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Capillary leak syndrome with massive intestinal edema after appendectomy
Capillary Leak Syndrome with Massive Intestinal Edema after Appendectomy
Michael C. Fishbein, MD, Los Angeles, California David State, MD, Los Angeles, Cdifornia Frank Hirose, MD, Los Angeles, California John Castagna, MD, Los Angeles, California
Complications pendicitis
after
appendectomy
are common.
They
for acute
are usually
ap-
septic
in
in most instances are manifested as wound infections or pelvic or subphrenic abscesses. The patient we are reporting on exhibited distinctly unusual complications after appendectomy, iri’cluding fatal hypovolemia, massive edema of the intestines, and anasarca. Although many disease processes must be considered, we believe increased capillary permeability, recently referred to nature
and
as “capillary his death. drome
leak syndrome,”
was responsible
To the best of our knowledge
complicatjng
appendectomy
has
for
this synnot
pre-
viously been reported.
Case Report A previously healthy thirty-six year old man was admitted to Harbor General Hospital on March 22, 1972 with periumhilical pain and vomiting of twelve hours’ duration, The pain was dull and constant with radiation to the right lower quadrant. Neither the patient nor his family had a history of any allergic diseases, such as asthma, hay fever, or angioneurotic edema. His only previous surgery was performed for repair of a lacerated flexor tendon. On admission, the temperature was 97.4OF, blood pressure 169/90 mm Hg, pulse rate 60 per minute, and respirations 16 per minute. Physical examination revealed a healthy appearing man complaining of abdominal pain. The only positive physical findings were limited to the abdomen where there was localized tenderness with guarding in the right lower quadrant.
From the Departments of Pathology and Surgery, Harbor General Hospital and UCLA School of Medicine, Los Angeles, Califqmia. Reprint requests should be addressed to Dr State, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509.
740
Rectal examination revealed no abnormalities. The remainder of the physical examination was noncontributory. There was no evidence of any peripheral edema or skin rash. Admission laboratory data included a hematocrit of 44 per cent, white blood cell count of 9,700 per mm3, and amylase of 120 units (normal, less than 320 units). Serum bilirubin, total protein, albumin, alkaline phosphatase, lactic dehydrogenase, serum glutamic oxalacetic transaminase, calcium, phosphorus, glucose, and blood urea nitrogen levels were all within normal limits. Chest roentgenogram and plain abdominal films revealed no abnormalities. Eight hours after admission the patient underwent operation and an acutely inflamed retrocecal appendix was removed. There was no perforation and the area was not drained. The anesthetic agent was halothane, which was given after an unsuccessful attempt at spinal anesthesia. No unusual difficulties were encountered during the procedure. The patient did well until the third postoperative day when hypotension was noted and the hematocrit was 68 per cent. The abdomen was moderately distended and a diagnosis of postoperative ileus with significant “third spacing” was made. In an attempt to restore the patient’s intravascular volume, 5,000 ml of fluids, including 2,000 ml of plasma, was given. The blood urea nitrogen had risen to 31 mg per 100 ml, presumably from hypovolemia, but the electrolyte levels and results of liver function tests remained within normal limits. On the fourth postoperative day the hematocrit again was 68 per cent and after administration of 5,500 ml of plasma the hematocrit fell only to 64 per cent. Blood urea nitrogen was now 47 mg per 100 ml, but electrolyte levels and results of liver function tests continued to be within normal limits. On the fifth postoperative day the patient had persistent hypotension that improved with plasma administration. Because of abdominal distention and rebound tenderness, a diagnosis of peritonitis was made
The American Journal of Surgery
Capillary :_eak Syndrome
and the patient underwent laparotomy which revealed extensive edema of the retroperitoneum and small intestine. The large bowel also appeared edematous but less so than the small intestine. The distal 20 cm of terminal ileum was cyanotic and appeared nonviable, although there were strong arterial pulsations through the mesentery of the small bowel. The appendiceal stump closure was intact, and there was no evidence of abscess, peritonitis, or intestinal crepitus. The terminal 20 cm of ileum and major portion of the ascending colon, both of which appeared discolored, were removed. The patient survived twenty hours postoperatively, during which time 18,225 ml of plasma and 1,400 ml of salt-poor albumin were given intravenously. Despite the large amount of fluids administered during this time, the central venous pressure never exceeded 20 cm Hz0 and pulmonary wedge pressure measured by means of a Swan-Ganz@ catheter was always less than 5 mm Hg. Mean pulmonary artery pressure was always less than 15 mm Hg. Laboratory values obtained during the twenty-four hour period preceding the patient’s death included the following: creatinine 3.8 mg per 100 ml, blood urea nitrogen 84 mg per 100 ml, calcium 6.5 mg per 100 ml, fibrinogen 55 mg per 100 ml, prothrombin time 13.5 per cent, partial thromhoplastin time greater than three minutes, platelet count 72,000 per mm”, hematocrit 45 per cent, white blood cell count 14,700 per mms, bilirubin 2.1 mg per 100 ml, albumin 5.9 mg per 100 ml, calcium 6.5 mg per 100 ml, phosphorus 4.5 mg per 100 ml, and negative latex fixation, antinuclear antibodies, and serologic test for syphilis. During the last day the patient was oliguric despite large doses of furosemide. Bilateral pleural effusions, anasarca, and progressive shock developed, which were unresponsive to vasopressors, heparin, and massive doses of steroids. A total of 3,600 ml of pleural fluid was removed from both hemithoraces by multiple thoracenteses. The patient died on the sixth postoperative day in a state of progressive shock, hypoxia, and anuria. Premortem bacterial cultures of blood and the peritoneal cavity gave negative results. Microscopically, the appendix showed a fibrinosuppurative exudate of the serosal surface, diffuse infiltration of polymorphonuclear leukocytes into the muscularis, and mucosal ulceration. No vascular abnormalities or specific infectious or parasitic agents were present. The resected terminal ileum and right hemicolon consisted of 20 cm of terminal ileum and 15 cm of proximal colon with marked reddish black discoloration of the serosal surface. (Figure 1.) The muscular wall was pliable and diffusely thickened by intramural accumulation of fluid. The mucosa was intact with no masses or ulcerations present. Patchy hyperemia of the mucosa of the cecal region was noted. The appendectomy site was hyperemic with firm granulation tissue present. The most striking finding was marked submucosal swelling due to fluid accumulation through the entire specimen. Multiple microscopic sections showed marked congestion and dilatation of mesenteric vessels and lymphatits. Mesenteric lymph nodes showed only sinusoidal
Volume
127,
June
1974
edema. Serosal hemorrhage with a mmimwl acute itiflammatory cell infiltrate was noted. NC\abnormalities of the muscularis of the small or large bt)wel were present. Massive cell-free submucosal edema with marked dilatation of submucosal lymphatics was seen. (Figures 2, 3, and 4.) There was no abnormality of’ the mucosa. No evidence of vasculitis was present. Gram’s, periodic acid Schiff, and methenamine silver stams failed to reveal any organisms. At necropsy, the body was that of a muscular, well developed black man thirty-six years old whose external abnormalities consisted of marked penile and scrotal edema, abdominal distention, and a X0 cm transverse surgical incision with an ileostomy and colostomy on the anterior abdominal wall. The pleural cavities contained large amounts of serosanguineous fluid (left, 1,500 ml; right, 1,000 ml). The lungs were atelectatic bilaterally. The pericardial cavity contained 150 ml of yellow serous fluid. The peritoneal cavity was markedly distended by 3,000 ml of serous fluid. The abdominal viscera all showed reddish black discoloration of the serosal surfaces with the remaining segments of small and large bowel most severely affected. Careful search revealed no abnormalities of the abdominal vasculature or lymphatic vessels. Hyperemia and edema of the retroperitoneal region were noted, and grossly affected bowel revealed reddish black serosal discoloration, a normal muscularis, submucosal edema, and an intact, viable appearing mucosal surface with no ulceration or other abnormalities. Microscopic examination confirmed atelectasis of the lungs with patchy pulmonary edema and histologic changes of the intestines identical to those described for the previously resected segments of ileum and colon. Significant submucosal change was also noted in the stomach and esophagus. Cultures of peritoneal fluid and blood revealed no bacterial growth.
Comments Hypovolemia, shock, and ileus developed after appendectomy for classic symptoms and signs of acute appendicitis in a previously healthy thirtysix year old man, leading to re-exploration with removal of a segment of terminal ileum and proximal colon that appeared nonviable. The histologic sections of the appendix showed typical acute appendicitis. Sections of the resected bowel showed no gangrene but marked submucosal edema with virtually no accompanying cellular inflammatory response. This unusual complication of appendectomy was rapidly followed by massive anasarca and death. Massive submucosal edema of the intestines, stomach, and esophagus without a concomitant cellular inflammatory response is a rare pathologic finding and several disorders were considered in the differential diagnosis.
741
Fishbein et al
Figure 1. Resected terminal ileum and colon. Note hyperemia and edema. Granulation tissue is present in the region of the appendectomy stump (arrows).
Figure 2. Small bowel with submucosal edema (hematoxylin and eosin stain; original magnification X 7.5).
Edema is noted in acute regional enteritis and does characteristically involve the terminal small bowel. Cellular infiltration in submucosal lymphatics and mucosal ulceration usually occurs early and progression to total involvement of the bowel and anasarca has not been reported [I]. That the present case represents a “hyperacute” form of regional enteritis is a remote possibility since this histologic picture has been reported in cases that have progressed to typical regional enteritis [2,3]. However, in the cases reported, the extent of edema has not been as great as in our patient nor has it terminated fatally. In acute nonspecific ileitis, a self-limiting, spontaneously resolving condition in which histopathologic material is rarely available, cellular prolifera-
742
Figure 3. Large bowel with massive submucosal edema. Note absence of inflammatory cells (hematoxylin and eosin stain; original magnification X 7.5).
tion with mucosal involvement would be expected to occur early in the course. Massive edema would be very unusual [4]. Many infectious agents can cause edema of the bowel. Again the absence of any inflammatory infiltrates, the multiple negative cultures of tissue and blood (both aerobic and anaerobic), and the inability to identify organisms with special histochemical stains make infection as a cause for this edema unlikely. Anaphylactoid purpura (Henoch-Schonlein) can be manifested initially by abdominal symptoms. The age of our patient and the absence of other findings such as melena, petechiae, renal abnormalities, or arthralgias make this diagnosis unlikely.
Colonic lymphangiectasia, a syndrome with marked edema of the intestines, is a rather distinct entity presenting with watery diarrhea, hypokalemia, and protein loss. The history and clinical presentation of this disorder bear little resemblance to our case [5]. Inappropriate administration of fluids postoperatively as a possible cause for the edema should also be considered, but this was not borne out by a careful review of events and hemodynamic measurements. At no time in the patient’s course was there an elevation in the central venous pressure or pulmonary wedge pressure. During the early phases of the postoperative course, the patient had a markedly elevated hematocrit, which suggested “third space” sequestration of fluids and inadequate fluid intake. When progressive ascites and anasarca became apparent
The American Journal of Surgery
Caplllara :.eaic Syndrome
despite administration of massive amounts of colloid (namely. plasma), the hemodynamic studies showed normal pulmonary artery and wedge pressures as well as a central venous pressure that did not exceed 12 cm of saline. With these data the possibility of excessive administration of fluids resulting in cardiac decompensation and massive edema is untenable. The terminal hematocrit value of 41 per cent, normal blood electrolyte levels. and serum albumin of 5 gm per 100 ml are also evidence against the possibility of dilutional hypervolemia due to excessive fluid administration. Allergic phenomena, which must be strongly considered in this case, are usually accompanied by a family history of allergy or exposure to a known antigenic substance. One cannot rule out, however, that after appendectomy, angioneurotic edema initially involving one local area and subsequently resulting in massive anasarca might have occurred. R,enton [6] in 1965 stated, “There are only a few cases of established angioneurotic edema localized to the gastrointestinal tract and proved to be of allergic origin with a known allergen.” Passively sensitized ileostomy and colostomy sites have exhibited allergic responses consisting of edema replaced in one or two hours by hyperemia [7]. Attacks of angioneurotic edema are often circumscribed and reports exist describing changes localized to the skin, mucous membranes, viscera, joints, and brain. These have lasted for hours to days and have recurred over years. Exposure to allergens, heat, cold, light, and physical or psychic trauma has been implicated. Histologic findings include submucosal edema and occasionally eosinophilic cell infiltration. Usually a long family history is present and sometimes a specific inciting agent is known [8]. There is no evidence in this case to support such a diagnosis. The normal appearing large and small bowel at the time of appendectomy makes it likely that the remarkable changes observed afterwards developed independent of the characteristic acute inflammation of the appendix. Recently, Robin et al [9] described two patients with fatal hypovolemic shock, generalized edema, hemoconcentration, and pulmonary edema, possibly related to circulating endotoxin. Similar cases have been described with widespread leakage of fluids through capillary membranes as a prpminent feature [lO,ll]. The patients reported on by Robin et, al [9] were carefully studied, and abnormal permeability of pulmonary membranes was documented as the major pathophysiologic factor. In the so-called capillary leak syndrome described
Volume
127, June 1974
Figure 4. Higher power magnification of large bowel demonstrating edema and dilated lymphatic channels (hematoxylin and eosin stain: original magnification X 130).
by Robin et al [9], no underlying cause was identified and no morphologic abnormality of’ capillaries was seen histologically. Therapeutic measures to maintain intravascular volume were partially successful, but both patients eventually died. A variety of disorders can lead to increased capillary permeability with loss of plasma into tissues. Sepsis, angioneurotic edema, and pregnancy have been associated in some of the reported cases, and the one patient of Clarkson et al [IL’\ manifested . the capillary leak syndrome only during the premenstrual phase of the menstrual cycie. The case we are reporting is certainly consistent with the capillary leak syndrome with increased permeability of capillary membranes manifested by hypovolemic shock, hemoconcentration, and anasarca without fluid overload, congestive failure, or blockage of lymphatic or venous channels. Although the cause of massive edema of the bowel in this case remains obscure, capillary leakage occurred and directly led to the death of the patient. The extremely critical condition of patients with this syndrome makes exhaustive studies difficult,
743
Fishbein et al
because emergency measures are required to sustain life. However, once fluid overload and heart failure have been ruled out as a cause for the massive edema, capillary leak syndrome should be suspected. Awareness of the rare clinical entity with aggressive diagnostic and therapeutic measures may decrease the high mortality. Summary Ileus and ascites developed in a previously healthy thirty-six year old man after appendectomy for acute appendicitis. Re-exploration revealed a grossly gangrenous appearing segment of terminal ileum and proximal colon that histologically showed only massive acellular submucosal edema with dilatation of lymphatics and serosal hyperemia without necrosis. Severe anasarca developed and the patient died after this second operation. Necropsy revealed submucosal edema of the remaining large and small intestines, anasarca, and Regional enteritis, acute pulmonary atelectasis. nonspecific ileitis, infectious enterocolitis, iatrogenie accident, and allergic phenomena were considered in the differential diagnosis. We believe this case is an example of the rare “capillary leak syndrome,” which has not been reported previously after appendectomy.
744
Acknowledgment: We wish to thank Hideo H. Itabashi, MD, who has contributed substantially in the preparation of this report. References 1. Horn RC Jr: Alimentary tract. Pathology, 6th ed (Anderson WA, ed). St. Louis, Mosby, 1971, p 1131. 2. Ammann RW, Bockus HL: Pathogenesis of regional enteritis. Archhtern Med107: 504, 1961. 3. Meadow TR, Bratsakis JG: Histopathological spectrum of regional enteritis. Arch Surg 87: 976, 1963. 4. Ammann RW: Regional enteritis. Gastroenterology, 2nd ed (Bockus HL, ed). Philadelphia, Saunders, 1964. p 243. 5. Griffen WO Jr, Belin RP, Forman RW, et al: Colonic lymphangiectasis: report of two cases. Dis Colon Rectum 15: 49, 1972. 6. Renton CJC: Recurrent edema of small intestine. Br J Surg 52: 536, 1965. 7. Gray I, Harten M. Walzer M: Studies in mucous membrane hypersensitiveness; the allergic reaction in the passively sensitized mucous membranes of the ileum and colon in humans. Ann Intern Med 13: 2050, 1940. 8. Reimann HA: Hereditary periodic edema. The interrelationship of familial periodic disorders. Am J Med Sci243: 727, 1962. 9. Robin ED, Carey LC, Grenvik A, et al: Capillary leak syndrome with pulmonary edema. Arch Intern Med 130: 66, 1972. 10. Clarkson B. Thompson D. Horwfth M, Luckey EH: Cyclical edema and shock due to increased capillary permeability. Am JMed29: 193, 1960. 11. Luke IW, Rubenstein E: Fatal postpartum shock due to massive angioneurotic edema. Am J Obstet Gynecol83: 322, 1962.
The Amerlcan Journal of Surgery
Michael C. Fishbein, MD, Los Angeles, California David State, MD, Los Angeles, Cdifornia Frank Hirose, MD, Los Angeles, California John Castagna, MD, Los Angeles, California
Complications pendicitis
after
appendectomy
are common.
They
for acute
are usually
ap-
septic
in
in most instances are manifested as wound infections or pelvic or subphrenic abscesses. The patient we are reporting on exhibited distinctly unusual complications after appendectomy, iri’cluding fatal hypovolemia, massive edema of the intestines, and anasarca. Although many disease processes must be considered, we believe increased capillary permeability, recently referred to nature
and
as “capillary his death. drome
leak syndrome,”
was responsible
To the best of our knowledge
complicatjng
appendectomy
has
for
this synnot
pre-
viously been reported.
Case Report A previously healthy thirty-six year old man was admitted to Harbor General Hospital on March 22, 1972 with periumhilical pain and vomiting of twelve hours’ duration, The pain was dull and constant with radiation to the right lower quadrant. Neither the patient nor his family had a history of any allergic diseases, such as asthma, hay fever, or angioneurotic edema. His only previous surgery was performed for repair of a lacerated flexor tendon. On admission, the temperature was 97.4OF, blood pressure 169/90 mm Hg, pulse rate 60 per minute, and respirations 16 per minute. Physical examination revealed a healthy appearing man complaining of abdominal pain. The only positive physical findings were limited to the abdomen where there was localized tenderness with guarding in the right lower quadrant.
From the Departments of Pathology and Surgery, Harbor General Hospital and UCLA School of Medicine, Los Angeles, Califqmia. Reprint requests should be addressed to Dr State, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509.
740
Rectal examination revealed no abnormalities. The remainder of the physical examination was noncontributory. There was no evidence of any peripheral edema or skin rash. Admission laboratory data included a hematocrit of 44 per cent, white blood cell count of 9,700 per mm3, and amylase of 120 units (normal, less than 320 units). Serum bilirubin, total protein, albumin, alkaline phosphatase, lactic dehydrogenase, serum glutamic oxalacetic transaminase, calcium, phosphorus, glucose, and blood urea nitrogen levels were all within normal limits. Chest roentgenogram and plain abdominal films revealed no abnormalities. Eight hours after admission the patient underwent operation and an acutely inflamed retrocecal appendix was removed. There was no perforation and the area was not drained. The anesthetic agent was halothane, which was given after an unsuccessful attempt at spinal anesthesia. No unusual difficulties were encountered during the procedure. The patient did well until the third postoperative day when hypotension was noted and the hematocrit was 68 per cent. The abdomen was moderately distended and a diagnosis of postoperative ileus with significant “third spacing” was made. In an attempt to restore the patient’s intravascular volume, 5,000 ml of fluids, including 2,000 ml of plasma, was given. The blood urea nitrogen had risen to 31 mg per 100 ml, presumably from hypovolemia, but the electrolyte levels and results of liver function tests remained within normal limits. On the fourth postoperative day the hematocrit again was 68 per cent and after administration of 5,500 ml of plasma the hematocrit fell only to 64 per cent. Blood urea nitrogen was now 47 mg per 100 ml, but electrolyte levels and results of liver function tests continued to be within normal limits. On the fifth postoperative day the patient had persistent hypotension that improved with plasma administration. Because of abdominal distention and rebound tenderness, a diagnosis of peritonitis was made
The American Journal of Surgery
Capillary :_eak Syndrome
and the patient underwent laparotomy which revealed extensive edema of the retroperitoneum and small intestine. The large bowel also appeared edematous but less so than the small intestine. The distal 20 cm of terminal ileum was cyanotic and appeared nonviable, although there were strong arterial pulsations through the mesentery of the small bowel. The appendiceal stump closure was intact, and there was no evidence of abscess, peritonitis, or intestinal crepitus. The terminal 20 cm of ileum and major portion of the ascending colon, both of which appeared discolored, were removed. The patient survived twenty hours postoperatively, during which time 18,225 ml of plasma and 1,400 ml of salt-poor albumin were given intravenously. Despite the large amount of fluids administered during this time, the central venous pressure never exceeded 20 cm Hz0 and pulmonary wedge pressure measured by means of a Swan-Ganz@ catheter was always less than 5 mm Hg. Mean pulmonary artery pressure was always less than 15 mm Hg. Laboratory values obtained during the twenty-four hour period preceding the patient’s death included the following: creatinine 3.8 mg per 100 ml, blood urea nitrogen 84 mg per 100 ml, calcium 6.5 mg per 100 ml, fibrinogen 55 mg per 100 ml, prothrombin time 13.5 per cent, partial thromhoplastin time greater than three minutes, platelet count 72,000 per mm”, hematocrit 45 per cent, white blood cell count 14,700 per mms, bilirubin 2.1 mg per 100 ml, albumin 5.9 mg per 100 ml, calcium 6.5 mg per 100 ml, phosphorus 4.5 mg per 100 ml, and negative latex fixation, antinuclear antibodies, and serologic test for syphilis. During the last day the patient was oliguric despite large doses of furosemide. Bilateral pleural effusions, anasarca, and progressive shock developed, which were unresponsive to vasopressors, heparin, and massive doses of steroids. A total of 3,600 ml of pleural fluid was removed from both hemithoraces by multiple thoracenteses. The patient died on the sixth postoperative day in a state of progressive shock, hypoxia, and anuria. Premortem bacterial cultures of blood and the peritoneal cavity gave negative results. Microscopically, the appendix showed a fibrinosuppurative exudate of the serosal surface, diffuse infiltration of polymorphonuclear leukocytes into the muscularis, and mucosal ulceration. No vascular abnormalities or specific infectious or parasitic agents were present. The resected terminal ileum and right hemicolon consisted of 20 cm of terminal ileum and 15 cm of proximal colon with marked reddish black discoloration of the serosal surface. (Figure 1.) The muscular wall was pliable and diffusely thickened by intramural accumulation of fluid. The mucosa was intact with no masses or ulcerations present. Patchy hyperemia of the mucosa of the cecal region was noted. The appendectomy site was hyperemic with firm granulation tissue present. The most striking finding was marked submucosal swelling due to fluid accumulation through the entire specimen. Multiple microscopic sections showed marked congestion and dilatation of mesenteric vessels and lymphatits. Mesenteric lymph nodes showed only sinusoidal
Volume
127,
June
1974
edema. Serosal hemorrhage with a mmimwl acute itiflammatory cell infiltrate was noted. NC\abnormalities of the muscularis of the small or large bt)wel were present. Massive cell-free submucosal edema with marked dilatation of submucosal lymphatics was seen. (Figures 2, 3, and 4.) There was no abnormality of’ the mucosa. No evidence of vasculitis was present. Gram’s, periodic acid Schiff, and methenamine silver stams failed to reveal any organisms. At necropsy, the body was that of a muscular, well developed black man thirty-six years old whose external abnormalities consisted of marked penile and scrotal edema, abdominal distention, and a X0 cm transverse surgical incision with an ileostomy and colostomy on the anterior abdominal wall. The pleural cavities contained large amounts of serosanguineous fluid (left, 1,500 ml; right, 1,000 ml). The lungs were atelectatic bilaterally. The pericardial cavity contained 150 ml of yellow serous fluid. The peritoneal cavity was markedly distended by 3,000 ml of serous fluid. The abdominal viscera all showed reddish black discoloration of the serosal surfaces with the remaining segments of small and large bowel most severely affected. Careful search revealed no abnormalities of the abdominal vasculature or lymphatic vessels. Hyperemia and edema of the retroperitoneal region were noted, and grossly affected bowel revealed reddish black serosal discoloration, a normal muscularis, submucosal edema, and an intact, viable appearing mucosal surface with no ulceration or other abnormalities. Microscopic examination confirmed atelectasis of the lungs with patchy pulmonary edema and histologic changes of the intestines identical to those described for the previously resected segments of ileum and colon. Significant submucosal change was also noted in the stomach and esophagus. Cultures of peritoneal fluid and blood revealed no bacterial growth.
Comments Hypovolemia, shock, and ileus developed after appendectomy for classic symptoms and signs of acute appendicitis in a previously healthy thirtysix year old man, leading to re-exploration with removal of a segment of terminal ileum and proximal colon that appeared nonviable. The histologic sections of the appendix showed typical acute appendicitis. Sections of the resected bowel showed no gangrene but marked submucosal edema with virtually no accompanying cellular inflammatory response. This unusual complication of appendectomy was rapidly followed by massive anasarca and death. Massive submucosal edema of the intestines, stomach, and esophagus without a concomitant cellular inflammatory response is a rare pathologic finding and several disorders were considered in the differential diagnosis.
741
Fishbein et al
Figure 1. Resected terminal ileum and colon. Note hyperemia and edema. Granulation tissue is present in the region of the appendectomy stump (arrows).
Figure 2. Small bowel with submucosal edema (hematoxylin and eosin stain; original magnification X 7.5).
Edema is noted in acute regional enteritis and does characteristically involve the terminal small bowel. Cellular infiltration in submucosal lymphatics and mucosal ulceration usually occurs early and progression to total involvement of the bowel and anasarca has not been reported [I]. That the present case represents a “hyperacute” form of regional enteritis is a remote possibility since this histologic picture has been reported in cases that have progressed to typical regional enteritis [2,3]. However, in the cases reported, the extent of edema has not been as great as in our patient nor has it terminated fatally. In acute nonspecific ileitis, a self-limiting, spontaneously resolving condition in which histopathologic material is rarely available, cellular prolifera-
742
Figure 3. Large bowel with massive submucosal edema. Note absence of inflammatory cells (hematoxylin and eosin stain; original magnification X 7.5).
tion with mucosal involvement would be expected to occur early in the course. Massive edema would be very unusual [4]. Many infectious agents can cause edema of the bowel. Again the absence of any inflammatory infiltrates, the multiple negative cultures of tissue and blood (both aerobic and anaerobic), and the inability to identify organisms with special histochemical stains make infection as a cause for this edema unlikely. Anaphylactoid purpura (Henoch-Schonlein) can be manifested initially by abdominal symptoms. The age of our patient and the absence of other findings such as melena, petechiae, renal abnormalities, or arthralgias make this diagnosis unlikely.
Colonic lymphangiectasia, a syndrome with marked edema of the intestines, is a rather distinct entity presenting with watery diarrhea, hypokalemia, and protein loss. The history and clinical presentation of this disorder bear little resemblance to our case [5]. Inappropriate administration of fluids postoperatively as a possible cause for the edema should also be considered, but this was not borne out by a careful review of events and hemodynamic measurements. At no time in the patient’s course was there an elevation in the central venous pressure or pulmonary wedge pressure. During the early phases of the postoperative course, the patient had a markedly elevated hematocrit, which suggested “third space” sequestration of fluids and inadequate fluid intake. When progressive ascites and anasarca became apparent
The American Journal of Surgery
Caplllara :.eaic Syndrome
despite administration of massive amounts of colloid (namely. plasma), the hemodynamic studies showed normal pulmonary artery and wedge pressures as well as a central venous pressure that did not exceed 12 cm of saline. With these data the possibility of excessive administration of fluids resulting in cardiac decompensation and massive edema is untenable. The terminal hematocrit value of 41 per cent, normal blood electrolyte levels. and serum albumin of 5 gm per 100 ml are also evidence against the possibility of dilutional hypervolemia due to excessive fluid administration. Allergic phenomena, which must be strongly considered in this case, are usually accompanied by a family history of allergy or exposure to a known antigenic substance. One cannot rule out, however, that after appendectomy, angioneurotic edema initially involving one local area and subsequently resulting in massive anasarca might have occurred. R,enton [6] in 1965 stated, “There are only a few cases of established angioneurotic edema localized to the gastrointestinal tract and proved to be of allergic origin with a known allergen.” Passively sensitized ileostomy and colostomy sites have exhibited allergic responses consisting of edema replaced in one or two hours by hyperemia [7]. Attacks of angioneurotic edema are often circumscribed and reports exist describing changes localized to the skin, mucous membranes, viscera, joints, and brain. These have lasted for hours to days and have recurred over years. Exposure to allergens, heat, cold, light, and physical or psychic trauma has been implicated. Histologic findings include submucosal edema and occasionally eosinophilic cell infiltration. Usually a long family history is present and sometimes a specific inciting agent is known [8]. There is no evidence in this case to support such a diagnosis. The normal appearing large and small bowel at the time of appendectomy makes it likely that the remarkable changes observed afterwards developed independent of the characteristic acute inflammation of the appendix. Recently, Robin et al [9] described two patients with fatal hypovolemic shock, generalized edema, hemoconcentration, and pulmonary edema, possibly related to circulating endotoxin. Similar cases have been described with widespread leakage of fluids through capillary membranes as a prpminent feature [lO,ll]. The patients reported on by Robin et, al [9] were carefully studied, and abnormal permeability of pulmonary membranes was documented as the major pathophysiologic factor. In the so-called capillary leak syndrome described
Volume
127, June 1974
Figure 4. Higher power magnification of large bowel demonstrating edema and dilated lymphatic channels (hematoxylin and eosin stain: original magnification X 130).
by Robin et al [9], no underlying cause was identified and no morphologic abnormality of’ capillaries was seen histologically. Therapeutic measures to maintain intravascular volume were partially successful, but both patients eventually died. A variety of disorders can lead to increased capillary permeability with loss of plasma into tissues. Sepsis, angioneurotic edema, and pregnancy have been associated in some of the reported cases, and the one patient of Clarkson et al [IL’\ manifested . the capillary leak syndrome only during the premenstrual phase of the menstrual cycie. The case we are reporting is certainly consistent with the capillary leak syndrome with increased permeability of capillary membranes manifested by hypovolemic shock, hemoconcentration, and anasarca without fluid overload, congestive failure, or blockage of lymphatic or venous channels. Although the cause of massive edema of the bowel in this case remains obscure, capillary leakage occurred and directly led to the death of the patient. The extremely critical condition of patients with this syndrome makes exhaustive studies difficult,
743
Fishbein et al
because emergency measures are required to sustain life. However, once fluid overload and heart failure have been ruled out as a cause for the massive edema, capillary leak syndrome should be suspected. Awareness of the rare clinical entity with aggressive diagnostic and therapeutic measures may decrease the high mortality. Summary Ileus and ascites developed in a previously healthy thirty-six year old man after appendectomy for acute appendicitis. Re-exploration revealed a grossly gangrenous appearing segment of terminal ileum and proximal colon that histologically showed only massive acellular submucosal edema with dilatation of lymphatics and serosal hyperemia without necrosis. Severe anasarca developed and the patient died after this second operation. Necropsy revealed submucosal edema of the remaining large and small intestines, anasarca, and Regional enteritis, acute pulmonary atelectasis. nonspecific ileitis, infectious enterocolitis, iatrogenie accident, and allergic phenomena were considered in the differential diagnosis. We believe this case is an example of the rare “capillary leak syndrome,” which has not been reported previously after appendectomy.
744
Acknowledgment: We wish to thank Hideo H. Itabashi, MD, who has contributed substantially in the preparation of this report. References 1. Horn RC Jr: Alimentary tract. Pathology, 6th ed (Anderson WA, ed). St. Louis, Mosby, 1971, p 1131. 2. Ammann RW, Bockus HL: Pathogenesis of regional enteritis. Archhtern Med107: 504, 1961. 3. Meadow TR, Bratsakis JG: Histopathological spectrum of regional enteritis. Arch Surg 87: 976, 1963. 4. Ammann RW: Regional enteritis. Gastroenterology, 2nd ed (Bockus HL, ed). Philadelphia, Saunders, 1964. p 243. 5. Griffen WO Jr, Belin RP, Forman RW, et al: Colonic lymphangiectasis: report of two cases. Dis Colon Rectum 15: 49, 1972. 6. Renton CJC: Recurrent edema of small intestine. Br J Surg 52: 536, 1965. 7. Gray I, Harten M. Walzer M: Studies in mucous membrane hypersensitiveness; the allergic reaction in the passively sensitized mucous membranes of the ileum and colon in humans. Ann Intern Med 13: 2050, 1940. 8. Reimann HA: Hereditary periodic edema. The interrelationship of familial periodic disorders. Am J Med Sci243: 727, 1962. 9. Robin ED, Carey LC, Grenvik A, et al: Capillary leak syndrome with pulmonary edema. Arch Intern Med 130: 66, 1972. 10. Clarkson B. Thompson D. Horwfth M, Luckey EH: Cyclical edema and shock due to increased capillary permeability. Am JMed29: 193, 1960. 11. Luke IW, Rubenstein E: Fatal postpartum shock due to massive angioneurotic edema. Am J Obstet Gynecol83: 322, 1962.
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