OBSERVATION Endovascular Closure of a Patent in the Fat Syndrome Changes in the Embolic Patterns as Detected by Transcranial Doppler

Alejandro M. Forteza, MD; Alejandro Rabinstein, MD; Sebastian Koch, MD; Gregory Zych, DO; Jay Chandar, MD; Jose G. Romano, MD; Iszet Campo Bustillo, MD

Background: The posttraumatic fat embolism syn- shed territories. Percutaneous PFO closure with a but- drome (FES) is characterized by petechiae and pulmo- toned device was successfully performed. nary and cerebral dysfunction. A patent foramen ovale (PFO) could worsen the of FES by allowing Results: Closure of PFO was associated with marked re- larger emboli to reach the systemic circulation. Trans- duction in the number and intensity of microembolic sig- cranial Doppler ultrasonography can be used to diag- nals. Subsequent surgical repair of the fracture with the nose and monitor cerebral microembolism in FES. patient under transcranial Doppler monitoring was un- eventful. There was excellent correlation between clini- Objective: To describe a case of successful percutane- cal course and microembolic signal load by transcranial ous closure of PFO in a patient with posttraumatic FES Doppler. with excellent clinical outcome. Conclusions: Cerebral fat embolism after long- frac- Patient and Methods: A 17-year-old girl presented tures can be detected in vivo and monitored over time with a posttraumatic long- complicated by with the use of transcranial Doppler techniques. If a PFO typical severe FES. Transcranial Doppler disclosed mul- is present, its closure before surgical manipulation of the tiple microembolic signals over both middle cerebral and fracture is feasible and could have important protective basilar arteries. A large PFO was diagnosed by trans- effects against massive systemic embolization. esophageal echocardiogram. A brain magnetic reso- nance image with diffusion-weighted sequences showed multiple bilateral areas of abnormal diffusion in water- Arch Neurol. 2002;59:455-459

HE POSTTRAUMATIC fat em- fractures were monitored with TCD within bolism syndrome (FES) is 24 hours of trauma. Our preliminary re- a multisystem disorder sults, presented elsewhere,7 suggest that characterized by the clini- the presence of a PFO is a risk factor for cal triad of petechial rash, developing more severe manifestations of dyspnea, and signs of cerebral dysfunc- FES. If this holds true, it may be helpful T1,2 tion. Pathological studies of patients who to occlude the right-to-left shunt before a died after having FES typically show wide- critical embolic load has caused irrevers- spread microvascular occlusion by fat em- ible or significant damage. boli, particularly within the lungs and We describe a patient with severe brain.3,4 The presence of a patent fora- posttraumatic FES and a PFO who suc- men ovale (PFO) has been suggested to cessfully underwent percutaneous clo- worsen the prognosis of FES by allowing sure of the intracardiac shunt followed by From the Division of a larger embolic load to reach the sys- excellent clinical recovery. Cerebrovascular Diseases, temic circulation,4-6 and it has been shown Department of Neurology that during bone surgery large fat glob- REPORT OF A CASE (Drs Forteza, Rabinstein, Koch, ules may cross a PFO, causing severe ce- Romano, and Campo Bustillo), rebral complications, including death.4 A 17-year-old girl had a car crash and was Department of Orthopedic Our group recently reported that ce- brought to our Trauma Emergency Room. Surgery (Dr Zych), and Division of Pediatric rebral microembolism in patients with FES No loss of consciousness or head trauma Cardiology, Department of can be diagnosed and monitored in real occurred. Her Glasgow Scale score 6 Pediatrics (Dr Chandar), time with transcranial Doppler (TCD). was 15 at the scene of the accident and on University of Miami School Two years ago, we began a prospective arrival to the hospital. Initial evaluation of Medicine, Miami, Fla. study in which patients with long bone showed a fully alert patient in no sig-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 cm/s cm/s cm/s A 24 B 30 C 22 180 200 200 160 180 180 140 160 160 120 140 140 100 120 120 80 100 100 60 80 80 40 60 60 20 40 40 0 20 20 –20 0 0 –40 –20 –20 –60 –40 –40 0 6 –2

cm/s cm/s D 24 E 22 200 200 180 180 160 160 140 140 120 120 100 100 80 80 60 60 40 40 20 20 0 0 –20 –20 –40 –40 0 –2

Figure 1. Microembolic signal (MES) characteristics. A, Large MES with an intensity greater than 12 dB (arrowhead) detected in the left middle cerebral artery. B, Small MES of less than 12 dB (long arrow) detected in the left middle cerebral artery. C-E, Multiple MES over the right middle cerebral artery observed within seconds of intravenous injection of aerated, agitated isotonic sodium chloride solution.

nificant distress who complained only of left thigh pain. tient was transferred to the and intu- Vital signs showed a regular of 100 beats per bated orally. At that time, she was stuporous, respond- minute, a blood pressure of 120/80 mm Hg, and a res- ing with eye opening, grimacing, and withdrawing limbs piratory frequency of 16/min. The left thigh was swol- to painful stimuli. Bilateral Babinski signs and bilateral len and deformed, but there was no disruption of the skin subconjunctival petechiae were noted. continuity. A TCD examination disclosed multiple microem- A radiologic survey was performed, including a com- bolic signals (MES) over both middle cerebral arteries puterized tomographic scan of the brain, with normal (MCAs) and the basilar artery (Figure 1A-B shows MES results. An x-ray film of the left femur showed a com- over left MCA). Two seconds after the injection of agi- minuted, transverse fracture at the junction of the proxi- tated isotonic sodium chloride solution in an antecubi- mal and middle thirds of the shaft, with lateral and pos- tal vein, numerous MES appeared over both MCAs and terior displacement of the distal fragment. Routine blood the basilar artery, indicating the presence of a right-to- work showed leukocytosis (white blood cell count, 22.7 left shunt (Figure 1C-E). A venous duplex scan of the ϫ103/µL) and mild anemia ( level, 11.9 g/dL; lower extremities and a ventilation-perfusion nuclear scan , 37%). Prothrombin time was 14 seconds, and of the lungs obtained during the following 12 hours were activated thromboplastin time, 24 seconds. Initial blood unremarkable. A transesophageal echocardiogram per- gas values while the patient was breathing room air were formed during the third hospital day showed a redun- as follows: pH 7.41, PCO2,34mmHg;PO2,61mmHg; dant interatrial septum, confirmed the presence of a PFO, bicarbonate, 21 mEq/L; and arterial oxygen saturation, and showed spontaneous passage of aerated micro- 92%. The patient was placed in skeletal traction and bubbles across the septum (Figure 2A-B). A brain mag- received nonopiate pain medication. netic resonance image with diffusion-weighted images Fourteen hours after admission, she suddenly be- obtained that same day showed multiple areas of abnor- came confused and agitated. Tachycardia and tachyp- mal diffusion on diffusion-weighted images, some with nea worsened and pulse oximetry showed that the arte- high T2 and fluid-attenuated inversion recovery signal rial oxygen saturation had dropped to 85% while the intensity, located in the subcortical and periventricular patient was breathing room air, improving to 98% when white matter of both cerebral hemispheres in the distri- 4 L of oxygen by nasal cannula was administered. Re- bution of the watershed territories (Figure 3). peated blood gas measurement showed a pH of 7.42, PCO2 On the fourth day of admission, after informed con- of 35 mm Hg, PO2 of 45 mm Hg, bicarbonate level of 22 sent was signed by proxy, a transcatheter device closure mEq/L, and arterial oxygen saturation of 83%. The pa- of the PFO was successfully performed with the patient

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A L B L

T LA T LA 90 0 Contrast

RA

Contrast LV

RA RV

I

C D L L

T T 0 0 LA LA

RA RA Device

Contrast

LV LV RV RV

Figure 2. Transesophageal view of redundant interatrial septum and patent foramen ovale (A) with spontaneous passage of contrast (aerated isotonic sodium chloride solution) from right (RA) to left atrium (LA) (B). After deployment of the occluding device, there is no further passage of contrast from right to left (C and D). T indicates transverse axis; L, longitudinal axis; RV, right ; and LV, left ventricle.

under general anesthesia and transesophageal echocar- TCD EXAMINATIONS diographic control (Figure 2C-D). A 40-mm buttoned de- vice (Custom Medical Devices, Amarillo, Tex) was placed detection monitoring was performed on admis- in the left atrium with the use of a 10F sheath from the sion, intraoperatively, and daily until a 1-hour monitor- femoral vein. The right-to-left shunt was eliminated by ing period failed to identify MES. All studies were per- adding a 25-mm inverted counter occluder in the right formed with a TCD unit (Pioneer TC 4040; Nicolet atrium. Treatment with clopidogrel bisulfate and enoxa- Biomedical Inc, Madison, Wis) equipped with microem- parin sodium was started. bolus detection software, version 2.31, 256-point fast Fou- During the next 36 hours, the patient exhibited pro- rier transform with a sample volume of 10 mm. Each study gressive improvement, eventually recovering normal men- lasted 1 hour. A 2-MHz probe was used to insonate the tal status. An echocardiogram performed 5 days after the right and left MCAs and the basilar artery through tem- catheterization confirmed that the device remained in poral and transforaminal windows. All studies were per- place with no passage of microbubbles from right to left. formed at a depth of insonation between 5 and 5.6 cm for On the 10th day of admission, the patient underwent sur- the MCAs and between 8 and 9 cm for the basilar artery. gical repair of her without complica- A headband was used to immobilize the probe against the tions. Continuous TCD monitoring was performed dur- temporal window. Two experienced technicians (includ- ing surgery. Close clinical follow-up did not show any ing I.C.B.) performed all studies, and any suspicious sig- suggestion that the surgery worsened the patient’s men- nals were saved manually. Two independent blinded ob- tal status. On the contrary, during the days after the sur- servers (A.M.F. and S.K.) reviewed all studies. gery, she continued to improve and was discharged home The initial study on the day after trauma showed 14 while receiving warfarin sodium on the 16th hospital day. MES per hour, with only 2 MES smaller than 12 dB. Daily

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8

6

4 No. of MESs/60 min 2

0 1 3 PFO 5 7 Femur 11 Closure Surgery Days After

Figure 4. Daily embolus detection monitoring demonstrating large emboli C D from the day of injury until patent foramen ovale (PFO) closure, with a small increase the day of femur surgery. Gray bars indicate emboli of 12 dB or more; black bars, emboli less than 12 dB. MES indicates microembolic signals.

in posttraumatic cases of FES proposes that damaged in- tramedullary veins allow the intravasation and subse- quent embolism of marrow fat.11 Fat emboli are sus- pected to be able to modify their shape to reach the systemic circulation either through pulmonary precap- illary shunts or directly across the pulmonary-capillary bed.12-14 However, presence of a PFO has been shown to Figure 3. Brain magnetic resonance images showing fluid-attenuated be responsible for the occurrence of paradoxic embo- 4-6 inversion recovery signal changes in the deep anterior and posterior lism in some patients with FES, and it may be associ- watershed areas (A and B) and abnormal diffusion on diffusion-weighted ated with a worse outcome. By blocking the lumen of pul- images (C and D). monary capillaries, fat emboli could lead to an increase in right ventricular filling pressures, thereby favoring right- studies during the next 2 days demonstrated a similar pat- to-left shunting in patients with PFO. tern, with more than 80% of all emboli having an inten- Our patient presented with a typical clinical pic- sity of 12 dB or more. Percutaneous closure of the PFO ture of posttraumatic FES. The elements of the diagnos- eliminated all large emboli and decreased the embolic load, tic clinical triad were present: acute respiratory distress, so that on day 8 only 1 MES per hour was detected. An petechiae, and signs of cerebral dysfunction. Embolus increase in the number of emboli to 16 MES per hour monitoring showed the presence of numerous MES in was noted during femur surgery, of which 75% were the absence of any evidence of deep smaller than 12 dB. Postoperative monitoring was con- in the lower extremities. Magnetic resonance imaging of tinued for 72 hours, when only 1 MES per hour was found the brain showed multiple areas of abnormal diffusion (Figure 4). suggesting acute ischemia distributed throughout wa- tershed regions. This pattern of magnetic resonance im- DETECTION OF RIGHT-TO-LEFT SHUNT aging findings has been previously reported in patients with FES.6,15,16 Nine milliliters of isotonic sodium chloride solution was The embolic load and the intensity of the emboli as vigorously mixed with 1 mL of air and injected into an assessed by TCD were significantly reduced after our pa- antecubital vein, while 1 MCA was monitored. A second tient underwent successful percutaneous closure of her injection was performed with the patient performing a Val- PFO, but the emboli did not disappear immediately, ris- salva maneuver 5 seconds after the injection. The study ing again during the surgical repair of the fracture (Fig- was considered positive with the appearance of embolic ure 4). Our results suggest that the endovascular clo- signals within 60 seconds of the injection (Figure 1C-E). sure of the PFO stopped large emboli from being shunted through the heart, but small emboli continued to reach COMMENT the brain (although in smaller numbers) for several days, possibly crossing through intrapulmonary shunts.12,13 Pro- The clinical spectrum of the FES ranges from asymp- gressive clinical improvement followed this procedure, tomatic to fulminant cases.2,8 The incidence of FES after and subsequent surgical repair of her femoral fracture did single long-bone fractures is estimated to be between 0.5% not alter this favorable course. and 3%, even though fat globules can be detected in the Our case brings out issues with both clinical and venous blood of almost every patient with these frac- pathophysiologic implications. Several aspects of the case tures.9 The factors that determine the development and reaffirm the concept of FES as a microembolic state.3 Mi- severity of FES remain incompletely understood. croembolic signals were clearly demonstrated through- The occurrence of fat microembolism has been sol- out the course of the disease and were maximal at the idly documented in vivo,1,6,10 and the prevailing theory time of worst clinical status. Their clinical relevance was

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 further supported by the appearance in the magnetic reso- (Drs Forteza, Rabinstein, Koch, Zych, Chandar, and Campo nance image of the brain of multiple areas of abnormal Bustillo); analysis and interpretation of data (Drs Forteza, diffusion along the watershed distribution. Further- Rabinstein, Koch, Romano, and Campo Bustillo); drafting more, after closure of the PFO, the reduction of MES of the manuscript (Drs Forteza and Rabinstein); critical re- reaching the systemic circulation was associated with a vision of the manuscript for important intellectual content clear and persistent clinical improvement. (Drs Forteza, Koch, Zych, Chandar, and Romano); obtain- Presence of a PFO has previously been implicated ing funding (Dr Forteza), administrative, technical, or ma- as a poor prognostic factor in patients with FES.4-6 The terial support (Drs Forteza, Chandar, and Campo Bustillo); severity of the clinical presentation in our case and the study supervision (Drs Forteza and Zych). improvement after correction of the intracardiac shunt Correspondingauthorandreprints:AlejandroM.Forteza, add further credence to this notion. The presence of a MD, Professional Arts Center, 1150 NW 14th St, Suite 304, PFO allows the passage of larger and therefore more dan- Miami, FL 33136 (e-mail: [email protected]). gerous fat particles, as suggested by the MES detected be- fore and after PFO closure in Figure 4. In fact, our de- REFERENCES cision to close the PFO in this case was based on the 1. Gurd AR. Fat embolism: an aid to diagnosis. J Bone Joint Surg Br. 1970;52:732- experience with a previous patient with FES and PFO who 737. 6 ultimately developed severe neurologic sequelae. 2. Levy DL. The fat embolism syndrome: a review. Clin Orthop. 1990;261:281- This case also illustrates the value of TCD monitor- 286. ing and magnetic resonance imaging with diffusion- 3. Kamenar E, Burger PC. Cerebral fat embolism: a neuropathological study of a weighted images in the evaluation of patients with long- microembolic state. . 1980;11:477-484. 4. Pell ACH, Hughes D, Keating J, Christie J, Busuttil A, Sutherland GR. Fulminat- bone fractures and early neurologic symptoms. We believe ing fat embolism caused by paradoxical embolism through a patent foramen that the presence of numerous and particularly of large ovale. N Engl J Med. 1993;329:926-929. MES as well as the evidence of areas of abnormal diffu- 5. Etchells EE, Wong DT, Davidson G, Houston PL. 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Crit Care Med. 1990; diography has been proposed as a useful diagnostic tool 18:42-46. 4 to monitor these patients. 9. ten Duis HJ. The fat embolism syndrome. Injury. 1997;28:77-85. The periprocedural rates of percuta- 10. Kelly GL, Dodi G, Eisman B. Ultrasound detection of fat emboli. Surg Forum. 1972; neous PFO closure vary with the method and device used, 23:459-461. 18-20 11. Peltier LF. Fat embolism: a perspective. Clin Orthop. 1990;261:281-286. and they have ranged between 0% and 10%. Com- 12. Sevitt S. The significance and pathology of fat embolism. Ann Clin Res. 1977;9: plications may include damage to the peripheral vessels 173-180. with ensuing retroperitoneal hematoma, perforation of 13. Watson AJ. Genesis of fat emboli. J Clin Pathol Suppl. 1970;4:132-142. the right atrium with pericardial tamponade, intrapro- 14. Byrick RJ, Mullen B, Mazer CD, Guest CB. Transpulmonary systemic fat embo- cedural stroke presumably due to , and em- lism: studies in mongrel dogs after cemented arthroplasty. Am J Respir Crit Care 18 Med. 1994;150:1416-1422. bolization of the device. Success rates as defined by trivial 15. Stoeger A, Daniaux M, Felber S, Stockhammer G, Aichner F, zur Nedde D. MRI or no residual shunt seen on echocardiography have findings in cerebral fat embolism. Eur Radiol. 1998;8:1590-1593. ranged between 86% and 98%.18,19 Follow-up for up to 5 16. Takashashi M, Suzuki R, Osakabe Y, et al. Magnetic resonance imaging findings years showed an incidence of recurrent thromboem- in cerebral fat embolism: correlation with clinical manifestations. J Trauma. 1999; 18,19 46:324-327. bolic events of 3.2% to 3.4%, and these events were 17. Pell ACH, Keating JF, Black S, Christie J, Sutherland GR. Use of transesopha- more frequent in cases of suboptimal closure. How this geal echocardiography to predict patients at risk of the fat embolism syndrome transcatheter percutaneous technique compares with sur- following traumatic [abstract]. J Am Coll Cardiol. 1993;21(suppl A): gical closure remains to be determined.21,22 264A. In summary, we present a provocative case of se- 18. Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent fora- men ovale in patients with paradoxical embolism: long-term risk of recurrent throm- vere posttraumatic FES in a patient with PFO who was boembolic events. Circulation. 2000;101:893-898. successfully treated by percutaneous closure of the in- 19. Hung J, Landzberg MJ, Jenkins KJ, et al. Closure of patent foramen ovale for tracardiac shunt. This case reaffirms that cerebral fat em- paradoxical emboli: intermediate-term risk of recurrent neurological events bolism after long-bone fractures can be detected in vivo following transcatheter device placement. 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