases of poisoning, and removal or placement of hip prostheses (8, 26, 34, 35, 52, 56). It is surprising that fat embolism is not more frequently reported in patients with fractured hips. However, Sevitt (60) found an incidence ranging from 0.7 to 7% among various groups of patients following hip fractures. Support for mechanical release of emboli from fat depots has also been found in decompression experiments in which rapid expansion and rupture of fat cells by sudden nitrogen release result in fat and nitrogen embolization (24). CLINICAL FEATURES
The clinical onset of the fat embolism syndrome is most commonly sudden, but after a delay averaging 24 to 48 hours following the trauma, and with a range of from hours to a week. The major manifestations are those of pulmonary dysfunction with dyspnea, tachypnea, hyperpnea, and cyanosis. Although the roentgen evidence often suggests pulmonary edema, these patients have little excess secretions in the bronchial tree, and the lung density does not clear after the usual diuretic and cardiotonic treatment. Signs of generalized dysfunction of the central nervous system are often prominent. Changes in mental state may be the first clinical evidence of the fat emboli syndrome (64). The patient may suddenly become confused, restless, and rambunctious or drowsy, stuporous, or comatose. When seizures occur they are most commonly nonfocal with occasional long-tract signs, posturing, and decerebrate rigidity. The disturbances might be interpreted as manifestations of cerebral contusion or hematoma, delirium tremens, as in one of our cases, or shock. Localizing signs are more characteristic of direct traumatic brain injury than of the fat emboli syndrome. Decerebrate rigidity, an early event in the fat embolism syndrome, is usually a terminal event in craniocerebral trauma (64). Fever is nearly always present; it may be of sudden onset and was as high as 103 0 F in some of our patients. Milder temperature elevations may be overlooked or labelled a "hematoma fever" or "fever of unknown
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Fig. 2. Photomicrographs of the autopsied lung and kidney. A. Pulmonary fat embolism: The fat (black areas) fills pulmonary vessels as well as some alveolar spaces (osmic acid stain) B. Note fat emboli (dark area s) lodged in glomeruli (osmic acid stain) .
origin ." Tachypnea with increased pulse rate to 140 or higher and normal blood pressure are also characteristic . Petechiae of the skin and mucous membranes. which fail to blanche on pressure. are important signs suggesting the fat embolism syndrome. They most often appear on the second or third day after injury . Detection may require careful and repeated search since the petechiae may be sparse and frequently fade within a few hours . They are most commonly noted in the conjunctivae and in the skin at the base of the neck , the anterior thorax or the axillae. perhaps reflecting the greater visibility of these regions . The petechiae have been attributed to hemorrhage secondary to capillary endothelial damage caused by fat embolization and are classic physical findings in the fat emboli syndrome. being found in 50 % of the cases (45). Retinal fat embolism is another valuable diagnostic sign. Funduscopy may reveal retinal hemorrhage as well as intra-arterial fat emboli. Eventually tiny yellowish plaques (Purtscher 's sign) and microinfarcts (described as " ro sary around the macula ") may be manifest (15, 19. 29 ). Retinal changes have been noted in about 50 % of patients with fat embolism syndrome . from two days to two weeks following trauma . Fat embolism may be a cause of shock . but. on the other hand. it has been considered a manifestation of the general shock phenomenon (21). Fat embolism per se, however. is not related to periods of hypotension ; in fact , hypotension itself has been advocated as a treatment of fat embolism (45-47). In patients with the " shock lung" syndrome, fat embolism is frequently present. LASORATORY FINDINGS
Early repeated measurements of arterial blood gases have become a cornerstone in patient management and a gauge of treatment effectiveness in the fat emboli syndrome . Other laboratory findings , though not pathognomonic. may support the diagnosis . which is generally
a presumptive one made on the basis of the observed clinical features together with a knowledge of the disease pattern. Numerous instances have been cited of clinical failure to recognize the severity or degree of arterial hypoxia in the fat emboli syndrome. Other frequent findings are substantial decreases in platelets. hemoglobin, and hematocrit despite blood loss correction and without obvious evidence of further bleeding from the trauma site . Intrapulmonary hemorrhage . transient hemolysis, and associated disseminated intravascular coagulation have been proffered as causative factors (4, 9. 3D, 32 . 37 . 50 , 51. 56. 57. 66). Fibrinogen levels , initially normal or reduced. may show a delayed rapid rise to double the upper limits of normal (36 ). Low platelet counts have been related to aggregation about fat droplets in the lung and at other sites of injury . A significant correlation between a low platelet count and a large A-aP0 2 (alveolar compared to arterial oxygen tension gradient) has been noted (36) . Patients with the lowest platelet counts had the most severe pulmonary manifestations as evidenced by an A-aP0 2 of 40 mm or more . Lipuria. although reported in many cases of fat embolism syndrome, has also not been universally regarded as a reliable indicator of the syndrome. Free fat in the sputum is considered diagnostically worthless since it is frequently found in the normal population . Serum lipase elevation has been regarded as a gauge of fat depot mobilization and embolization (45, 55). Some authors. however. believe this is an unreliable yardst ick. usually reflecting pancreatic rather than lipoprotein lipase (16). Morphine, which is commonly used in the injured. may elevate the serum lipase to 20 times normal (65). This factor further negates the value of serum lipase as a reliable indicator of fat embolization. Serum electrophoresis demonstrating alterations in lipid compartments and cryostat frozen sections of clotted blood stained with "oil red-o " are other techniques being evaluated (18). The amount of neutral fat present in the clotted blood of traumatized patients has been
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B
Fig. 3. A. A 19-year.old man with a grossly normal chest film was alert and oriented on admission despite multiple injuries . However, he became somnolent within two days and comatose by three days , at which time the chest film exhibited diffuse bilateral increase in pulmonary dens ity . He was severely hypo xic . Cerebral symptoms improved on a regimen of nasal oxygen , steroids, and intravenous heparin. Pulmonary symptoms progressed, however, requir ing intubation and mechanically arrested respiration. B. At five days widespread , somewhat patchy pulmonary densities are distributed throughout both lungs . Note the normal-size heart and the absence of pleural fluid as is common in this syndrome .
Fig. 4. This 31-year-old woman became confused within twentyfour hours after she sustained multiple pelvic and long-bone fractures . A chest film at twenty-four hours revealed a generalized increase in lung dens ity. At fort y-eight hours , the chest film (above) showed a more diffuse and evenly distributed involvement, with a striking air bronchogram effect whic h was accentuated by me chanically ass isted resp irat ion .
said to closely relate to clinical manifestations of the fat embolism syndrome (16, 27). Serum calcium may be decreased after trauma due to its interaction with fatty acids . RADIOGRAPHIC FINDINGS
Acute cor pulmonale secondary to massive fat emboiization, though possible, is extremely rare. Charac-
teristically, after an interval of up to 72 or more hours, during which the lungs appear roentgenographically grossly normal (Fig. 3,A), widespread lung density develops (Fig. 3,B). At first this density is usually more marked in the perihilar and basilar regions, but subsequently it tends to become generalized . The diffuse lung density is a combination of interstitial and alveolar patterns (Figs. 4, 6, and 7). Such radiographic findings, though nonspecific, are characteristic of this syndrome. In some patients the densities have a more patchy appearance (Figs. 3,B and 5,B), perhaps related to uneven distribution of the fat emboli or due to preexisting variations in lung architecture. At the onset, as well as later, in milder cases the portable chest radiograph may appear relatively normal despite considerable arterial hypoxia and impressive clinical manifestations of fat embolism including dyspnea , cerebral dysfunction, and petechiae (Fig. 7,C). In summary, the roentgen findings are nonspecific (6, 41) and of varying severity but most often involve diffuse lung density with relative sparing of the apices (Fig. 6). Pleural effusions are not part of the fat embolism syndrome. Both the heart and the pulmonary vasculature, when visible, appear normal in size-unless abnormal due to another disease process. After a day or two the lung density tends to become greatest at the periphery. In most cases the pulmonary densities clear after several days to a week or more . Particularly in cases in which assisted respiration is required, the central and larger air ducts, as well as some better ventilated or emphysematous peripheral air spaces, become conspicuous as contrasted against the
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Diagnostic Radiology
A
Fig. 5. A 23-year-old girl with a femoral shaft fracture sustained in an automobile accident had a grossly normal admission portable chest film (A), but became cyanotic within forty-eight hours, The chest film then (B) showed confluent densities in both lungs which promptly responded to O 2 and steroids. Note again the absence of effusions. The large patches of density are not so typical of the fat embolism syndrome as is the more homogeneous lung density of Figure 4. This case, too , demonstrates the acute development of respiratory symptoms after an initial delay. Of additional interest is the development in this patient of petechiae and generalized convulsions one week later. These were presumably related to a shower of fat emboli from a poorly immobilized fracture site .
Fig. 6. This 21-year-old camp counselor fractured her femur in an automobile accident . She became confused three days afterward, at which time a chest film showed a diffuse pattern of reticular densities . More extensive changes were noted on the fourth day (right) with a combination of diffuse interstitial and alveolar densities. These are more difficult to see here in reproduction than on the original portable chest radiograph .
surrounding opaque lung (Figs. 4 and 5,B). These patchy lucent regions may become very striking during positive pressure ventilation, an expression of the pressure effects and heterogeneity of distribution of the forced ventilation. Severe cases requiring high levels of inspired oxygen and positive pressure mechanical ventilation have a guarded prognosis and are subject to all of the hazards (including oxygen toxicity. pneumothorax , etc.) as well as the benefits of such treatment. The pathologic basis for the acute development of diffuse lung density is a combination of pulmonary edema and hemorrhage plus diffuse microatelectasis
apparently secondary to the loss of pulmonary surfactant. The differential diagnoses include aspiration or viral pneumonia, post-traumatic or postoperative atelectasis. and other causes of acute pulmonary edema with or without pulmonary hemorrhage, such as fluid overload. intracranial injury, pulmonary embolism, lung contusion, left heart failure, drug reaction, Gram-negative sepsis, transfusion reaction, disseminated intravascular coagulation, and perhaps pulmonary hypoxia . The most severe cases become clinically indistinguishable from the " shock lung." The course of these patients may be complicated by
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superimposed processes such as CHF and later acquired pneumonia and pulmonary embolism, particularly in the older age group. CLINICAL FINDINGS IN CURRENT CASES
Since this report was solely concerned with the fat embolism syndrome after trauma, all nine of our current cases followed accidental injury. Seven were injured in or by automobiles, one fell from a fourth-story window, while one had a horse fall on him. There was a 5:4 male to female ratio. The average age was 34 years with a range from 19 to 56 years. The group sustained 41 fractures: 7 femoral, 6 tibial, 6 fibular, 5 pelvic, 5 ribs, 3 ankles, 3 vertebral, 2 humeral, 1 foot, 1 skull, 1 clavicular, 1 nasal. Symptoms appeared as early as four hours and as late as ten days following trauma. Respiratory rates of 60/minute, pulse rates of up to 105/minute and abrupt elevations in temperature to as high as 103 0 F were noted. All were alert on admission. One patient reputedly had a transient loss of consciousness at the scene of the accident. Another with a skull fracture and small subdural hematoma also showed predominantly pulmonary manifestations within 48 hours. Most patients exhibited features of both pulmonary and cerebral dysfunction. Of the two patients symptomatic within four hours, one had had closed manipulation for hip fracture reduction. The latent period folloWing early fracture manipulation, particularly under general anesthesia, tends to be shorter (3). Presumably routine postoperative hypoxemia superimposed upon the hypoxia produced by the effects of fat emboli hastens the onset of the fat embolism syndrome. One patient had generalized seizures concomitant with petechiae ten days after injury, but she had also had predominantly pulmonary symptoms two days postinjury, requiring mechanically assisted respiration. Unusually delayed onset or repeated symptomatic episodes have been attributed to rough handling or poor immobilization of fractures, which presumably release showers of fat emboli from traumatized tissues (1). Fular and Kraft (22) also contend that circulatory shock induced by pulmonary fat emboli results in retained fat in the lungs which, in recovery, spills into the systemic circulation. Another explanation for delayed manifestations emphasizes the accumulation of fat macroglobules in lung capillaries on the basis of their size and viscosity. Resultant mounting peripheral resistance raises pulmonary artery pressure until it is high enough to force a shower of emboli through the capillary network. After a consequent fall in pulmonary artery pressure, the cycle may be repeated (51). These theories suggest and are in accord with clinical observations that fat embolization may not be a "one time," but rather a continuous or repetitive event (1). Of additional interest was severe abdominal pain manifested by one of our patients; it was ascribed clini-
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cally to visceral and peritoneal fat embolization. The accompanying illustrations and case abstracts (Figs. 3-7) serve to illustrate some of the more typical clinical and roentgen features of the fat embolism syndrome. TREATMENT
Correction of significant arterial hypoxemia is the most important aspect of therapy for the fat emboli syndrome. The whole gamut of respiratory care may be required, ranging from supplemental nasal oxygen to intubation and mechanical positive pressure ventilation. The arterial oxygen tension should be kept above 60 mm Hg. The hypoxic patient must be very closely monitored, ideally in a respiratory care unit. Improvement in oxygenation usually relieves not only the respiratory manifestations but also the cerebral symptoms. Since prognosis is improved by early recognition of the arterial hypoxia, arterial blood gas measurement (Pa02; PaC02; pH) should routinely be obtained initially and daily for at least several days in patients who are good candidates for the fat emboli syndrome, e.g., patients with severe and/or multiple fractures. In the clinically more severe cases, additional treatment with relatively high dose corticosteroid therapy has apparently been of significant value and is now widely recommended (2). Anti-inflammatory effects on the lung reaction to toxic substances, including free fatty acids, is the presumed mechanism of action. Heparin therapy has been advocated as a means of reducing intravascular platelet aggregation and blood coagulation and also for its chylolytic and lipase-activator actions. Administration of heparin to severely traumatized patients with many potential bleeding sites, however, risks further bleeding. Such treatment is controversial at this time. Some have advocated the use of intravenous ethyl alcohol as a fat emulsifier and lipase inhibitor. Low-molecular-weight dextran has also been recommended as a means of improving hemodynamics and decreasing platelet aggregation, thus minimiZing the adverse effects of fat emboli. SUMMARY
The fat emboli syndrome can be broadly viewed as one pathway leading toward acute respiratory failure or the "acute respiratory distress syndrome." When the lung injury is most clearly due to fat emboli, there is an interval between the time of the trauma (up to 72 hoursbut occasionally longer) and the onset of clinical respiratory symptoms and the chest roentgenographic findings. Cerebral symptoms, skin and conjunctival petechiae, retinal fat emboli, and fat in the urine all tend to confirm the diagnosis. The most typical cases occur in young adults or in children who were in good health prior to the episode of trauma. In severe cases marked respiratory embarrassment requires the use of both
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Fig. 7. This 33-year-old man was seen at 2 A.M. after an auto accident. The admission chest film was normal , and there were multiple long-bone fractures (A). He had become disoriented by 6 A.M . and at 7 A .M. petechiae were noted about the base of the neck. the axillae. and the anterior chest wall (B). A 24-hour film (C) shows widespread. ill-defined nodular and interstitial densities which gradually cleared within four days. The roentgen findings, though not as impressive as those associated with the previous cases. serve as an example of another variation in pattern . The diagnosis was corroborated by clinical and laboratory evidence .
oxygen therapy and mechanical respirators for survival. The roentgenographic picture is that of diffuse alveolar and interstitial lung density. Such patients are clinically virtually identical to patients with the " shock lung" syndrome of respiratory failure. In fact, the " shock lung syndrome," whenever associated with trauma, is probably in part the consequence of fat emboli, though aspiration , disseminated intravascular coagulation, microatelectasis , pulmonary edema and hemorrhage due to other lung insults may be more important in the etiology of many cases . The diagnosis of the fat embolism syndrome depends on the chest roentgenogram in a clinical context of skeletal trauma with pulmonary and/or cerebral dysfunction . Important supporting evidence includes skin petechiae, lipuria, and retinal fat. 622 W. 168th St. New York, N. Y.. 10032
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47. Peltier LF: A few remarks on fat embolism. J Trauma 8: 812-820, Sep 1968 48. Petty TL, Ashbaugh DG: The adult respiratory distress syndrome: clinical features, factors influencing prognosis, and principles of management. Chest 60:233-239, Sep 1971 49.Powers SR Jr, Burdge R, Leather R, et al: Studies of pulmonary insufficiency in non-thoracic trauma. J Trauma 12:1-14, Jan 1972 50. Putman CE, Minagi H, Blaisdell FW: The roentgen appearance of disseminated intravascular coagulation (DIC). Radiology 109:13-18, Oct 1973 51. Rennie AM: Fat embolism. Can J Surg 13:41-49, Jan 1970 52. Reul GJ Jr, Greenberg SD, Lefrak EA, et al: Prevention of post-traumatic pulmonary insufficiency: fine-screen filtration of blood. Arch Surg 106:386-394, Apr 1973 53. Rokkanen P, Lahdensuu M, Kataja J, et al: The syndrome of fat embolism: analysis of thirty consecutive cases compared to trauma patients with similar injuries. J Trauma 10:299-306, Apr 1970 54. Rosborough D: Fat embolism in patients with fractured hips. Br Med J 2:528, 27 May 1972 55. Ross AP: The value of serum lipase estimations in the fat embolism syndrome. Surgery 65:271-273, Feb 1969 56. Saldeen T: Fat embolism and signs of intravascular coagulation in a posttraumatic autopsy material. J Trauma 10:273-286, Apr 1970 57. Saldeen T: The importance of intravascular coagulation and inhibition of the fibrinolytic system in experimental fat embolism. J Trauma 10:287-298, Apr 1970 58. Scully RE: Fat embolism in Korean battle casualties: its incidence, clinical significance and pathologic aspects. Am J Pathol 32: 379-403, May-Jun 1956 59. Sevitt S: Fat embolism. London, Butterworth, 1962, pp 1133 60. Sevitt S: Fat embolism in patients with fractured hips. Br Med J 2:257-262, 29 Apr 1972 61. Sevitt S, Clarke R, Badger FG: Fat embolism. [In] Modern Trends in Accident Surgery and Medicine. London, Butterworth, 1959, pp 214-272 62. Sproule BJ, Brady JL, Gilbert JAL: Studies on the syndrome of fat embolization. Can Med Assoc J 90:1243-1247, 30 May 1964 63. Szabo G, Serenyi P, Kocsar L: Fat embolism: fat absorption from the site of injury. Surgery 54:756-760, Nov 1963 64. Thomas JE, Ayyar DR: Systemic fat embolism: a diagnostic profile in 24 patients. Arch NeuroI26:517-523, Jun 1972 65. Wapshaw H: The pancreatic side-effects of morphine. Br Med J 1:373-375, 14 Feb 1953 66. Webb WR: Pulmonary complications of non-thoracic trauma: summary of the National Research Council Conference. J Trauma 9:700-711, Aug 1969 67. Weisz GM, Rang M, Salter RB: Posttraumatic fat embolism in children: review of the literature and of experience in the Hospital for Sick Children, Toronto, J Trauma 13:529-534, Jun 1973 68. Wilson RF, Kafi A, Asuncion Z, et al: Clinical respiratory failure after shock or trauma: prognosis and methods of diagnosis. Arch Surg 98:538-550, Apr 1969 69. Wilson RF, McCarthy B, LeBlanc LP, et al: Respiratory and coagulation changes after uncomplicated fractures. Arch Surg 106: 395-399, Apr 1973
Diagnostic Radiology
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Frieda Feldman, M.D., Kent Ellis, M.D., and William M. Green, M.D. The " shock lung syndrome," whenever associated with trauma, is probably in part the consequence of fat emboli, though aspiration, disseminated intravascular coagulation, microatelectasis, pulmonary edema, and hemorrhage due to other lung insults may be important in the etiology of man y cases. When lung injury is due to fat emboli, there is an interval between the time of trauma and the onsetof clinical symptoms and chest radiographic findings. The radiographic picture is that of a diffuse alveolar and interstitial lung density. In severe cases marked respiratory embarrassment requires the use of both oxygen therapy andmechanical respirators for survival. INDEX TERMS :
Embolism. pulmonary. Respiratory Tract, insufficiency' Trauma
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T
IS IMPORTANT for the radiologist to recognize the fat embolism syndrome as a serious complic ation of skeletal injury. Ear ly recognition and appropriate respiratory care may save a life . Although involving all age groups, the syndrome is most typ ically seen in otherwise healthy young adults (or even in children (67 )) who have experienced severe trauma-usually secondary to automobile accidents . It has been suggested that " the diagnosis of fat embolism syndrome is made on the basis of the clinical picture of pulmonary and cerebral dysfunction in a patient, who , most commonly, after long-bone fractures. manifests fever , abnormal arterial blood gases, and at least one other manifestation such as abnormality on a chest roentgenogram, petechiae, fat in the retinal vessels on funduscopy , fat on cryostat frozen section of clotted blood, or fat in the urine " (16 ).
I
INCIDENCE AND PATHOPHYSIOLOGY
Although fat emboli have been known to be associated with trauma for more than a century (5), their sour ce and mode of action are still disputed. Probably som e pulmonary fat embolization follows virtually every fracture or severe traumatic injury (38, 39 , 44, 49 , 54 , 56 , 59-61 ). A cross-table lateral film of the knee taken with a horizontal beam in the region of a distal femoral fracture site (Fig . 1) commonly reveals a fat-blood interface without any evidence of skin laceration . This is not surprising to surgeons who frequently aspirate fat from traumatized knee joints. Nor are fat and marrow aggregates in the lung (Fig . 2.A) unusual findings for pathologists who also frequently note fat emboli in the kidney, retina , and brain (Fig. 2,8). Obviously . the severity and extent of the fat embolization vary widely (3. 18,26,42, 45-47. 53, 62) . The full-blown clinical fat embolism syn drome, however. is relatively rare even among pat ients
Fig. 1. Note the extensive fat-fluid interface. This indicates a large amount of liquid fat released into the knee joint following trauma. Embolization of such fat to the lungs is a major mechanism in the fat embolization syndrome. Table I: Fa t Embolism Incidence Per No. of Cent Cases
Autopsy Batt lefield WW II (Mallory) Korea (Scully) Civilian Fuchsig
65 93 16
60 110 5265
Major Cau se of Death
5%
Palrn ovrc
Clinical
Immediately after death 80 969 6 hours aft er death 96 12 hours after death 100 Range 0 . 8-6% Fat l mbohsrn Syndrom e
4. 2%
with major fractures (3 % or less) (TABLE I). Note that in Palmovic 's series (43). patients surviving a number of hours after severe trauma had a greater incidence of fat emboli than those dying immediately. Prevailing opinion is that the fat emboli originate as
, From the Department of Radiology (F. F., Professor; K. E., Professor), College of Physicians and Surgeons, Columbia University, Columbia-Presbyterian Medical Center, New York , N. Y. Presented at the Fifty-ninth Scientific Assembly and Annual Meeting, Chicago, III., Nov. 253~ 1973. ah 535
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neutral fat released from disrupted adipose tissues mainly in the marrow spaces, and that they reach the lungs after direct entry into the vascular system via severed veins in the injured region and to a less extent via the lymphatic system (23, 45-47). These fat emboli mainly affect the small vessels of the lungs, though some of the fat traverses the pulmonary vascular bed and goes on to embolize the organs supplied by systemic arteries and so to produce the other features of the clinical syndrome, especially cerebral, skin, retinal, and renal manifestations. The major modes of action of these fat emboli are: 1. Mechanical Occlusion of Small Vessels: Even though the lung microvasculature is the primary target of fat emboli, acute cor pulmonale produced by fat emboli is a great rarity. Apparently very large amounts of embolized fat are necessary to have this effect. 2. Chemical Injury to the Small-Vessel Walls: Hydrolysis of the neutral fat produces chemically toxic fatty acids, which are known to cause local damage to the microvasculature. Such neutral-fat breakdown in the lung by action of lung lipase is a cause of local edema, hemorrhage, and loss of surfactant with secondary microatelectasis. The relevance of this mechanism of injury is supported by the known activation of lung lipase after fat embolization, by the injurious effects of certain free fatty acids on small blood vessels in experimental models (31), and also by the usual delay between the injury and gross clinical evidence of lung dysfunction in the syndrome (11-14, 20). 3. Aggregation of Blood Platelets and Stimulation of Intravascular Coagulation: Fat globules are known to induce platelet as well as erythrocyte aggregation on the basis of experimental studies (4, 18). Secondary local release of serotonin, histamine, and various other agents including kinins can cause local edema, hemorrhage, intravascular clotting, and vessel disruption. Each of the three mechanisms just outlined probably contributes to the lung dysfunction which is the most serious problem in the fat embolism syndrome. Similar actions on the small blood vessels of the brain, the retina, and the skin may cause the cerebral dysfunction, the funduscopic changes, and the typical skin petechiae which are so characteristic of the syndrome. Fat evidently traverses the glomeruli to reach the urine in about 50% of cases. In many, however, the cerebral dysfunction is probably more the consequence of hypoxia due to respiratory failure than of fat emboli in the brain (64). The major alternate theory for the pathogenesis of fat embolism is a metabolic one. The occurrence of fat embolization in nontraumatic conditions and the slow absorption of radioiodinated 3 11) triolein from traumatized bone ends of experimental animals (63) has led to the contention that the injured site per se is not the sole source of embolic fat and that a sizable contribution stems from body fat depots (33). Free fatty acids are normally mobilized and released into the blood in sub-
e
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stantial amounts as the consequence of many types of stress (7). These fatty acids may in some instances be aggregated and/or esterified in the blood stream into fat globules of sufficient size to cause substantial fat emboli (28). While such a mechanism for production of fat emboli is generally thought to be of minor importance, this may be the explanation for the occasional presence of fat emboli in the absence of conventional types of trauma (33). Other causes of this syndrome reported, which are not associated with conventional trauma, include burns, infections, diabetes mellitus, liver injury, fatty liver, pancreatitis, sickle-cell disease, blood transfusions, inhalation anesthesia, cardiac massage, lymphangiography, renal transplant and/or infarction, cardiopulmonary disease, childbirth, some cases of poisoning, and removal or placement of hip prostheses (8, 26, 34, 35, 52, 56). It is surprising that fat embolism is not more frequently reported in patients with fractured hips. However, Sevitt (60) found an incidence ranging from 0.7 to 7% among various groups of patients following hip fractures. Support for mechanical release of emboli from fat depots has also been found in decompression experiments in which rapid expansion and rupture of fat cells by sudden nitrogen release result in fat and nitrogen embolization (24). CLINICAL FEATURES
The clinical onset of the fat embolism syndrome is most commonly sudden, but after a delay averaging 24 to 48 hours following the trauma, and with a range of from hours to a week. The major manifestations are those of pulmonary dysfunction with dyspnea, tachypnea, hyperpnea, and cyanosis. Although the roentgen evidence often suggests pulmonary edema, these patients have little excess secretions in the bronchial tree, and the lung density does not clear after the usual diuretic and cardiotonic treatment. Signs of generalized dysfunction of the central nervous system are often prominent. Changes in mental state may be the first clinical evidence of the fat emboli syndrome (64). The patient may suddenly become confused, restless, and rambunctious or drowsy, stuporous, or comatose. When seizures occur they are most commonly nonfocal with occasional long-tract signs, posturing, and decerebrate rigidity. The disturbances might be interpreted as manifestations of cerebral contusion or hematoma, delirium tremens, as in one of our cases, or shock. Localizing signs are more characteristic of direct traumatic brain injury than of the fat emboli syndrome. Decerebrate rigidity, an early event in the fat embolism syndrome, is usually a terminal event in craniocerebral trauma (64). Fever is nearly always present; it may be of sudden onset and was as high as 103 0 F in some of our patients. Milder temperature elevations may be overlooked or labelled a "hematoma fever" or "fever of unknown
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Fig. 2. Photomicrographs of the autopsied lung and kidney. A. Pulmonary fat embolism: The fat (black areas) fills pulmonary vessels as well as some alveolar spaces (osmic acid stain) B. Note fat emboli (dark area s) lodged in glomeruli (osmic acid stain) .
origin ." Tachypnea with increased pulse rate to 140 or higher and normal blood pressure are also characteristic . Petechiae of the skin and mucous membranes. which fail to blanche on pressure. are important signs suggesting the fat embolism syndrome. They most often appear on the second or third day after injury . Detection may require careful and repeated search since the petechiae may be sparse and frequently fade within a few hours . They are most commonly noted in the conjunctivae and in the skin at the base of the neck , the anterior thorax or the axillae. perhaps reflecting the greater visibility of these regions . The petechiae have been attributed to hemorrhage secondary to capillary endothelial damage caused by fat embolization and are classic physical findings in the fat emboli syndrome. being found in 50 % of the cases (45). Retinal fat embolism is another valuable diagnostic sign. Funduscopy may reveal retinal hemorrhage as well as intra-arterial fat emboli. Eventually tiny yellowish plaques (Purtscher 's sign) and microinfarcts (described as " ro sary around the macula ") may be manifest (15, 19. 29 ). Retinal changes have been noted in about 50 % of patients with fat embolism syndrome . from two days to two weeks following trauma . Fat embolism may be a cause of shock . but. on the other hand. it has been considered a manifestation of the general shock phenomenon (21). Fat embolism per se, however. is not related to periods of hypotension ; in fact , hypotension itself has been advocated as a treatment of fat embolism (45-47). In patients with the " shock lung" syndrome, fat embolism is frequently present. LASORATORY FINDINGS
Early repeated measurements of arterial blood gases have become a cornerstone in patient management and a gauge of treatment effectiveness in the fat emboli syndrome . Other laboratory findings , though not pathognomonic. may support the diagnosis . which is generally
a presumptive one made on the basis of the observed clinical features together with a knowledge of the disease pattern. Numerous instances have been cited of clinical failure to recognize the severity or degree of arterial hypoxia in the fat emboli syndrome. Other frequent findings are substantial decreases in platelets. hemoglobin, and hematocrit despite blood loss correction and without obvious evidence of further bleeding from the trauma site . Intrapulmonary hemorrhage . transient hemolysis, and associated disseminated intravascular coagulation have been proffered as causative factors (4, 9. 3D, 32 . 37 . 50 , 51. 56. 57. 66). Fibrinogen levels , initially normal or reduced. may show a delayed rapid rise to double the upper limits of normal (36 ). Low platelet counts have been related to aggregation about fat droplets in the lung and at other sites of injury . A significant correlation between a low platelet count and a large A-aP0 2 (alveolar compared to arterial oxygen tension gradient) has been noted (36) . Patients with the lowest platelet counts had the most severe pulmonary manifestations as evidenced by an A-aP0 2 of 40 mm or more . Lipuria. although reported in many cases of fat embolism syndrome, has also not been universally regarded as a reliable indicator of the syndrome. Free fat in the sputum is considered diagnostically worthless since it is frequently found in the normal population . Serum lipase elevation has been regarded as a gauge of fat depot mobilization and embolization (45, 55). Some authors. however. believe this is an unreliable yardst ick. usually reflecting pancreatic rather than lipoprotein lipase (16). Morphine, which is commonly used in the injured. may elevate the serum lipase to 20 times normal (65). This factor further negates the value of serum lipase as a reliable indicator of fat embolization. Serum electrophoresis demonstrating alterations in lipid compartments and cryostat frozen sections of clotted blood stained with "oil red-o " are other techniques being evaluated (18). The amount of neutral fat present in the clotted blood of traumatized patients has been
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B
Fig. 3. A. A 19-year.old man with a grossly normal chest film was alert and oriented on admission despite multiple injuries . However, he became somnolent within two days and comatose by three days , at which time the chest film exhibited diffuse bilateral increase in pulmonary dens ity . He was severely hypo xic . Cerebral symptoms improved on a regimen of nasal oxygen , steroids, and intravenous heparin. Pulmonary symptoms progressed, however, requir ing intubation and mechanically arrested respiration. B. At five days widespread , somewhat patchy pulmonary densities are distributed throughout both lungs . Note the normal-size heart and the absence of pleural fluid as is common in this syndrome .
Fig. 4. This 31-year-old woman became confused within twentyfour hours after she sustained multiple pelvic and long-bone fractures . A chest film at twenty-four hours revealed a generalized increase in lung dens ity. At fort y-eight hours , the chest film (above) showed a more diffuse and evenly distributed involvement, with a striking air bronchogram effect whic h was accentuated by me chanically ass isted resp irat ion .
said to closely relate to clinical manifestations of the fat embolism syndrome (16, 27). Serum calcium may be decreased after trauma due to its interaction with fatty acids . RADIOGRAPHIC FINDINGS
Acute cor pulmonale secondary to massive fat emboiization, though possible, is extremely rare. Charac-
teristically, after an interval of up to 72 or more hours, during which the lungs appear roentgenographically grossly normal (Fig. 3,A), widespread lung density develops (Fig. 3,B). At first this density is usually more marked in the perihilar and basilar regions, but subsequently it tends to become generalized . The diffuse lung density is a combination of interstitial and alveolar patterns (Figs. 4, 6, and 7). Such radiographic findings, though nonspecific, are characteristic of this syndrome. In some patients the densities have a more patchy appearance (Figs. 3,B and 5,B), perhaps related to uneven distribution of the fat emboli or due to preexisting variations in lung architecture. At the onset, as well as later, in milder cases the portable chest radiograph may appear relatively normal despite considerable arterial hypoxia and impressive clinical manifestations of fat embolism including dyspnea , cerebral dysfunction, and petechiae (Fig. 7,C). In summary, the roentgen findings are nonspecific (6, 41) and of varying severity but most often involve diffuse lung density with relative sparing of the apices (Fig. 6). Pleural effusions are not part of the fat embolism syndrome. Both the heart and the pulmonary vasculature, when visible, appear normal in size-unless abnormal due to another disease process. After a day or two the lung density tends to become greatest at the periphery. In most cases the pulmonary densities clear after several days to a week or more . Particularly in cases in which assisted respiration is required, the central and larger air ducts, as well as some better ventilated or emphysematous peripheral air spaces, become conspicuous as contrasted against the
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A
Fig. 5. A 23-year-old girl with a femoral shaft fracture sustained in an automobile accident had a grossly normal admission portable chest film (A), but became cyanotic within forty-eight hours, The chest film then (B) showed confluent densities in both lungs which promptly responded to O 2 and steroids. Note again the absence of effusions. The large patches of density are not so typical of the fat embolism syndrome as is the more homogeneous lung density of Figure 4. This case, too , demonstrates the acute development of respiratory symptoms after an initial delay. Of additional interest is the development in this patient of petechiae and generalized convulsions one week later. These were presumably related to a shower of fat emboli from a poorly immobilized fracture site .
Fig. 6. This 21-year-old camp counselor fractured her femur in an automobile accident . She became confused three days afterward, at which time a chest film showed a diffuse pattern of reticular densities . More extensive changes were noted on the fourth day (right) with a combination of diffuse interstitial and alveolar densities. These are more difficult to see here in reproduction than on the original portable chest radiograph .
surrounding opaque lung (Figs. 4 and 5,B). These patchy lucent regions may become very striking during positive pressure ventilation, an expression of the pressure effects and heterogeneity of distribution of the forced ventilation. Severe cases requiring high levels of inspired oxygen and positive pressure mechanical ventilation have a guarded prognosis and are subject to all of the hazards (including oxygen toxicity. pneumothorax , etc.) as well as the benefits of such treatment. The pathologic basis for the acute development of diffuse lung density is a combination of pulmonary edema and hemorrhage plus diffuse microatelectasis
apparently secondary to the loss of pulmonary surfactant. The differential diagnoses include aspiration or viral pneumonia, post-traumatic or postoperative atelectasis. and other causes of acute pulmonary edema with or without pulmonary hemorrhage, such as fluid overload. intracranial injury, pulmonary embolism, lung contusion, left heart failure, drug reaction, Gram-negative sepsis, transfusion reaction, disseminated intravascular coagulation, and perhaps pulmonary hypoxia . The most severe cases become clinically indistinguishable from the " shock lung." The course of these patients may be complicated by
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superimposed processes such as CHF and later acquired pneumonia and pulmonary embolism, particularly in the older age group. CLINICAL FINDINGS IN CURRENT CASES
Since this report was solely concerned with the fat embolism syndrome after trauma, all nine of our current cases followed accidental injury. Seven were injured in or by automobiles, one fell from a fourth-story window, while one had a horse fall on him. There was a 5:4 male to female ratio. The average age was 34 years with a range from 19 to 56 years. The group sustained 41 fractures: 7 femoral, 6 tibial, 6 fibular, 5 pelvic, 5 ribs, 3 ankles, 3 vertebral, 2 humeral, 1 foot, 1 skull, 1 clavicular, 1 nasal. Symptoms appeared as early as four hours and as late as ten days following trauma. Respiratory rates of 60/minute, pulse rates of up to 105/minute and abrupt elevations in temperature to as high as 103 0 F were noted. All were alert on admission. One patient reputedly had a transient loss of consciousness at the scene of the accident. Another with a skull fracture and small subdural hematoma also showed predominantly pulmonary manifestations within 48 hours. Most patients exhibited features of both pulmonary and cerebral dysfunction. Of the two patients symptomatic within four hours, one had had closed manipulation for hip fracture reduction. The latent period folloWing early fracture manipulation, particularly under general anesthesia, tends to be shorter (3). Presumably routine postoperative hypoxemia superimposed upon the hypoxia produced by the effects of fat emboli hastens the onset of the fat embolism syndrome. One patient had generalized seizures concomitant with petechiae ten days after injury, but she had also had predominantly pulmonary symptoms two days postinjury, requiring mechanically assisted respiration. Unusually delayed onset or repeated symptomatic episodes have been attributed to rough handling or poor immobilization of fractures, which presumably release showers of fat emboli from traumatized tissues (1). Fular and Kraft (22) also contend that circulatory shock induced by pulmonary fat emboli results in retained fat in the lungs which, in recovery, spills into the systemic circulation. Another explanation for delayed manifestations emphasizes the accumulation of fat macroglobules in lung capillaries on the basis of their size and viscosity. Resultant mounting peripheral resistance raises pulmonary artery pressure until it is high enough to force a shower of emboli through the capillary network. After a consequent fall in pulmonary artery pressure, the cycle may be repeated (51). These theories suggest and are in accord with clinical observations that fat embolization may not be a "one time," but rather a continuous or repetitive event (1). Of additional interest was severe abdominal pain manifested by one of our patients; it was ascribed clini-
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cally to visceral and peritoneal fat embolization. The accompanying illustrations and case abstracts (Figs. 3-7) serve to illustrate some of the more typical clinical and roentgen features of the fat embolism syndrome. TREATMENT
Correction of significant arterial hypoxemia is the most important aspect of therapy for the fat emboli syndrome. The whole gamut of respiratory care may be required, ranging from supplemental nasal oxygen to intubation and mechanical positive pressure ventilation. The arterial oxygen tension should be kept above 60 mm Hg. The hypoxic patient must be very closely monitored, ideally in a respiratory care unit. Improvement in oxygenation usually relieves not only the respiratory manifestations but also the cerebral symptoms. Since prognosis is improved by early recognition of the arterial hypoxia, arterial blood gas measurement (Pa02; PaC02; pH) should routinely be obtained initially and daily for at least several days in patients who are good candidates for the fat emboli syndrome, e.g., patients with severe and/or multiple fractures. In the clinically more severe cases, additional treatment with relatively high dose corticosteroid therapy has apparently been of significant value and is now widely recommended (2). Anti-inflammatory effects on the lung reaction to toxic substances, including free fatty acids, is the presumed mechanism of action. Heparin therapy has been advocated as a means of reducing intravascular platelet aggregation and blood coagulation and also for its chylolytic and lipase-activator actions. Administration of heparin to severely traumatized patients with many potential bleeding sites, however, risks further bleeding. Such treatment is controversial at this time. Some have advocated the use of intravenous ethyl alcohol as a fat emulsifier and lipase inhibitor. Low-molecular-weight dextran has also been recommended as a means of improving hemodynamics and decreasing platelet aggregation, thus minimiZing the adverse effects of fat emboli. SUMMARY
The fat emboli syndrome can be broadly viewed as one pathway leading toward acute respiratory failure or the "acute respiratory distress syndrome." When the lung injury is most clearly due to fat emboli, there is an interval between the time of the trauma (up to 72 hoursbut occasionally longer) and the onset of clinical respiratory symptoms and the chest roentgenographic findings. Cerebral symptoms, skin and conjunctival petechiae, retinal fat emboli, and fat in the urine all tend to confirm the diagnosis. The most typical cases occur in young adults or in children who were in good health prior to the episode of trauma. In severe cases marked respiratory embarrassment requires the use of both
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Fig. 7. This 33-year-old man was seen at 2 A.M. after an auto accident. The admission chest film was normal , and there were multiple long-bone fractures (A). He had become disoriented by 6 A.M . and at 7 A .M. petechiae were noted about the base of the neck. the axillae. and the anterior chest wall (B). A 24-hour film (C) shows widespread. ill-defined nodular and interstitial densities which gradually cleared within four days. The roentgen findings, though not as impressive as those associated with the previous cases. serve as an example of another variation in pattern . The diagnosis was corroborated by clinical and laboratory evidence .
oxygen therapy and mechanical respirators for survival. The roentgenographic picture is that of diffuse alveolar and interstitial lung density. Such patients are clinically virtually identical to patients with the " shock lung" syndrome of respiratory failure. In fact, the " shock lung syndrome," whenever associated with trauma, is probably in part the consequence of fat emboli, though aspiration , disseminated intravascular coagulation, microatelectasis , pulmonary edema and hemorrhage due to other lung insults may be more important in the etiology of many cases . The diagnosis of the fat embolism syndrome depends on the chest roentgenogram in a clinical context of skeletal trauma with pulmonary and/or cerebral dysfunction . Important supporting evidence includes skin petechiae, lipuria, and retinal fat. 622 W. 168th St. New York, N. Y.. 10032
REFERENCES 1. Aach R. Kissane J: Fat embolism. Am J Med 51: 258-268. 1971 2. Ashbaugh DG, Petty TL: The use of corticosteroids in the treatment of respiratory failure associated with massive fat embolism. Surg Gynecol Obstet 123:493-500. Sep 1966 3. Benatar SA, Ferguson AD. Goldschmidt RB: Fat ernbojsrn-; some clinical observations and a review of controversial aspects . a J Med 41:85-98, Jan 1972 4. Bergentz SE: Studies on the genesis of posttraumatic fat embolism . Acta Chir Scand [Suppl!282:1-72, 1961 5. Bergmann EB: Ein Fall todlicher Fettembolie . Berl Klin Wochenschr 10:385-387, 1873 6. Berrigan TJ. Jr. Carsky EW, Heitzman ER: Fat embolism: roentgenographic pathologic correlation in 3 cases . Am J RoentgenoI96:967-971. Apr 1966
7. Beveridge RJ. Webster JW: Fat embolism : recognitiontreatment-prognosiS . Angiology 23:338-344, Jun 1972 8. Blaisdell FW: Respiratory insufficiency syndrome: clinical and pathological definition . J Trauma 13:195-199. Mar 1973 9. Bradford OS. Foster RR. Nossel HL: Coagulation alterations. hypoxemia. and fat embolism in fracture patients . J Trauma 10: 307-321 , Apr 1970 10. Bredenberg CEoJames PM, Collins J, et al: Respiratory failure in shock . Ann Surg 169:392-403. Mar 1969 11. Bruecke P, Burke JF, Lam KW. et al: The pathophysiology of pulmonary fat embolism . J Thorac Cardiovasc Surg 61:949-955, June 1971 12. Carlson LA . Liljedahl S: Lipid metabolism and trauma . II. Studies on the effect of nicotinic acid on nor-epinephrine-induced fatty liver . Acta Med Scand 173:787-791, Jun 1963 13. Carlson LA. Liljedahl SO. Wirsen C: Blood and tissue changes in the dog during and after excessive free fatty acid mobilization: a biochemical and morphological study. Acta Med Scand 178;81-102, Jul1965 14. Degner RL, Lewis K, Mitchinson MJ: Fat embolism in monkeys exposed to cyclic acceleration . J Trauma 13:229-234. Mar 1973 15. DeVoe AG: Ocular fat embolism : a clinical and pathologic report. Arch OphthalmoI43:857-863 , May 1950 16. Dines DE. Linscheid RL. Didier EP: Fat embolism syndrome. Mayo Clin Proc 47:237-240, Apr 1972 17. Dyck DR, Zylak CJ: Acute respiratory distress in adults . Radiology 106:497-501. Mar 1973 18. Evarts CM: The fat embolism syndrome : a review . Surg Clin North Am 50:493-507. Apr 1970 19. Finley JF, Raban RJ. Lehman CL: Traumatic retinopathy of Purtscher complicated by secondary glaucoma: a case report. Am J OphthalmoI55:367-370. Feb 1963 20. Fonte DA, Hausberger FX: Pulmonary free fatly acids in experimental fat embolism . J Trauma 11:668-672. Aug 1971 21. Fuchsig P, Brucke P, Blumel G. et al: A new clinical and experimental concept on fat embolism. N Engl J Med 276:1192-1193, 25 May 1967 22 . Fular W, Kraft E: Prophylaxe der Fettembolie durch Blutdrucksenkung. Arch Klin Chir 278:548-556, 1954 23 . Gauss H: The pathology of fat embolism. Arch Surg 9: 593-605, Nov (pt. 1) 1924
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