FAT EMBOLIZATION WITH CARDIOTOMY WITH THE USE OF CARDIOPULMONARY BYPASS

FAT EMBOLIZATION W I T H CARDIOTOMY W I T H THE USE OF C A R D I O P U L M O N A R Y

BYPASS

Feodor Caguin, M.D.*

(by invitation),

M. G. Carter, M.D.,**

New Haven,

and Conn.

refinement of techniques and apparatus has widened the ap­ plication of extracorporeal circulation for the correction of both congenital and acquired heart defects. However, in addition to some unsolved technical prob­ lems, various undesirable biological reactions have been encountered in patients subjected to extracorporeal circulation. Among the most serious were the central nervous system changes sometimes encountered in patients postoperatively. Several possible causes have been suggested including cerebral air embolism, 1,2 fluid and electrolyte changes, calcium embolism,3 hypoxia and cold, and antifoam embolism,4 but none of these seemed definitely responsible for changes noted in certain of our patients. This paper records our experiences with patients who developed central nervous system manifestations and suggests fat embolization as a possible cause.

^^ONTINUED

MATERIAL

Ninety-three operations with the use of cardiopulmonary bypass were per­ formed on 92 patients during the period from April, 1958, to January, 1962. Ages of the patients ranged from 3 to 52 years, and only 16 patients were less than 17 years of age. One child required two operations; the original one was for correction of tetralogy of Fallot but the ventricular septal defect reopened which required a second operation. The indications for surgery are noted in Table I. Early in our experience we noted that occasional patients exhibited a variety of neurological symptoms which occurred in a vague pattern. Symptoms usually did not begin before the third postoperative day and often not until the fifth to seventh postoperative day. The search for fat emboli was started because an orthopedic patient was seen in whom similar neurological changes occurred From the Thoracic ami Cardiovascular Surgical Service, Hospital of St. Raphael, New Haven, Conn. Read a t the Forty-third Annual Meeting of The American Association for Thoracic Sur­ gery at Houston, Texas, April 8-10, 1963. •Formerly Chief Resident, Thoracic and Cardiovascular Surgical Service, Hospital of St. Raphael, New Haven, Conn. ••Chief, Thoracic and Cardiovascular Surgical Service, Hospital of St. Raphael, New Haven, Conn., and Assistant Clinical Professor of Surgery (Thoracic), Yale University School of Medicine.

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CAGUIN AND CARTER TABLE I. DIAGNOSES OF 93

P A T I E N T S W H O UNDERWENT B Y P A S S

SURGERY

Atrial septal defect Ventricular septal defect Pulmonic valve stenosis Tetralogy of Fallot Mitral valve lesions Aortic valve lesions Mitral and aortic valve lesions, combined Left ventricular aneurysm Total

18 3 7 7 36 19 2 1

which were apparently due to fat embolization. These changes included appre­ hension, headache, amnesia, confusion, tremor, and, sometimes, delirium and generalized convulsions. Localizing neurological signs were never present except for an occasional patient with Horner's syndrome. For purposes of review, the patients have been divided into two groups: those observed between April, 1958, and January, 1961, in whom no special fat studies were performed (Group I ) , and those seen from January, 1961, to January, 1962, in whom efforts were made to demonstrate fat embolization which included a search for fat globules in serially collected urine samples (Group I I ) . Hospital deaths will not be reported here because no deaths occurred in those patients exhibiting neurological symptoms. In no fatal case during this period could death be attributed directly to cardiopulmonary bypass or embolism, fat or otherwise. METHODS

A modified Gibbon-type vertical-screen oxygenator with nonocclusive roller pumps was used in all operations. Venous cannulation was performed in the two venae cavae in all patients with congenital lseions, with a single right atrial cannula for some patients with aortic valve lesions and, usually, with a single right ventricular cannula for patients with mitral valve lesions. Arterialized blood was returned to the patient through either the left subclavian or one of the femoral or external iliac arteries. Thoracotomy was accomplished initially with a bilateral intercostal and sternal transecting technique but subsequently TABLE

II.

CLINICAL

DATA

OF

PATIENTS

EXHIBITIN

INCISION AND OPERATION

CASE

1

43

M

Aortic stenosis, calcification

Midsternotomy with decalcification and bicuspidization of valve

2

32

F

Mitral stenosis and insufficiency, calcification

Left thoracotomy, valvulotomy and annuloplasty

3

50

M

Mitral stenosis and insufficiency, calcification

Left thoracotomy with valvulotomy, decalcificatio and annuloplasty

4

20

F

Pulmonic stenosis

Midsternotomy with valvulotomy

43

F

Mitral stenosis and insufficiency, calcification

Left thoracotomy with valvulotomy, decalcificatio: and annuloplasty

5

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this was changed to either a unilateral subcostal incision without rib resection or a vertical midline sternal splitting incision. After total cardiopulmonary bypass was achieved, the wound was continuously flooded with carbon dioxide gas and a cardiotomy incision was made appropriate to the underlying lesion. Moderate systemic hypothermia was used in most patients and the electroencephalogram was constantly monitored throughout the operation in all. A constant flow of intracardiac blood was always present unless the aorta was occluded. This came from the coronary sinus, through septal defects, from Thebesian veins or the bronchial circulation and was returned to the pumpoxygenator circuit by an intracardiac sucker. Occasionally, an excess of intra­ cardiac flow or temporary inadequacy of the intracardiac sucker would result in overflow of blood from the heart into the pericardium and, in rare instances, into the pleural space before it would be returned to the pump circuit. All patients were studied by serial hemoglobin, hematocrit, serum bilirubin, and electrolyte determinations, as well as carefully recorded fluid intake and urinary ouput observations and electrocardiograms. Almost all patients with any of the neurological changes were given serial neurological evaluation by a competent consultant. Twenty-four hour urine specimens were collected from each patient in Group I I before operation and was tested for the presence of fat globules. Following operation, 24 hour urine specimens were collected daily and special precautions were taken to prevent fat contamination from glass­ ware, feces, or other sources. The bottles were allowed to stand and the supernatant urine was acidified with 36 per cent glacial acetic acid and stained with Sudan I I I to demonstrate fat.5 A very small amount of Dow-Corning Antifoam A was used in the intracardiac suction reservoir for patients in Group I but omitted thereafter. RESULTS

Group I.—Of 48 patients undergoing operation between April, 1958, and January, 1961, in whom no special fat studies were done, 5 patients exhibited reversible central neurological damage. These patients ranged in age from 20 to 50 years, there were 3 females and 2 males, and the periods of bypass varied from 29 minutes to one hour and 34 minutes (Table I I ) . NEUROLOGICAL SYMPTOMS AFTER EXTRACORPOREAL

CIRCULATION

DURATION OF BYPASS (MIN.)

SIGNS AND SYMPTOMS CENTRAL NERVOUS SYSTEM

91

Headache, vague complaints, apprehension, amnesia, beginning third postop. day H o m e r ' s syndrome

94

Confusion for 24 hours beginning fifth postop. day

52

Delirium and bilateral plantar reflexes 24 hours, beginning fifth postop. day

29 66

Amnesia, first to fifth postop. days Tremor upper extremities beginning seventh postop. day Horner's syndrome

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TABLE I I I .

CASE

J. Thoracic and Cardiovas. Surg.

CLINICAL DATA OF P A T I E N T S EXHIBITING LIPURIA AND

AOE

SEX

6

26

M

Aortic insufficiency

Midsternotomy and valve replacement with Hufnagel leaflets

7

36

F

Mitral stenosis and insufficiency

Left thoracotomy, valvulotomy and annuloplasty

8

43

F

Mitral stenosis

Left thoracotomy and valvulotomy

9

41

M

Atrial septal defect

Midsternotomy and closure of atrial septal defect

10

28

M

Aortic stenosis

Midsternotomy and valvulotomy

11

35

M

Aortic insufficiency

Midsternotomy, bicuspidization and leaflet suspension

12

50

F

Mitral stenosis and insufficiency

Left thoracotomy, valvulotomy

13

32

M

Mitral stenosis and insufficiency

Left thoracotomy, valvulotomy and insertion of annular prosthesis

14

52

F

Mitral stenosis

15

43

M

Mitral stenosis

INCISION AND OI'KKATION

Left thoracotomy, valvulotomy Left thoracotomy, valvulotomy

Group II.—Of 45 patients undergoing operation between February, 1961, and January, 1962, 10 developed lipuria and 8 of these exhibited central nervous system symptoms. The patients ranged in age from 26 to 52 years, 6 were male and 4 female. The periods of cardiopulmonary bypass varied from 13 and Yo minutes to one hour and 52 minutes (Tables I I I ) . During this same period, urinary fat studies were performed on 15 random patients who underwent thoracotomy for closed mitral valvulotomy, esophageal or pulmonary surgery. Lipuria was found in none of these patients. Treatment of all patients in both groups was symptomatic and included light sedation. Heparin was not used. One patient was given cortisone with no apparent change in the rate of gradual improvement and all patients recovered. DISCUSSION

The first 5 patients in whom the neurological findings were encountered were very puzzling. We were impressed that the signs and symptoms in Cases 2 and 3 resembled delirium tremens, responded relatively well to sedation, and were similar to those seen in a patient with multiple fractures. This led us to suspect the possibility of fat embolization. We recognized the difficulty in diag­ nosis but the careful study of the urine for fat globules offered one practical approach. The most disturbing symptoms in our patients were related to the central

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NEUROLOGICAL SYMPTOMS A F T E R EXTRACORPOREAL CIRCULATION DURATION OP BYPASS (MIN.)

CENTRAL NERVOUS S Y S T E M S I G N S AND S Y M P T O M S

LABORATORY DATA

70

Mental confusion, hallucinations, delirium and suicidal tendencies, seventh to thirteenth postop. day

Lipuria, thirteenth postop. day Spinal fluid negative

14

H o m e r ' s syndrome

Lipuria, first to ninth postop. day

21

None

Lipuria, on third and fourth postop. days

69

Hallucinations, delirium, tetany from sixth to twenty-second postop. day; optic fundi showed " f a t " lesions

Lipuria, second to fourteenth postop. day Spinal fluid contained fat globules on seventh postop. day

16 112 47 110

"Pricking" sensations left arm and leg on Lipuria, first to eighth postop. day third postoperative day Forgetfulness, partial amnesia, third postop. day Amnesia first to fifth postop. day

Lipuria, third postop. day Lipuria, second postop. day

Confusion and disorientation, first to third postop. day

Lipuria, second and third postop. day

62

Amnesia and hallucinations fifth to twelfth postop. day

Lipuria, sixth postop. day

41

None

Lipuria, first to third postop. day

nervous system and included hallucinations, delirium tremens, amnesia, confu­ sion, and muscular disturbances. Lumbar punctures were performed on 2 pa­ tients and fat globules were reported in the spinal fluid of one. Neurological consultants observed lesions consistent with fat embolism in the fundi of 2 pa­ tients. None showed petechiae as suggested by some authors. 12 ' 13 ' 14 ' " Eespiratory difficulty was not observed unless related to heart failure which was pres­ ent before operation. The serum lipase was never elevated.15 Neither elevation in blood urea nitrogen nor significant electrolyte disturbance was noted, even in patients with lipuria. Temperature rises from 100° to 103° F . (rect.al) were commonly seen but these were in no way different from the temperature rises in patients without neurological symptoms. None of the patients developing de­ lirium gave a history of significant alcohol consumption. We could detect no relation between the severity of the symptoms and the duration or time of onset of lipuria, the type of thoracic incision, the extent of the intracardiac sur­ gery, or the duration of extracorporeal circulation. The electroencephalograms were normal throughout operation in all patients. Two of the 10 patients in (iroup II showing lipuria did not develop neurological symptoms. We noted that symptoms seemed to occur only in patients in whom blood overflowed from the cardiac chambers into either the pericardial sac or pleural space and was then returned to the pump circuit by the intracardiac (coronary) suction apparatus.

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F a t globules could be seen on the surface of blood allowed to pool in either of these cavities. Free fat was demonstrated in blood samples from these cavities when stained by Sudan III, whereas blood samples drawn from veins of the same patients failed to show free fat. Presumably these globules came from the mar­ row of the ribs or sternum or from other cut surfaces containing fat. We cannot be sure that this minute amount of fat was sufficient to cause significant fat em­ bolism but other authors also suggest this possibility.18 Several presumably causative factors have been observed in fat embolism: trauma to long bones,7 acute hemorrhagic pancreatitis, 8 hypoxia by decompres­ sion,9 and blood transfusions. 10 A fat center in the hypothalamus has also been postulated with disturbances producing changes in fat metabolism.10 It is pos­ sible that any of these factors plus operative trauma could trigger changes in lipid metabolism to mobilize fat globules from systemic fat stores or to produce agglomeration of chilomycra already present in circulating blood.6 Patients with traumatic fat embolism usually manifest respiratory difficulty and frequently succumb to acute right heart failure with pulmonary hyperten­ sion. This is presumably due to pulmonary vascular spasm, unless the embolism is so severe that cerebral and other visceral involvement occurs, which usually results in early high mortality. 7 '" In contrast, none of our patients developed respiratory difficulty or pulmonary findings not readily explained by their sur­ gical procedures. They were probably spared because the blood containing free fat was returned to the systemic circulation from the pump oxygenator, by­ passing the lungs. The amount of circulating fat and the viscera in which this lodged presumably determined the type and severity of symptoms as well as the duration of lipuria. In 56 consecutive patients undergoing bypass operation since January, 1962, only one has developed neurological symptoms and shown severe lipuria. This was predicted at operation since technical problems made it necessary to return blood that had escaped into the pericardial cavity. In all other cases, every ef­ fort was made to discard all blood spilling from the heart anH minimal lipuria was present in only 2 patients, both without symptoms. SUMMARY

A constellation of neurological symptoms including confusion, amnesia, hallucinations, and muscular disturbances has been observed in 13 of 93 patients undergoing open cardiac operations with the use of cardiopulmonary bypass. A study of these patients suggested that fat embolization which occurred during perfusion was possibly responsible for the abnormalities. These changes were apparently prevented in subsequent operations by discarding all blood that over­ flowed from the heart during perfusion. REFERENCES 1. Kunkler, A., and King, H . : Comparison of Air, Oxygen and Carbon Dioxide Embolization, Ann. Surg. 149: 95, 1959. 2. Fries, C. C , Levowitz, B., Adler, S., Cook, A. W., Karlson, K. E., and Dennis, C : Ex­ perimental Cerebral Gas Embolism, Ann. Surg. 145: 461, 1957.

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3. Baglio, C. M., and Hunter, W. C.: Calcine Arterial Embolization Accompanying Commissurotomy, J . THORACIC SUKG. 37: 490, 1959.

4. Penru, J . K., Cordell, A. R., Johnston, F . R., and Netsky, M. G.: Experimental Cerebral Embolism With Antifoam A, J . THORACIC SURG. 37: 342, 1959.

5. Kolmer, J . A., Spaulding, E . H., and Robinson, H. W . : Approved Laboratory Technic, ed. 5, New York, 1951, Appleton-Century-Crofts, Inc., p. 271. 6. Owens, G., Adams, J . E., McElhannon, F . M., and Youngblood, R. W . : Experimental Alterations of Certain Colloidal Properties of Blood During Cardiopulmonary Bypass, J . Appl. Physiol. 14: 947, 1959. 7. Peltier, L. F . : An Appraisal of the Problem of F a t Embolism, Surg. Gynec. & Obst. 104: 313, 1954. 8. Lynch, M. J . : Nephrosis and F a t Embolism in Acute Hemorrhage Pancreatitis, Arch I n t . Med. 94: 709, 1954. 9. LeQuire, V. S., Shapiro, J . L., LeQuire, C. B., Cobb, C. A., J r . , and Fleet, W. F . , J r . : A Study of the Pathogenesis of F a t Embolism Based on Human Necropsy Material and Animal Experiments, Am. J . Path. 35: 999, 1959. 10. Miller, J . A., Fonkalsrud, E. W., Latta, H. L., and Maloney, J . V., J r . : F a t Embolism Associated With Extracorporeal Circulation and Blood Transfusion, Surgery 5 1 : 448, 1962. 11. Halasz, N. A., and Morasco, J . P . : An Eperimental Study of F a t Embolism, Surgery 41: 921, 1957. 12. Sevitt, S.: The Significance and Classification of F a t Embolism, Lancet 2 : 825, 1960. 13. Sage, R. H., and Tudor, R. W . : Treatment of F a t Embolization With Heparin, Brit. M. J . 1: 1160, 1958. 14. Carty, J . B . : F a t Embolization in Childhood, Am. J . Surg. 94: 970, 1957. 15. Peltier, L. F . , Adler, F . , and Lai, S. P . : F a t Embolism: The Significance of an Elevated Serum Lipase After Trauma to Bone, Am. J . Surg. 99: 821, 1960. 16. Murray, G.: F a t Embolism and a F a t Center, Am. J . Surg. 100: 676, 1960. 17. Cooley, D. A., Beall, A. C , and Grondin ; P . : Open-Heart Operations With Disposable Oxygenator3, 5 P e r Cent Dextrose Prime and Normothermia, Surgery 52: 713, 1962. 18. Wright, E. S., Sarkozy, E., Dobell, A. R. C , and Murphy, D. R.: F a t Globulemia in Ex­ tracorporeal Circulation, Surgery 53: 500, 1963.

DISCUSSION

DR. E S T E N L I N D S E T , Minneapolis, Minn.—Dr. Gross, Dr. Bahnson, members and guests. I wish to congratulate Dr. Carter for his attempt a t solving the mechanism of the immediate post-perfusion syndrome. This is a phenomenon with which all of us are quite familiar who have spent considerable time in the intensive care unit taking care of patients who have had open-heart operations. The problem certainly deserves investigation so that a rational approach to its prevention can be made as the symptoms most likely are an expression of some inadequacies in today's perfusion techniques. What struck me about the symp­ tomatology in these cases was the great similarity to the behavior and reaction of patients on the general surgery ward who were recovering from hemorrhagie or endotoxic shock. I t is quite obvious from these remarks that in our attempts at elucidating the cause or a major participating cause to this classical post-perfusion syndrome, we used an entirely different approach, anticipating that the major portion of the perfusion period is actually a shock-like or shock-mimicking condition. A t the meeting of the Society of University Surgeons in Seattle in February, 1963, I had the opportunity to discuss some of our results in measuring renal functional parameters in the extraeorporeally perfused dog and mentioned at the same time some of our results in measuring cerebral blood flow changes in the extra­ eorporeally perfused dog and rat. We measured in essence the distribution of the cardiac output or the pump output in the extraeorporeally perfused animal. We employed a technique originally suggested by Sapirstein. We injected a radionuclide, K42 and RB86 into the arterial perfusion cannula after a perfusion time of 10 to 15 minutes. The perfusion was stopped one minute after the injection of ionic nuclide. The organs were weighed and radioassayed and the fraction of the radioactivity of the aliquots represented then the per cent flow to the various organs. Our data for the cerebral and renal blood flow values in the perfused animal showed great correlation with t h e previously obtained data in animals that had been in shock for 3 hours at 50 mm. Hg, using the Lamson Fine technique.

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Some of the animals were perfused through the left ventricle and another group was perfused in retrograde fashion a t the level of the aortic bifurcation. We also have data for a hypothermia and normothermic perfusion group. The per cent change in cerebral blood flow as compared with the nonperfuscd control showed tho same directional trend. With the use of the K42 data for the cerebral blood flow in hypothermia and normothermia perfusion, the per cent changed from the nonperfused control was 170 and 250. I t is obvious that such blood flow changes hardly can be tolerated by the brain. The only two other possible ex­ planations a r e : (1) that there is pooling of blood in the cerebral vascular system so that a higher extraction ratio of the ionic potassium chloride occurs a n d / o r (2) that there is a breakdown in the blood brain barrier during the period of perfusion. Our data with RB86 chloride indicate that these two cations are tissue kinetic dependent, varying with each organ and the temperature of the organ. These bi-nuclide data would then allow us to con­ clude that there is actually a partial breakdown of the blood brain barrier during the per­ fusion period. As to the other fact, the data suggesting an actual increase in the cerebral blood, it must be noted that this was not seen in Type 2 perfusion but only in the animals perfused through the left ventricle. I n order to prove or disprove this we used a third technique consisting of the injection of a known aliquot of 28 micron graded microspheres labeled with Scandium 46. The theoretical principle that they will distribute themselves at arterial bifurcations in the same proportion as does the blood flow has been validated from previous experiments. The advantage with this method is that they are independent upon tissue kinetics. With this method we found an actual increase in the cerebral blood flow except as mentioned in the group of animals that were perfused from the aortic bifurcations. Here we actually got a very significant decrease in the cerebral blood flow. I n order to render final proof of what is really happening to the cerebral blood flow during perfusion from below, we gave the animals 1 mg. of Dibenzyline per kilogram of body weight at the end of the perfusion and this reverted the changes in blood flow back to practically normal. Dibenzyline is a Smith, Kline, and French drug which is claimed to be sympathicolytie and antihistaminic. The intravenous form is still not approved by the FDA. From our previous experience with this experimental drug on fractional renal blood flow parameters, we believe that the action of Dibenzyline was a release of both precapillary arteriolar (sympathicolytie) spasm and postcapillary venous (antihistaminis a n d / o r antiserotonin) spasm with the subsequent release of pooled blood in the brain and establishment of adequate capillary perfusion. I believe that this experimental evidence demonstrates conclusively that the post-perfusion neuropsychiatric symptoms have other causes than fat embolism. We all remember the studies made years ago that there is an increasing incidence of lipemia and lipuria even after abdominal operations in very obese people. I believe firmly that this drug has a real place in the clinical field of extracorporeal circulation and I am sure we will hear reports of clinical trials with this drug when we meet again next year. This work was supported by a grant from the Tobacco Industry Research Committee.