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Fatal postpartum shock due to massive angioneurotic edema
Fatal postpartum shock due to massive angioneurotic edema The syndrome of transcapillary plasmapheresis
IAN W. LUKE, M.D. EDWARD
RUBE~STEI~,
M.D.
San Mateo, California
T H I s report describes an instance of fatal shock due to extraordinary plasmapheresis through the walls of abnormally porous capillaries. The syndrome presented as postpartum angioneurotic edema of the vulva with rapid centrifugal spread of the edema to involve almost the entire body. The transcapillary plasma leakage continued at such an overwhelming rate that the blood volume could not be maintained despite the administration of 14,200 c.c. of plasma and 237.5 Gm. of serum albumin during a pet·iod of 42 hours. This case is strikingly similar to that reported recently by Clarkson. 1
at age 12. She had always menstruated normally for 3 to 4 days, the cycles being regular at intervals of 28 to 30 days. She completed her second pregnancy at full term without difficulty. After a rather slow labor of 18 hours, on Aug. 8, 1960, she was delivered from a normal presentation of a normal tnalc infant, \Vt.~ighing 7 pounds, 15 ounces. A. left midline episiotomy was done and low forceps were uwd. Meperidine and scopolamine were given for analgesia and nitrous oxide and cyclopropane for anesthesia. Her postpartum course was uneventful until the third day, when it was noted that there was giant angioneurotic edema of the left labia. On the following day the edema spread to the entire vulva, perineum, buttocks, and thighs. Although she was afebrile, as she was to remain thereafter, and although inspection and probing of the wound failed to disclose any evidence of infection, it was deemed prudent to give antibiotics, :md accordingly 400,000 F. of penicillin and 1.0 Gm. of streptomycin were administered intramuscularly every 6 hours. Cultures of the wound taken prior to administration of the antibiotics failed to grow pathogens. On the fifth postpartum day it "V\·as obvious that the angioneurotic edema was becoming even more marked in the involved structures and spreading in a centrifugal fashion from the vuiva. ACTH was then given, in an initial dose of 80 units, and 40 units was given 8 and 16 hours later. She also received 50 mg. of diphenhydramine hydrochloride every 4 hours by mouth. In the succeeding interval she began to complain of marked weakness, irritability, and restlessness. She became increasingly nauseated and
Case report The patient was a 28-year-old white woman of Scotch descent who had enjoyed good health until her final illness. Of significance in her past history was the occurrence of childhood urticaria and several episodes of facial angioneurotic edema in adulthood. The latter were thought to have been due to sensitivity to hexachlorophene soap and to eye make-up. Some years prior to her death she had an abscess of Bartholin's gland on the left, which was treated by incision and drainage. One and one-half years later she underwent uterine dilatation and curettage for an incomplete spontaneous abortion of a 2 months' pregnancy. The onset of her menses was From the Department of Obstetrics and Gynecology, Mills Memorial Hospital. San Mateo, and the Department of Medicine, Stanford University School of Medicine, Palo Alto.
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retched incessantly. Hiccups ensued and were very troublesome. About 12 hours later, on the sixth postpartum day, she was found to be in shock with a blood pressure level of 90 j60 mm. Hg, the previous level having been about 110j70. Despite the administration of 1,000 c.c. of glucose in half-normal saline and 1,000 c.c. of glucose in water during the previous 12 hours, the hematocrit had risen from 37 per cent on the first postpartum day to 64 per cent, and the white blood count increased from 9,300 per cubic millimeter to 56,600, with 83 per cent polymorphonuclear cells, of which 7 per cent were nonsegmented forms, 1 per cent eosinophils, and 16 per cent lymphocytes. An electrocardiogram showed sinus tachycardia and nonspecific ST-T changes. Because of the intractable retching and hiccups and the marked leukocytosis, the possibility of an intraperitoneal perforation was seriously considered. At that point it did not seem likely that the edematous tissues were sequestering enough fluid to account for the shock. She was then given 3,000 c.c. of 5 per cent glucose, the first liter in half-normal saline, and the other 2 in water. After the first 1,500 c.c. had been given rapidly it was evident that the shock was not responding to the fluid alone. Intravenous phenylephrine hydrochloride, 1 per cent, 1 c.c., and 12 c.c. of norepinephrine were successively given without effect on the blood pressure. As the last 1,500 c.c. of the intravenous infusion was given the shock deepened, the blood pressure became unobtainable, and, after several hours in a nearly terminal state, the patient had a generalized convulsion and lapsed into deep coma. She had been anuric for the previous 4 hours. At that time the hematocrit was found to be 68 per cent, and it was obvious that extreme hemoconcentration had occurred as a result of enormous losses of plasma into the extracellular space of the increasingly edematous tissues. Plasma was then given at a rate of approximately 40 to 50 c.c. per minute; at the end of 2 hours the hematocrit had fallen to 44 per cent, urine flow resumed, the patient regained consciousness, and the blood pressure rose to levels of about 90 j60. Thereafter she received I 00 mg. of hydrocortisone intravenously every 6 hours. During the next 24 hours efforts to maintain the blood volume were made by the administration of some 10 L. of plasma; however, the blood pressure often fell to 70j50, and at times was unobtainable. The hematocrit ranged from
Fatal shock due to angioneurotic edema
323
40 to 50 per cent. After 30 hours of oliguria with urine volumes of approximately 25 to 40 c.c. per hour, anuria developed. At this time it was found that despite the large amounts of plasma which had been given the total serum protein concentration had fallen to 5.0 Grn. per cent, with 2.3 Gm. per cent albumin and 2.7 Gm. per cent globulin. Apparently the capillaries were leaking plasma protein to such an extent that the oncotic pressure of the plasma could not be maintained resulting in further escape of fluid from the capillary bed. This fact, along with the growing concern over the large volume of fluid which she had received in the face of the anuria, led to the decision to slow the rate of administration of plasma and to use large quantities of sodiumpoor albumin. Despite these measures, although the serum protein level rose within 6 hours to 6.1 Gm. per cent, with 3. 7 Gm. per cent albumin and 2.4 Gm. per cent globulin, the extraordinary edema advanced to involve almost her entire body with marked edema of the neck and face. Only the distal extremities and scalp were spared. Ascites developed and a small right pleural effusion was noted. During the next several hours edema of the chest wall made evaluation of the size of the effusion difficult. Digitalization was accomplished with 1.6 mg. of lanatoside C. Southey tubes were inserted into several edematous areas of the thighs, but they quickly became plugged and did not drain. Pressure bandages were wrapped around the thighs, but they had no discernible effect on the edema. An abdominal paracentesis was done in preparation for peritoneal dialysis; however, the blood pressure thereafter never rose to sufficiently high levels to permit successful dialysis. Approximately 500 c.c. of ascitic fluid was removed. Thoracentesis was considered but was abandoned because it was thought that the patient's extreme restlessness made it imposible to advance the needle safely through the markedly edematous chest wall. At that time, approximately 10 hours before her death, the effusion was not believed to be large enough to be playing a significant role in the shock or to be causing ventilatory insufficiency. In the ensuing hours she remained in shock, was exceedingly restless, often delirious, and slightly cyanotic. After a total of some 14,000 c.c. of plasma and 237.5 Gm. of albumin had been given, the shock persisted, the respiratory distress became more marked, the cyanosis deep-
324 luke and Rubenstein
ened, and the patient, exhausted and stuporous, died. Postmortem examination. The autopsy was performed 14 hours after the patient's death. There was marked pitting edema of the periorbital tissues, neck, entire trunk, thighs, buttocks, and perineum. The upper extremities were only slightly edematous and the lower legs were free of edema. Both pleural cavities were completely filled with clear straw-colored fluid, and the pericardia! sac contained 200 c.c. of similar fluid. There was an abdominal collection of approximately 2 L. of ascitic fluid. The pleural and pericardia! surfaces were smooth and glistening. The neck structures were normal except for edema and injection of the laryngeal mucosa. The airway was patent. The thyroid was normal. The heart weighed 300 grams and was entirely normal. The pelvic veins and inferior vena cava were free of thrombi. The right and left lungs weighed 310 and 290 grams, respectively. They were almost airless as a result of compression atelectasis. The extrahepatic bile ducts, the hepatic artery, the portal vein, and the gall bladder were unremarkable. The spleen weighed 170 grams. The capsule was thin and the substance n1arkedly congested and mushy in consistency. The Malpighian corpuscles were ill defined. The pancreas was normal except for marked edema of the peripancreatic and retroperitoneal fatty tissue. This was particularly pronounced and extended down into the pelvis. The esophagus showed only minimal superficial erosion of the mucosa in the distal portion. The stomach contained about 150 c.c. of watery, slightly bile-stained fluid. The gastric mucosa was normal, as were the small and large intestines. The mucosa was intact in all segments. The adrenal glands were of normal size and shape. The cortices averaged about 1.5 mm. in depth and showed very slight diminution in lipoid content. The medullary parenchyma was congested. The right and left kidneys weighed 170 and 200 grams, respectively. The capsules stripped readily, revealing smooth, pale, pinkish tan cut surfaces in which a fetal lobular pattern was apparent. The cortices averaged 9 to 10 mm. in depth and the cut surface was flat and exceedingly pale. Corticomedullary demarcation was accentuated by this differential in depth of coloration. The renal parenchyma was otherwise
.February 1, 1962 Am.
J.
Obst. & (;ynrc.
unremarkable. The pelves, renal vessels, and ureters were normal. The bladder was contracted and contained only a few drops of thick, turbid, yellowish tan fluid. Marked congestion with focal hemorrhage and fine granularity was apparent over the trigone. The uterus was enlarged to a degree consistent with involutional change, measuring 17 em. in length and i i em. at its greatest width. The myometrium was normal except for a soft consistency. The uterine cavity was relatively smooth except in the posterosuperior region, where in what was probably the placental site there was some shagginess as a result of adherent blood clot and decidual tissue. The cervix was large and exhibited moderate edema and extensive hemorrhagic discoloration. The ovaries were of normal size and a relatively small corpus luteum was found within the left gonad. The lumbar vertebral bone marrow was of grossly normal appearance. Cultures taken from heart blood and from the edematous subcutaneous tissues of the pt·rineum revealed no growth. On microscopiC- examination a few scattered petechial hemorrhages were noted in the myocardium and in the subepicardial fat. There was central passive congestion in the liver. In the central lobular areas a few of the cells exhibited early fat vacuolization. A striking feature was the presence of many leukocytes within the sinusoids. There was no necrosis and the portal areas were normal. The spleen showed prominent lymphoid depletion. There was marked inter· stitial edema of the pancreas. The distal portion of the esophagus exhibited patchy superficial erosion with associated acute inflammatory cellular infiltration. Sections of the stomach and small and large bowel were normal except for serosal edema and prominent serosal mesothelial cells. The thyroid was normal. The adrenal cortices were normal except for distinct depletion of lipoid content and scattered small petechial hemorrhages. The kidneys revealed prominent hydropic change of the proximal convoluted tubular epithelium. Hemoglobin casts were present in the lumina of some of the collecting tubules. There were also a number of cellular casts incorporating degenerating and desquamating cellular debris. Large collections of proteinaceous material were present within Bowman's spaces and the lumina of the proximal tubules. There also was histologic evidence of interstitial edema, and a number of large peri-
Volume 83 Number 3
pelvic hemorrhages were present. The ovaries were normal histologically; a regressing corpus luteum was present. Multiple sections of the uterus showed very early involutional change and obvious hypertrophy of the muscle fibers '.vas still apparent.
Sections of the skeletal muscle obtained from various sites showed the presence of edema manifested by wide separation of muscle fibers. The bone marrow exhibited a considerable increase in cellularity as a result of granulocytic hyperplasia; eosinophils were not conspicuous. Multiple sections of the episiotomy wound revealed extensive edema and acute inflammatory change consistent with what might ordinarily be expected. A number of gut sutures were seen within the depths of the wound. There was no histologic evidence of an associated hypersensitivity reaction. The subcutaneous fat was massively edematous and a number of interstitial hemorrhages, some associated with leukocytic infiltration, were present. The latter occurred without intrinsic vascular abnormalities and appeared to be simply mechanical stretch phenomena.
No abnormalities of the capillaries in any of the tissues could be recognized under the light microscope. The final anatomic diagnoses were: ( 1) idiopathic angioedema-like syndrome with hypovolemic shock; (2) hemoglobinuric nephrosis; ( 3) terminal anasarca with massive bilateral hydrothorax with extensive compression atelectasis, hydroperitoneum, hydropericardium; ( 4) granulocytic hyperplasia of the bone marrow with marked leukocytosis. Comment
The clinical disorder was postpartum hypovolemic shock associated with a marked elevation of the hematocrit. The process began as angioneurotic edema of the tissues around the episiotomy wound and then spread in a centrifugal" fashion; death was due to prolonged shock and to compression atelectasis of the lungs caused by a rapid collection of pleural fluid. Had death not occurred as a result of the ventilatory insufficiency, the ensuing problems would have been, in all likelihood, overwhelming. The spread of the edema, the persistence of the
shock, and the tendency of the hematocrit to rise despite the administration of large
Fatal shock due to angioneurotic edema
325
quantities of plasma and albumin indicated that the underlying disorder was becoming The shock was undoubtedly due to hypovolemia, and the high hematocrit indicated that the· reduced blood volume was due to loss of plasma into the massively edematous tissues. The syndrome, which could
be termed "transcapillary plasmapheresis," might be explained in terms of any of the following mechanisms: ( 1) increased intracapillary hydrostatic pressure, due either to venous hypertension with "back pressure" or to altered tone of the vascular sphincters controlling the microcirculation 2 ; (2) sudden obstruction of the major lymph channels; ( 3) abnormal serum proteins, especially an abnormally small or otherwise defective albumin molecule; ( 4) increased capillary porosity, due either to primary damage to the capillary endothelium (hypersensitivity reaction?), or to defective activity on the part of unidentified agents (steroid hormones?) which normally influence capillary permeability, or to the concomitance of both of these factors. Although the urgencies of the very acute illness did not allow for detailed and reflective laboratory study, analysis of the clinical and autopsy data leads to a surprisingly firm conclusion about the nature of the underlying disorder, namely, that it was the result of increased capillary permeability. The first hypothesis, that of intracapillary hypertension, is not tenable. There was no evidence of venous stasis or increased venous pressure in the tissues surrounding the initial lesion and the autopsy failed to disclose evidence of peripheral or central venous obstruction. If there were increased intracapillary pressure and flow as a result of altered precapillary arteriolar tone, then change in the color of the involved skin should have been apparent3 ; this was not the case. Furthermore, the histologic sections did not show distended capillary lumina. The second hypothesis, that of obstruction of one or several of the major lymph channels, likewise can be readily refuted. The
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Ft'bJilaJ y 1, l9fi:.!
Luke and Rubenstein
assumption that the disorder resulted only from lymphatic obstruction, even with virtua!!y complete sequestration of the continuously formed lymph in the extracellular space, is inconsistent with the lack of response to the administration of the large volume of plasma and albumin. For, under ordinary conditions, only 50 to 100 per cent of the serum albumin diffuses into the extracellular space each day/ an amount exceeded several fold by the quantity of protein administered to this patient as plasma and albumin in a period of 42 hours. Therefore, simple lymphatic obstruction is an inadequate explanation. The third hypothesis, which proposes that the extravascular escape of the plasma was due to abnormal serum proteins is untenable, since, as already pointed out, the patient received a fivefold replacement with exogenous plasma protein, which should have reversed the falling blood volume had it been due to defective endogenous proteins. The last hypothesis, that of abnormal capillary porosity starting as localized angioneurotic edema and becoming generalized, best explains the extraordinary syndrome. It is consistent \-Vith a localized onset, 1.vith the failure to respond to plasma and serum albumin, and with the absence of necropsy evidence of venous or lymphatic disease. Furthermore, it is in accord with the concept that angioneurotic edema represents localized increased capillary permeability. 1 The nature of the underlying capillary disorder is a matter for conjecture. The fact that there was a past history of urticaria and facial angioneurotic edema, presumably due to allergy to cosmetics, and possibly to hexachlorophene soap, suggests a hypersensitivity basis for the generalized capillary disorder. The development of edema at the site of the episiotomy wound tends to implicate several agents, including hexachlorophene soap used in the preparation of the perineum for delivery, the chromic sutures placed in the episiotomy wound, and the trauma due to the delivery itself. ~Jo local
anesthetic substance was employed. The alternative postulate that the in-
\m .
.J. Ob:--t.
&
(;~·,we.
creased t"apillary permeability was due to faulty (steroid?) hormone activity is supported by the fact that the onset was in the immediate postpartum period, and that the two similar cases in the literature showed a pronounced association between the edema and the menstrual cycle. That estrogenic and nroP"PSt::Jtional romnounrls haVf~ dfects on -----1-------------capillary permeability has repeatedly been demonstrated, 5 • 6 and the possible influence of capillary permeability in premenstrual edema has often been considered, although its precise role remains unclear. 7 Furthermore, a high incidence of angioneurotic edema during the menopause has been reported.8 It has been shown m some persons with hypoproteinemia and altered capillary permeability that there may be a number of coexisting pathologic processes, including disordered protein anabolism and catabolism. n There was, of course, insufficient tiine to study this patient from the point of view of protein metabolism or gonadal or adrenal steroid function. 1~--o-------------
Suggested therapy
..!\!though this syndrome must be rare, it seems worthwhile to call attention to its occurrence and to emphasize the principles of therapy which may prove lifesaving. In such an instance of hypovolemic shock with an elevated hematocrit due to massive transcapillary plasmapheresis, the clinician should probably disregard his conventional concepts about the amqunt of fluid required to maintain blood volume. Plasma should be given at any rate and in any amount required to maintain blood pressure. The risk of overwhelming the heart by excessive venous return seems far less than that of anuria, which is an especially distastrous complication in ·vie\-',r of the large volume of fluid that may be given to the patient. Hematocrit determinations should be done at very frequent intervals and, if the serum albumin level falls, then large quantities of sodium-poor albumin should be given. The experience gained from this case would indicate that the soft-tissue accumulations of
Volume 83 Number 3
edema should be disregarded, since they are not life threatening and appear not to respond to the use of pressure bandages or Southey tubes, both of which are probably worth trying. Although medication with antihistamines and adrenal steroid hormones failed to have a favorable effect in this patient, their use in very large doses is probably indicated. Of paramount importance in the management of such a case is the continuous removal of life-endangering fluid collections in the pleural, pericardia!, and possibly in the peritoneal cavities. Inasmuch as the pleural fluid appeared to accumulate quite rapidly in this patient, it would seem essential to maintain a constant vigil for such a development. In summary, the two cardinal principles of management appear to be these: ( 1) to administer any volume of plasma required
Fatal shock due to angioneurotic edema
327
to keep the patient out of shock, and (2) to remove continuously significant collections of fluid in the pleural and, possibly, in the pericardia! and abdominal cavities. Summary
An instance of fatal postpartum hypovolemic shock is described, in which the mechanism was that of generalized increased capillary permeability with massive transcapillary plasmapheresis. Suggested principles of management of such a case are given. We wish to acknowledge the advice and assistance given by Drs. Maurice R. Luke, Otto E. L. Schmidt, George D. Guido, Ralph Levin, Peter Packard, and Charles R. Campbell, and to express our gratitude to the members of the staff of the Hospital blood banking laboratory for their generous he! p.
REFERENCES
1. Clarkson, B., Thompson, D., Horwith, M.,
and Luckey, E. H.: Am. J. Med. 29: 193, 1960. 2. Fulton, G. P., Lutz, B. R., and Callahan, A. B.: Physiol. Rev. 40: 57, 1960. 3. Ponder, E.: Fulton's Textbook of Physiology, ed. 17, Phildalephia, 1955, W. B. Saunders Company, p. 572. 4. Taylor, G. B., Kinmonth, J. B., Rollinson, E., Rotblat, J., and Francis, G. E.: Brit. M. J. 1: 133, !957.
5. Camurri, M.: Monit. ostet. ginec. 3: 186, 1955. 6. Brewer, J. I.: AM. J. 0BST. & GYNEC. 36: 597, 1938. 7. Thorn, G. W.: Am. J. Med. 23: 507, 1957. 8. Donald, H. R.: Brit. M. J. 2: 899, 1937. 9. Gross, P. A. M., Embree, L. J., Bally, P., Shipp, J. C., and Thorn, G. W.: Am. J. Med. 29: 386, 1960.
IAN W. LUKE, M.D. EDWARD
RUBE~STEI~,
M.D.
San Mateo, California
T H I s report describes an instance of fatal shock due to extraordinary plasmapheresis through the walls of abnormally porous capillaries. The syndrome presented as postpartum angioneurotic edema of the vulva with rapid centrifugal spread of the edema to involve almost the entire body. The transcapillary plasma leakage continued at such an overwhelming rate that the blood volume could not be maintained despite the administration of 14,200 c.c. of plasma and 237.5 Gm. of serum albumin during a pet·iod of 42 hours. This case is strikingly similar to that reported recently by Clarkson. 1
at age 12. She had always menstruated normally for 3 to 4 days, the cycles being regular at intervals of 28 to 30 days. She completed her second pregnancy at full term without difficulty. After a rather slow labor of 18 hours, on Aug. 8, 1960, she was delivered from a normal presentation of a normal tnalc infant, \Vt.~ighing 7 pounds, 15 ounces. A. left midline episiotomy was done and low forceps were uwd. Meperidine and scopolamine were given for analgesia and nitrous oxide and cyclopropane for anesthesia. Her postpartum course was uneventful until the third day, when it was noted that there was giant angioneurotic edema of the left labia. On the following day the edema spread to the entire vulva, perineum, buttocks, and thighs. Although she was afebrile, as she was to remain thereafter, and although inspection and probing of the wound failed to disclose any evidence of infection, it was deemed prudent to give antibiotics, :md accordingly 400,000 F. of penicillin and 1.0 Gm. of streptomycin were administered intramuscularly every 6 hours. Cultures of the wound taken prior to administration of the antibiotics failed to grow pathogens. On the fifth postpartum day it "V\·as obvious that the angioneurotic edema was becoming even more marked in the involved structures and spreading in a centrifugal fashion from the vuiva. ACTH was then given, in an initial dose of 80 units, and 40 units was given 8 and 16 hours later. She also received 50 mg. of diphenhydramine hydrochloride every 4 hours by mouth. In the succeeding interval she began to complain of marked weakness, irritability, and restlessness. She became increasingly nauseated and
Case report The patient was a 28-year-old white woman of Scotch descent who had enjoyed good health until her final illness. Of significance in her past history was the occurrence of childhood urticaria and several episodes of facial angioneurotic edema in adulthood. The latter were thought to have been due to sensitivity to hexachlorophene soap and to eye make-up. Some years prior to her death she had an abscess of Bartholin's gland on the left, which was treated by incision and drainage. One and one-half years later she underwent uterine dilatation and curettage for an incomplete spontaneous abortion of a 2 months' pregnancy. The onset of her menses was From the Department of Obstetrics and Gynecology, Mills Memorial Hospital. San Mateo, and the Department of Medicine, Stanford University School of Medicine, Palo Alto.
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Volume83 Number 3
retched incessantly. Hiccups ensued and were very troublesome. About 12 hours later, on the sixth postpartum day, she was found to be in shock with a blood pressure level of 90 j60 mm. Hg, the previous level having been about 110j70. Despite the administration of 1,000 c.c. of glucose in half-normal saline and 1,000 c.c. of glucose in water during the previous 12 hours, the hematocrit had risen from 37 per cent on the first postpartum day to 64 per cent, and the white blood count increased from 9,300 per cubic millimeter to 56,600, with 83 per cent polymorphonuclear cells, of which 7 per cent were nonsegmented forms, 1 per cent eosinophils, and 16 per cent lymphocytes. An electrocardiogram showed sinus tachycardia and nonspecific ST-T changes. Because of the intractable retching and hiccups and the marked leukocytosis, the possibility of an intraperitoneal perforation was seriously considered. At that point it did not seem likely that the edematous tissues were sequestering enough fluid to account for the shock. She was then given 3,000 c.c. of 5 per cent glucose, the first liter in half-normal saline, and the other 2 in water. After the first 1,500 c.c. had been given rapidly it was evident that the shock was not responding to the fluid alone. Intravenous phenylephrine hydrochloride, 1 per cent, 1 c.c., and 12 c.c. of norepinephrine were successively given without effect on the blood pressure. As the last 1,500 c.c. of the intravenous infusion was given the shock deepened, the blood pressure became unobtainable, and, after several hours in a nearly terminal state, the patient had a generalized convulsion and lapsed into deep coma. She had been anuric for the previous 4 hours. At that time the hematocrit was found to be 68 per cent, and it was obvious that extreme hemoconcentration had occurred as a result of enormous losses of plasma into the extracellular space of the increasingly edematous tissues. Plasma was then given at a rate of approximately 40 to 50 c.c. per minute; at the end of 2 hours the hematocrit had fallen to 44 per cent, urine flow resumed, the patient regained consciousness, and the blood pressure rose to levels of about 90 j60. Thereafter she received I 00 mg. of hydrocortisone intravenously every 6 hours. During the next 24 hours efforts to maintain the blood volume were made by the administration of some 10 L. of plasma; however, the blood pressure often fell to 70j50, and at times was unobtainable. The hematocrit ranged from
Fatal shock due to angioneurotic edema
323
40 to 50 per cent. After 30 hours of oliguria with urine volumes of approximately 25 to 40 c.c. per hour, anuria developed. At this time it was found that despite the large amounts of plasma which had been given the total serum protein concentration had fallen to 5.0 Grn. per cent, with 2.3 Gm. per cent albumin and 2.7 Gm. per cent globulin. Apparently the capillaries were leaking plasma protein to such an extent that the oncotic pressure of the plasma could not be maintained resulting in further escape of fluid from the capillary bed. This fact, along with the growing concern over the large volume of fluid which she had received in the face of the anuria, led to the decision to slow the rate of administration of plasma and to use large quantities of sodiumpoor albumin. Despite these measures, although the serum protein level rose within 6 hours to 6.1 Gm. per cent, with 3. 7 Gm. per cent albumin and 2.4 Gm. per cent globulin, the extraordinary edema advanced to involve almost her entire body with marked edema of the neck and face. Only the distal extremities and scalp were spared. Ascites developed and a small right pleural effusion was noted. During the next several hours edema of the chest wall made evaluation of the size of the effusion difficult. Digitalization was accomplished with 1.6 mg. of lanatoside C. Southey tubes were inserted into several edematous areas of the thighs, but they quickly became plugged and did not drain. Pressure bandages were wrapped around the thighs, but they had no discernible effect on the edema. An abdominal paracentesis was done in preparation for peritoneal dialysis; however, the blood pressure thereafter never rose to sufficiently high levels to permit successful dialysis. Approximately 500 c.c. of ascitic fluid was removed. Thoracentesis was considered but was abandoned because it was thought that the patient's extreme restlessness made it imposible to advance the needle safely through the markedly edematous chest wall. At that time, approximately 10 hours before her death, the effusion was not believed to be large enough to be playing a significant role in the shock or to be causing ventilatory insufficiency. In the ensuing hours she remained in shock, was exceedingly restless, often delirious, and slightly cyanotic. After a total of some 14,000 c.c. of plasma and 237.5 Gm. of albumin had been given, the shock persisted, the respiratory distress became more marked, the cyanosis deep-
324 luke and Rubenstein
ened, and the patient, exhausted and stuporous, died. Postmortem examination. The autopsy was performed 14 hours after the patient's death. There was marked pitting edema of the periorbital tissues, neck, entire trunk, thighs, buttocks, and perineum. The upper extremities were only slightly edematous and the lower legs were free of edema. Both pleural cavities were completely filled with clear straw-colored fluid, and the pericardia! sac contained 200 c.c. of similar fluid. There was an abdominal collection of approximately 2 L. of ascitic fluid. The pleural and pericardia! surfaces were smooth and glistening. The neck structures were normal except for edema and injection of the laryngeal mucosa. The airway was patent. The thyroid was normal. The heart weighed 300 grams and was entirely normal. The pelvic veins and inferior vena cava were free of thrombi. The right and left lungs weighed 310 and 290 grams, respectively. They were almost airless as a result of compression atelectasis. The extrahepatic bile ducts, the hepatic artery, the portal vein, and the gall bladder were unremarkable. The spleen weighed 170 grams. The capsule was thin and the substance n1arkedly congested and mushy in consistency. The Malpighian corpuscles were ill defined. The pancreas was normal except for marked edema of the peripancreatic and retroperitoneal fatty tissue. This was particularly pronounced and extended down into the pelvis. The esophagus showed only minimal superficial erosion of the mucosa in the distal portion. The stomach contained about 150 c.c. of watery, slightly bile-stained fluid. The gastric mucosa was normal, as were the small and large intestines. The mucosa was intact in all segments. The adrenal glands were of normal size and shape. The cortices averaged about 1.5 mm. in depth and showed very slight diminution in lipoid content. The medullary parenchyma was congested. The right and left kidneys weighed 170 and 200 grams, respectively. The capsules stripped readily, revealing smooth, pale, pinkish tan cut surfaces in which a fetal lobular pattern was apparent. The cortices averaged 9 to 10 mm. in depth and the cut surface was flat and exceedingly pale. Corticomedullary demarcation was accentuated by this differential in depth of coloration. The renal parenchyma was otherwise
.February 1, 1962 Am.
J.
Obst. & (;ynrc.
unremarkable. The pelves, renal vessels, and ureters were normal. The bladder was contracted and contained only a few drops of thick, turbid, yellowish tan fluid. Marked congestion with focal hemorrhage and fine granularity was apparent over the trigone. The uterus was enlarged to a degree consistent with involutional change, measuring 17 em. in length and i i em. at its greatest width. The myometrium was normal except for a soft consistency. The uterine cavity was relatively smooth except in the posterosuperior region, where in what was probably the placental site there was some shagginess as a result of adherent blood clot and decidual tissue. The cervix was large and exhibited moderate edema and extensive hemorrhagic discoloration. The ovaries were of normal size and a relatively small corpus luteum was found within the left gonad. The lumbar vertebral bone marrow was of grossly normal appearance. Cultures taken from heart blood and from the edematous subcutaneous tissues of the pt·rineum revealed no growth. On microscopiC- examination a few scattered petechial hemorrhages were noted in the myocardium and in the subepicardial fat. There was central passive congestion in the liver. In the central lobular areas a few of the cells exhibited early fat vacuolization. A striking feature was the presence of many leukocytes within the sinusoids. There was no necrosis and the portal areas were normal. The spleen showed prominent lymphoid depletion. There was marked inter· stitial edema of the pancreas. The distal portion of the esophagus exhibited patchy superficial erosion with associated acute inflammatory cellular infiltration. Sections of the stomach and small and large bowel were normal except for serosal edema and prominent serosal mesothelial cells. The thyroid was normal. The adrenal cortices were normal except for distinct depletion of lipoid content and scattered small petechial hemorrhages. The kidneys revealed prominent hydropic change of the proximal convoluted tubular epithelium. Hemoglobin casts were present in the lumina of some of the collecting tubules. There were also a number of cellular casts incorporating degenerating and desquamating cellular debris. Large collections of proteinaceous material were present within Bowman's spaces and the lumina of the proximal tubules. There also was histologic evidence of interstitial edema, and a number of large peri-
Volume 83 Number 3
pelvic hemorrhages were present. The ovaries were normal histologically; a regressing corpus luteum was present. Multiple sections of the uterus showed very early involutional change and obvious hypertrophy of the muscle fibers '.vas still apparent.
Sections of the skeletal muscle obtained from various sites showed the presence of edema manifested by wide separation of muscle fibers. The bone marrow exhibited a considerable increase in cellularity as a result of granulocytic hyperplasia; eosinophils were not conspicuous. Multiple sections of the episiotomy wound revealed extensive edema and acute inflammatory change consistent with what might ordinarily be expected. A number of gut sutures were seen within the depths of the wound. There was no histologic evidence of an associated hypersensitivity reaction. The subcutaneous fat was massively edematous and a number of interstitial hemorrhages, some associated with leukocytic infiltration, were present. The latter occurred without intrinsic vascular abnormalities and appeared to be simply mechanical stretch phenomena.
No abnormalities of the capillaries in any of the tissues could be recognized under the light microscope. The final anatomic diagnoses were: ( 1) idiopathic angioedema-like syndrome with hypovolemic shock; (2) hemoglobinuric nephrosis; ( 3) terminal anasarca with massive bilateral hydrothorax with extensive compression atelectasis, hydroperitoneum, hydropericardium; ( 4) granulocytic hyperplasia of the bone marrow with marked leukocytosis. Comment
The clinical disorder was postpartum hypovolemic shock associated with a marked elevation of the hematocrit. The process began as angioneurotic edema of the tissues around the episiotomy wound and then spread in a centrifugal" fashion; death was due to prolonged shock and to compression atelectasis of the lungs caused by a rapid collection of pleural fluid. Had death not occurred as a result of the ventilatory insufficiency, the ensuing problems would have been, in all likelihood, overwhelming. The spread of the edema, the persistence of the
shock, and the tendency of the hematocrit to rise despite the administration of large
Fatal shock due to angioneurotic edema
325
quantities of plasma and albumin indicated that the underlying disorder was becoming The shock was undoubtedly due to hypovolemia, and the high hematocrit indicated that the· reduced blood volume was due to loss of plasma into the massively edematous tissues. The syndrome, which could
be termed "transcapillary plasmapheresis," might be explained in terms of any of the following mechanisms: ( 1) increased intracapillary hydrostatic pressure, due either to venous hypertension with "back pressure" or to altered tone of the vascular sphincters controlling the microcirculation 2 ; (2) sudden obstruction of the major lymph channels; ( 3) abnormal serum proteins, especially an abnormally small or otherwise defective albumin molecule; ( 4) increased capillary porosity, due either to primary damage to the capillary endothelium (hypersensitivity reaction?), or to defective activity on the part of unidentified agents (steroid hormones?) which normally influence capillary permeability, or to the concomitance of both of these factors. Although the urgencies of the very acute illness did not allow for detailed and reflective laboratory study, analysis of the clinical and autopsy data leads to a surprisingly firm conclusion about the nature of the underlying disorder, namely, that it was the result of increased capillary permeability. The first hypothesis, that of intracapillary hypertension, is not tenable. There was no evidence of venous stasis or increased venous pressure in the tissues surrounding the initial lesion and the autopsy failed to disclose evidence of peripheral or central venous obstruction. If there were increased intracapillary pressure and flow as a result of altered precapillary arteriolar tone, then change in the color of the involved skin should have been apparent3 ; this was not the case. Furthermore, the histologic sections did not show distended capillary lumina. The second hypothesis, that of obstruction of one or several of the major lymph channels, likewise can be readily refuted. The
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Ft'bJilaJ y 1, l9fi:.!
Luke and Rubenstein
assumption that the disorder resulted only from lymphatic obstruction, even with virtua!!y complete sequestration of the continuously formed lymph in the extracellular space, is inconsistent with the lack of response to the administration of the large volume of plasma and albumin. For, under ordinary conditions, only 50 to 100 per cent of the serum albumin diffuses into the extracellular space each day/ an amount exceeded several fold by the quantity of protein administered to this patient as plasma and albumin in a period of 42 hours. Therefore, simple lymphatic obstruction is an inadequate explanation. The third hypothesis, which proposes that the extravascular escape of the plasma was due to abnormal serum proteins is untenable, since, as already pointed out, the patient received a fivefold replacement with exogenous plasma protein, which should have reversed the falling blood volume had it been due to defective endogenous proteins. The last hypothesis, that of abnormal capillary porosity starting as localized angioneurotic edema and becoming generalized, best explains the extraordinary syndrome. It is consistent \-Vith a localized onset, 1.vith the failure to respond to plasma and serum albumin, and with the absence of necropsy evidence of venous or lymphatic disease. Furthermore, it is in accord with the concept that angioneurotic edema represents localized increased capillary permeability. 1 The nature of the underlying capillary disorder is a matter for conjecture. The fact that there was a past history of urticaria and facial angioneurotic edema, presumably due to allergy to cosmetics, and possibly to hexachlorophene soap, suggests a hypersensitivity basis for the generalized capillary disorder. The development of edema at the site of the episiotomy wound tends to implicate several agents, including hexachlorophene soap used in the preparation of the perineum for delivery, the chromic sutures placed in the episiotomy wound, and the trauma due to the delivery itself. ~Jo local
anesthetic substance was employed. The alternative postulate that the in-
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creased t"apillary permeability was due to faulty (steroid?) hormone activity is supported by the fact that the onset was in the immediate postpartum period, and that the two similar cases in the literature showed a pronounced association between the edema and the menstrual cycle. That estrogenic and nroP"PSt::Jtional romnounrls haVf~ dfects on -----1-------------capillary permeability has repeatedly been demonstrated, 5 • 6 and the possible influence of capillary permeability in premenstrual edema has often been considered, although its precise role remains unclear. 7 Furthermore, a high incidence of angioneurotic edema during the menopause has been reported.8 It has been shown m some persons with hypoproteinemia and altered capillary permeability that there may be a number of coexisting pathologic processes, including disordered protein anabolism and catabolism. n There was, of course, insufficient tiine to study this patient from the point of view of protein metabolism or gonadal or adrenal steroid function. 1~--o-------------
Suggested therapy
..!\!though this syndrome must be rare, it seems worthwhile to call attention to its occurrence and to emphasize the principles of therapy which may prove lifesaving. In such an instance of hypovolemic shock with an elevated hematocrit due to massive transcapillary plasmapheresis, the clinician should probably disregard his conventional concepts about the amqunt of fluid required to maintain blood volume. Plasma should be given at any rate and in any amount required to maintain blood pressure. The risk of overwhelming the heart by excessive venous return seems far less than that of anuria, which is an especially distastrous complication in ·vie\-',r of the large volume of fluid that may be given to the patient. Hematocrit determinations should be done at very frequent intervals and, if the serum albumin level falls, then large quantities of sodium-poor albumin should be given. The experience gained from this case would indicate that the soft-tissue accumulations of
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edema should be disregarded, since they are not life threatening and appear not to respond to the use of pressure bandages or Southey tubes, both of which are probably worth trying. Although medication with antihistamines and adrenal steroid hormones failed to have a favorable effect in this patient, their use in very large doses is probably indicated. Of paramount importance in the management of such a case is the continuous removal of life-endangering fluid collections in the pleural, pericardia!, and possibly in the peritoneal cavities. Inasmuch as the pleural fluid appeared to accumulate quite rapidly in this patient, it would seem essential to maintain a constant vigil for such a development. In summary, the two cardinal principles of management appear to be these: ( 1) to administer any volume of plasma required
Fatal shock due to angioneurotic edema
327
to keep the patient out of shock, and (2) to remove continuously significant collections of fluid in the pleural and, possibly, in the pericardia! and abdominal cavities. Summary
An instance of fatal postpartum hypovolemic shock is described, in which the mechanism was that of generalized increased capillary permeability with massive transcapillary plasmapheresis. Suggested principles of management of such a case are given. We wish to acknowledge the advice and assistance given by Drs. Maurice R. Luke, Otto E. L. Schmidt, George D. Guido, Ralph Levin, Peter Packard, and Charles R. Campbell, and to express our gratitude to the members of the staff of the Hospital blood banking laboratory for their generous he! p.
REFERENCES
1. Clarkson, B., Thompson, D., Horwith, M.,
and Luckey, E. H.: Am. J. Med. 29: 193, 1960. 2. Fulton, G. P., Lutz, B. R., and Callahan, A. B.: Physiol. Rev. 40: 57, 1960. 3. Ponder, E.: Fulton's Textbook of Physiology, ed. 17, Phildalephia, 1955, W. B. Saunders Company, p. 572. 4. Taylor, G. B., Kinmonth, J. B., Rollinson, E., Rotblat, J., and Francis, G. E.: Brit. M. J. 1: 133, !957.
5. Camurri, M.: Monit. ostet. ginec. 3: 186, 1955. 6. Brewer, J. I.: AM. J. 0BST. & GYNEC. 36: 597, 1938. 7. Thorn, G. W.: Am. J. Med. 23: 507, 1957. 8. Donald, H. R.: Brit. M. J. 2: 899, 1937. 9. Gross, P. A. M., Embree, L. J., Bally, P., Shipp, J. C., and Thorn, G. W.: Am. J. Med. 29: 386, 1960.