Spontaneous, Isolated Intestinal Perforations in Neonates With Birth Weight < 1,000 g Not Associated With Necrotizing Enterocolitis By Christopher
L. Meyer,
Nathaniel
R. Payne,
and Stacy A. Roback
Minneapolis, Minnesota l From January 1986 through December 1988, we have seen 7 cases of isolated intestinal perforation in 250 infants with birth weights < 1,000 g (3% incidence) without histological or clinical evidence of necrotiring enterocolitis (NEC). Patients had a mean birth weight of 670 g, gestational age of 25.1 weeks, and sustained a perforation at a chronological age of 10.4 days. No infants had been fed. A definite, blue-discolored abdomen was the only consistent clinical sign (n = 7). Free intraperitoneal air on radiograms was rarely observed (n = 1). Abdominal ultrasounds (n = 3) and metrizamide contrast studies (n = 3) were not diagnostic. The presence of an umbilical artery catheter (7/7), falling hematocrit (6/7), thrombocytopenia (5/7), and a positive diagnostic paracentesis were most commonly found. In 6 of 7 patients, this perforation was associated with coagulasenegative staphylococcal sepsis. Surgical or histological diagnosis showed focal perforation in either the terminal ileum (n = 4) or the transverse and descending colon (n = 3). Survival was 3 of 7; 2 patients died of intracranial hemorrhage and 2 died of Candida sepsis. We conclude that (1) intestinal perforation can occur in the absence of NEC; (2) bluish discoloration of the abdomen is the most reliable clinical finding; and (3) perforation may be associated with coagulase-negative staphylococcal infection. Copyright o 1991 by W.B. Saunders Company
INDEX WORDS:
Intestinal perforation,
neonatal.
I
NTESTINAL PERFORATION is a life-threatening complication in neonates that can be due to indomethacin therapy,‘,’ intestinal obstruction,3 ischemia,3 congenital defects in the intestinal musculature,4 cytomegalovirus infection (CMV),’ and necrotizing enterocolitis (NEC).738 Spontaneous, isolated intestinal perforation is particularly serious in very low birth weight infants (VLBW)” because diagnosing these perforations is difficult and may delay surgical intervention. Maintaining a high index of suspicion and accepting the paucity of reliable diagnostic signs are the essentials of early diagnosis and surgical treatment of intestinal perforations in VLBW infants. Prevention of these isolated perforations is not possible at this time because the etiology is unknown. We report our experience with seven patients with birth-
From the Departments of Neonatology and Pediattic Surgery, Minneapolis Children’s Medical Center, Minneapolis, MN. Date accepted: September 6, 1990. Address reprint requests to Christopher L. Meyer, MD, cio Stacy A. Roback, MD, Pediatric Surgical Assoc. Ltd, 2545 Chicago Ave. Minneapolis, MN 55404. Copyright o 1991 by WB. Saunders Company 00.X?-3468/91/2606-0017$03.00/0 714
weights < 1,000 g who had spontaneous, isolated perforations of the intestine that were not associated with any known etiologic factor and speculate that they may be related to coagulase-negative staphylococcal infection. CASE
REPORTS
All patients were hospitalized at the Neonatal Intensive Care Unit of Minneapolis Children’s Medical Center and inborn at the adjacent Abbott-Northwestern Hospital Perinatal Center. Patient data are summarized in Tables 1 and 2. The seven patients reported here represent an incidence of 7 of 250 (3%) and were all admitted between January 1,1986 and December 31,1988.
Case 1 This 560-g infant girl was born at 24 weeks’ gestation and had Apgar scores of 2 and 8 at 1 and 5 minutes, respectively. The infant was placed on the ventilator for moderate respiratory distress and an umbilical artery catheter (UAC) was placed in the midthoracic aorta. Over the first week of life she weaned to fairly low ventilator settings. Head ultrasound was normal. A patent ductus arteriosus (PDA) murmur was noted, but it was considered clinically insignificant. Indomethacin was not given. On day 13 the infant developed coagulase-negative staphylococcal sepsis and exhibited leukocystosis, metabolic acidosis, anemia, and thrombocytopenia. Despite antibiotics, she deteriorated. On day 15 she manifested a blue-discolored and mildly distended abdomen. X-rays showed only a gasless abdomen. A metrizimide gastrointestinal contrast study showed simply delayed transit. The baby deteriorated further, developing renal failure and pulmonary failure. By day 20 it was felt that the baby was dying, and that surgical exploration offered the only hope, afthough slim. The baby was found to have peritonitis se$ondary to an apparent spontaneous perforation of the transverse colon; the rest of the bowel was not ischemic. Postoperatively the infant fully decompensated showing profound acidosis and coagulopathy. She died despite maximal therapy. Autopsy was refused. Blood culture also grew Candida albicans postmortem.
Case 2 This 360-g, growth-retarded infant girl was born at 26 weeks’ gestation by emergency cesarean section. She had Apgar scores of 4 and 7 at 1 and 5 minutes, respectively. She was ventilated for severe respiratory distress and a UAC was placed in the midthoracic aorta. The baby stabilized over the first week of life. On day 10, the infant experienced an acute deterioration, needing increased respiratory support. The baby developed a very bluediscolored, distended, tender, and quiet abdomen. X-rays showed simply a gasless abdomen with no evidence of pneumatosis or free air. The infant also developed severe metabolic acidosis, thrombocytopenia, and anemia despite transfusions of packed red blood cells, platelets, and cryoprecipitate. The infant was started on antibiotics and subsequent blood cultures were positive for coagu./ourna/ofPediatric Surgery, Vol26, No 6 (June), 1991: pp 714-717
SPONTANEOUS
PERFORATIONS
715
IN NEONATES
Table 1. Patient Characteristics Coagulasa-Negative
Mean Age
Staphylococci
(d)
PDA
lndocin
lnotropic Agents
560
+
_
+
+
15
360
_
_
_
+
10
Case No.
Mean GA (wk)
Mean BW (g)
1
24
2
26
Midthoracic
UAC
3
26
590
+
+
_
+
8
4
23
620
+
16
24
710
+ _
+
5
+ _
+
+
11
6
26
995
+
+
+
7
7
26
860
+
+
+
+ _
25.1
670
71% (5/7)
57% (4i7)
71% (517)
86% (6/7)
10.4
Total
6
Abbreviations: GA, gestational age; BW, birth weight; UAC, umbilical artery catheter; PDA, patient ductus arteriosus.
In view of the infants’ poor prognosis due to massive intraventricular hemorrhages, aggressive therapy such as laparotomy was not offered. With the parents’ agreement, further support was discontinued and the infant died quickly. Autopsy showed large intraventricular hemorrhages and a perforation of the terminal ileum with peritonitis. The proximal small bowel was dilated but intact. The colon and appendix were unremarkable. Postmortem blood, spinal fluid, and peritoneal cultures were positive for coagulase-negative staphylococci.
staphylococci. The UAC was removed because there was concern that a vascular accident had occurred. Six days later, the infant developed a bulging fontanelle and rapidly increasing head size. Although initial head ultrasounds were normal, a third head ultrasound done at this time showed a massive intraventricular and intraparenchemal hemorrhage. Prognosis was felt to be extremely poor, and the decision was made with the parents to discontinue support of the infant. She died immediately. Autopsy confirmed massive cerebral hemorrhages. The infant also had evidence of CMV infection. Abdominal pathological examination showed meconium peritonitis and an isolated perforation of the transverse colon. The rest of the bowel was intact with no other lesions. Abdominal cultures were positive for coagulasenegative staphylococci. lase-negative
Case 4 This 620-g infant girl was delivered at 23 weeks’ gestation. Apgar scores were 1 and 5 at 1 and 5 minutes, respectively. She was ventilated immediately for severe respiratory distress and a UAC was placed in the midthoracic aorta. On day 5 she was treated with Indomethacin for a significant PDA. However, the medication was unsuccessful and she later had the PDA surgically ligated. On day 9 the infant developed a slightly bluish discoloration of her abdomen. X-rays showed simply a gasless abdomen with no pneumatosis or free air. Abdominal ultrasound was negative as well. Over the next 6 days the abdomen became more distended and blue. The infant also exhibited decreasing hematocrit and thrombocytopenia. On day 16, abdominal paracentesis showed stool and coagulase-negative staphylococci. The infant underwent laparotomy and was found to have a perforation of the midtransverse colon and meconium peritonitis. A section of colon was removed and a colostomy was made. The small bowel was completely normal. The infant tolerated surgery well. Six days postoperatively the infant had a wound dehiscence and had another operation to recreate a new stoma. She ultimately did well and was discharged on day 153.
Case 3 This 590-g infant girl was delivered at 26 weeks’ gestation by cesarean section. She was growth-retarded and the second of twins. Apgar scores were 3 and? at 1 and 5 minutes, respectively. She was ventilated immediately for severe respiratory distress and a UAC was placed in the midthoracic aorta. She improved in her respiratory status until 5 days of age, when she developed a PDA. Initially the use of indomethacin was deferred because the infant had developed a grade III to IV intraventricular hemorrhage on the right. The intraventricular hemorrhage ultimately progressed to grade IV hemorrhages bilaterally. Because of deteriorating pulmonary status, one dose of indomethacin was later given. Subsequently, the infant developed an upper gastrointestinal hemorrhage with a bright red blood per nasogastric tube. This resolved with suction and intermittent Maalox therapy. On day 7, she developed a blue-discolored and distended abdomen. She became neutropenic and acidotic. Antibiotics were restarted. Over the next 2 days, the abdominal distension progressed to obvious perforation; as evidence by free air observed on x-ray.
Case 5 This 710-g infant boy was born at 24 weeks‘ gestation and had Apgar scores of 4 and 8 at 1 and 5 minutes, respectively. A UAC
Table 2. Patient Signs and Diagnostic Studies Falling Case No.
Blue Abdomen
Elevated WBC
Thrombocytopenia
Hematocrit
Free Air
Positive GI
Positive Abdominal
Positive
(x-we.)
Series
Ultrasound
Paracentesis ND
1
+
+
+
+
_
ND
2
+
+
+
+
_
ND
ND
ND
3
+
_
_
_
+
ND
ND
ND
4
+
_
+
+
ND
_
t
5
t
_
_
t
_
6
t
t
t
+
_
7
+
_
t
+
_
ND
ND
ND
Total
100% (7/7)
43% (3/7)
71% (5/7)
86% (6/7)
14% (l/7)
0
0
66% (2/3)
Abbreviations: WBC, white blood cells; GI, gastrointestinal: ND, not done.
_
_ +
716
was placed in the midthoracic aorta and mechanical ventilation was initiated for moderately severe respiratory distress. He did well, weaning to modest ventilator settings without developing clinical signs of a PDA until day 9 when he experienced a significant deterioration. He required increased ventilator support, inotropic agents, and received antibiotics after cultures of the blood, urine, and cerebrospinal fluid were obtained. The blood culture grew coagulase-negative staphylococci. On day 11, 2 days after the sudden deterioration, he developed a blue, discolored abdomen without distention and with minimal tenderness. Although his hematocrit decreased from 45% to 35%, his white blood cell count, platelet count, and base excess were normal. Abdominal x-rays showed a gasless abdomen and the abdominal ultrasound was negative for fluid or masses. Abdominal paracentesis was performed but did not yield any fluid. Metrizamide contrast study of the gastrointestinal tract was performed but showed only a slow transit time and no obvious obstruction or extraluminal contrast material. Because the infant failed to improve, an exploratory laparotomy was performed on day 13. He was found to have a moderate amount of blood mixed with meconium in the peritoneal cavity. The bowel was normal except for an isolated perforation in the terminal ileum. This perforation was exteriorized to create an ileostomy. The infant tolerated surgery well and was discharged on day 130.
Case 6 This 995-g infant girl was delivered at 26 weeks’ gestation and had Apgar scores of 4 and 7 at 1 and 5 minutes, respectively. She was ventilated immediately for severe respiratory distress and a UAC was placed in the midthoracic aorta. Her respiratory distress was complicated by bilateral pneumothoraces for which she received chest tubes. On days 5 and 6 she received 3 doses of Indomethacin for a significant PDA. (The PDA later recurred and was surgically ligated.) On day 7, the infant developed a blue discolored and distended abdomen. Abdominal x-rays showed a gasless abdomen with no evidence of pneumatosis intestinalis. Abdominal ultrasound showed no masses or significant fluid collection. Metrizimide gastrointestinal series showed simply delayed transit with no extravasation of dye. Paracentesis produced little fluid, but grew mixed flora and was felt to be a contaminant. Clinically, the infant also exhibited a falling hematocrit, hypotension, thrombocytopenia, and neutrophilia. In view of the negative diagnostic studies, the infant was felt to have a vascular accident rather than intestinal pathology, and the infant was supported medically. The UAC was removed. However, the infant developed a persistently positive blood culture for coagulase-negative staphylococci despite appropriate antibiotics for 2 weeks. She underwent an exploratory laparotomy on day 21 and was found to have an abscess from an old ileal perforation. After abscess drainage, her sepsis cleared. She ultimately did well, tolerated feedings when initiated, and was discharged on day 85.
Case 7 This 860-g infant boy was delivered at 26 weeks’ gestation and had Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. The infant was ventilated for mild to moderate respiratory distress and a UAC was placed in the midthoracic aorta. On day 4 he developed a significant PDA and was given 2 doses of Indomethacin. On day 6 he developed a blue-discolored and distended abdomen. At this time he also experienced a decrease in his hematocrit and thrombocytopenia. Abdominal x-ray was gasless. Antibiotics were restarted; because of continued deterioration, he underwent exploratory laparotomy the next day. He was found to have an isolated
MEYER,
PAYNE, AND ROBACK
ileal perforation with no evidence of NEC according to the surgeon. He tolerated surgery well; however, postoperatively he developed overwhelming Can&da sepsis, renal failure, and an aortic thrombosis. Although the UAC had been removed, it was speculated that the clot had occluded his renal arteries. His renal failure progressed. He developed severe metabolic acidosis, hyperkalemia, and cardiac arrhythmias. He ultimately died of these complications despite maximal therapy. Autopsy was refused. Peritoneal cultures taken at surgery showed 4+ Candida albicans. RESULTS
Review of pathological and surgical findings showed that the perforations occurred in two sites: the terminal ileum (n = 4) or the transverse colon (n = 3). The perforations were described as isolated or “blowout” lesions either at the time of surgery, autopsy, or both. The remaining bowel was occasionally dilated and edematous but without evidence of NEC. Coagulase-negative staphylococci were cultured from blood (n = 5) or peritoneal fluid (n = 1) cultures at the time of diagnosis or surgery in 6 of 7 patients. Four patients died as a result of their intestinal perforation. Two patients died of overwhelming Candida sepsis despite surgical intervention. Due to their severe neurological injury, two additional patients did not receive surgical intervention and died. No late sequelae such as stricture formation or malabsorption were clinically evident in the three survivors. DISCUSSION
We report our experience only in patients with birth weights < 1,000 g because it is these patients in whom the diagnosis is most difficult and in whom surgical intervention is most likely to be delayed. Nonspecific signs of deterioration such as the need for inotropic agents and decreased perfusion were common (Table 1). However, the most characteristic and striking clinical finding was blue discoloration of the skin of the abdominal wall. This abnormality was present in all 7 patients and seemed at surgery to be due to spillage of meconium and blood into the peritoneal cavity. Two other patients had blue abdomens during the study period but were shown to have adrenal hemorrhage in one case and aortic thrombosis with a hematoma of the liver in the other, by abdominal ultrasound. Other clinical signs of intestinal perforation such as abdominal rigidity, tenderness, and erythema were not present. Radiological studies were not useful in identifying the perforation (Table 2) but abdominal ultrasound may serve to eliminate other possible diagnoses as noted previously. Laboratory abnormalities such as thrombocytopenia and decreasing hematocrit were
SPONTANEOUS
PERFORATIONS
717
IN NEONATES
common but not sufficiently specific to point to the diagnosis. Paracentesis, used in 3 patients, was diagnostic in 2 cases and might have been helpful in the third if a lavage had been carried out to obtain sufficient fluid for culture. Our recommendations for every VLBW infant with a blue abdomen are as follows: (1) a complete blood count; (2) abdominal x-ray; (3) abdominal ultrasound; and (4) paracentesis and/or lavage in those infants with unexplained thrombocytopenia and anemia. Histopathologic examination of the tissue immediately surrounding the perforations showed necrosis, ischemic changes, and in some cases localized inflammation. All patients had UACs. The possibility that ischemia caused these perforations is supported by the finding of 4 of 7 perforations in the terminal ileum, an area that receives its blood supply in a “watershed” fashion. However, perforations were also observed in the transverse and descending colon, areas that should have ample blood supply. It might be argued that these perforations are merely a manifestation of NEC.7,8If so, it is a form of NEC that is localized to an extremely small area of the bowel. Pathological specimens did not exhibit the widespread bowel ischemia and necrosis noted in
NEC. Similarly, the clinical signs of NEC such as abdominal tenderness, distention, hematochezia, and pneumatosis intestinalis were absent. Neither the etiology of NEC nor of these isolated intestinal perforations has been identified, and it is possible that the pathophysiology of these two clinically distinct syndromes overlap. This series of patients is similar to those reported by Aschner et al in that the patients were all extremely premature, lacked the usual clinical and radiographic signs of intestinal perforation and NEC, and always had a blue discoloration of the abdominal wa11.6That series of patients and the present series, combined, support the fact that spontaneous, isolated intestinal perforation is a definite clinical entity. A potentially significant difference in the present patients was the very high incidence of coagulasenegative staphylococcal infection. These bacteria may produce a delta-like toxin similar to the delta toxin of Staphylococcus aureus. ’ This coagulase-negative staphylococcal toxin or some other bacterial factor may be associated with NEC.9.10These perforations may be a toxin-mediated process or may simply reflect the most prominent species colonizing the gastrointestinal tract of these infants.
REFERENCES 1. Nagaraj HS, Sandhu AS, Cook LN, et al: Gastrointestinal perforation following indomethacin therapy in very-low-birthweight infants. J Pediatr Surg 16:1003-1007, 1981 2. Alpan G, Eyal F, Vinograd I, et al: Localized intestinal perforation after enteral indomethacin in premature infants. J Pediatr 106:277-281,1985 3. Lloyd JR: The etiology of gastrointestinal newborn. J Pediatr Surg 4:77-84,1969
perforations in the
4. Litwin A, Avidor I, Schujman E, et al: Neonatal intestinal perforation caused by congenital defects of the intestinal musculature. Am J Clin Pathol81:77-80,1984 5. Robbins SL, Keimar V: Pathologic Basis of Disease (ed 4). Philadelphia, PA, Saunders, 1989
6. Aschner JL, Deluga KS, Metlay LA, et al: Spontaneous focal gastrointestinal perforation in very low birth weight infants. J Pediatr 113:364-367,1988 7. Holzman IR, Brown DR: Necrotizing enterocolitis: A complication of prematurity. Semin Perinatol10:208-216. 1986 8. Kliegman RM, Fanaroff AA: Necrotizing enterocolitis. N Engl J Med 310:1093-1103,1984 9. Schiefele DW, Bjornson GL, Dyer RA, et al: Delta-like toxin produced by coagulase-negative staphylococci is associated with neonatal necrotizing enterocolitis. Infect Immun 55:2268-2273, 1987 10. Gruskay JA, Abbasi S, Anday E, et al: .Srqhylococcu.r epidemtis-associated necrotizing enterocolitis. J Pediatr 109:520525,1986
L. Meyer,
Nathaniel
R. Payne,
and Stacy A. Roback
Minneapolis, Minnesota l From January 1986 through December 1988, we have seen 7 cases of isolated intestinal perforation in 250 infants with birth weights < 1,000 g (3% incidence) without histological or clinical evidence of necrotiring enterocolitis (NEC). Patients had a mean birth weight of 670 g, gestational age of 25.1 weeks, and sustained a perforation at a chronological age of 10.4 days. No infants had been fed. A definite, blue-discolored abdomen was the only consistent clinical sign (n = 7). Free intraperitoneal air on radiograms was rarely observed (n = 1). Abdominal ultrasounds (n = 3) and metrizamide contrast studies (n = 3) were not diagnostic. The presence of an umbilical artery catheter (7/7), falling hematocrit (6/7), thrombocytopenia (5/7), and a positive diagnostic paracentesis were most commonly found. In 6 of 7 patients, this perforation was associated with coagulasenegative staphylococcal sepsis. Surgical or histological diagnosis showed focal perforation in either the terminal ileum (n = 4) or the transverse and descending colon (n = 3). Survival was 3 of 7; 2 patients died of intracranial hemorrhage and 2 died of Candida sepsis. We conclude that (1) intestinal perforation can occur in the absence of NEC; (2) bluish discoloration of the abdomen is the most reliable clinical finding; and (3) perforation may be associated with coagulase-negative staphylococcal infection. Copyright o 1991 by W.B. Saunders Company
INDEX WORDS:
Intestinal perforation,
neonatal.
I
NTESTINAL PERFORATION is a life-threatening complication in neonates that can be due to indomethacin therapy,‘,’ intestinal obstruction,3 ischemia,3 congenital defects in the intestinal musculature,4 cytomegalovirus infection (CMV),’ and necrotizing enterocolitis (NEC).738 Spontaneous, isolated intestinal perforation is particularly serious in very low birth weight infants (VLBW)” because diagnosing these perforations is difficult and may delay surgical intervention. Maintaining a high index of suspicion and accepting the paucity of reliable diagnostic signs are the essentials of early diagnosis and surgical treatment of intestinal perforations in VLBW infants. Prevention of these isolated perforations is not possible at this time because the etiology is unknown. We report our experience with seven patients with birth-
From the Departments of Neonatology and Pediattic Surgery, Minneapolis Children’s Medical Center, Minneapolis, MN. Date accepted: September 6, 1990. Address reprint requests to Christopher L. Meyer, MD, cio Stacy A. Roback, MD, Pediatric Surgical Assoc. Ltd, 2545 Chicago Ave. Minneapolis, MN 55404. Copyright o 1991 by WB. Saunders Company 00.X?-3468/91/2606-0017$03.00/0 714
weights < 1,000 g who had spontaneous, isolated perforations of the intestine that were not associated with any known etiologic factor and speculate that they may be related to coagulase-negative staphylococcal infection. CASE
REPORTS
All patients were hospitalized at the Neonatal Intensive Care Unit of Minneapolis Children’s Medical Center and inborn at the adjacent Abbott-Northwestern Hospital Perinatal Center. Patient data are summarized in Tables 1 and 2. The seven patients reported here represent an incidence of 7 of 250 (3%) and were all admitted between January 1,1986 and December 31,1988.
Case 1 This 560-g infant girl was born at 24 weeks’ gestation and had Apgar scores of 2 and 8 at 1 and 5 minutes, respectively. The infant was placed on the ventilator for moderate respiratory distress and an umbilical artery catheter (UAC) was placed in the midthoracic aorta. Over the first week of life she weaned to fairly low ventilator settings. Head ultrasound was normal. A patent ductus arteriosus (PDA) murmur was noted, but it was considered clinically insignificant. Indomethacin was not given. On day 13 the infant developed coagulase-negative staphylococcal sepsis and exhibited leukocystosis, metabolic acidosis, anemia, and thrombocytopenia. Despite antibiotics, she deteriorated. On day 15 she manifested a blue-discolored and mildly distended abdomen. X-rays showed only a gasless abdomen. A metrizimide gastrointestinal contrast study showed simply delayed transit. The baby deteriorated further, developing renal failure and pulmonary failure. By day 20 it was felt that the baby was dying, and that surgical exploration offered the only hope, afthough slim. The baby was found to have peritonitis se$ondary to an apparent spontaneous perforation of the transverse colon; the rest of the bowel was not ischemic. Postoperatively the infant fully decompensated showing profound acidosis and coagulopathy. She died despite maximal therapy. Autopsy was refused. Blood culture also grew Candida albicans postmortem.
Case 2 This 360-g, growth-retarded infant girl was born at 26 weeks’ gestation by emergency cesarean section. She had Apgar scores of 4 and 7 at 1 and 5 minutes, respectively. She was ventilated for severe respiratory distress and a UAC was placed in the midthoracic aorta. The baby stabilized over the first week of life. On day 10, the infant experienced an acute deterioration, needing increased respiratory support. The baby developed a very bluediscolored, distended, tender, and quiet abdomen. X-rays showed simply a gasless abdomen with no evidence of pneumatosis or free air. The infant also developed severe metabolic acidosis, thrombocytopenia, and anemia despite transfusions of packed red blood cells, platelets, and cryoprecipitate. The infant was started on antibiotics and subsequent blood cultures were positive for coagu./ourna/ofPediatric Surgery, Vol26, No 6 (June), 1991: pp 714-717
SPONTANEOUS
PERFORATIONS
715
IN NEONATES
Table 1. Patient Characteristics Coagulasa-Negative
Mean Age
Staphylococci
(d)
PDA
lndocin
lnotropic Agents
560
+
_
+
+
15
360
_
_
_
+
10
Case No.
Mean GA (wk)
Mean BW (g)
1
24
2
26
Midthoracic
UAC
3
26
590
+
+
_
+
8
4
23
620
+
16
24
710
+ _
+
5
+ _
+
+
11
6
26
995
+
+
+
7
7
26
860
+
+
+
+ _
25.1
670
71% (5/7)
57% (4i7)
71% (517)
86% (6/7)
10.4
Total
6
Abbreviations: GA, gestational age; BW, birth weight; UAC, umbilical artery catheter; PDA, patient ductus arteriosus.
In view of the infants’ poor prognosis due to massive intraventricular hemorrhages, aggressive therapy such as laparotomy was not offered. With the parents’ agreement, further support was discontinued and the infant died quickly. Autopsy showed large intraventricular hemorrhages and a perforation of the terminal ileum with peritonitis. The proximal small bowel was dilated but intact. The colon and appendix were unremarkable. Postmortem blood, spinal fluid, and peritoneal cultures were positive for coagulase-negative staphylococci.
staphylococci. The UAC was removed because there was concern that a vascular accident had occurred. Six days later, the infant developed a bulging fontanelle and rapidly increasing head size. Although initial head ultrasounds were normal, a third head ultrasound done at this time showed a massive intraventricular and intraparenchemal hemorrhage. Prognosis was felt to be extremely poor, and the decision was made with the parents to discontinue support of the infant. She died immediately. Autopsy confirmed massive cerebral hemorrhages. The infant also had evidence of CMV infection. Abdominal pathological examination showed meconium peritonitis and an isolated perforation of the transverse colon. The rest of the bowel was intact with no other lesions. Abdominal cultures were positive for coagulasenegative staphylococci. lase-negative
Case 4 This 620-g infant girl was delivered at 23 weeks’ gestation. Apgar scores were 1 and 5 at 1 and 5 minutes, respectively. She was ventilated immediately for severe respiratory distress and a UAC was placed in the midthoracic aorta. On day 5 she was treated with Indomethacin for a significant PDA. However, the medication was unsuccessful and she later had the PDA surgically ligated. On day 9 the infant developed a slightly bluish discoloration of her abdomen. X-rays showed simply a gasless abdomen with no pneumatosis or free air. Abdominal ultrasound was negative as well. Over the next 6 days the abdomen became more distended and blue. The infant also exhibited decreasing hematocrit and thrombocytopenia. On day 16, abdominal paracentesis showed stool and coagulase-negative staphylococci. The infant underwent laparotomy and was found to have a perforation of the midtransverse colon and meconium peritonitis. A section of colon was removed and a colostomy was made. The small bowel was completely normal. The infant tolerated surgery well. Six days postoperatively the infant had a wound dehiscence and had another operation to recreate a new stoma. She ultimately did well and was discharged on day 153.
Case 3 This 590-g infant girl was delivered at 26 weeks’ gestation by cesarean section. She was growth-retarded and the second of twins. Apgar scores were 3 and? at 1 and 5 minutes, respectively. She was ventilated immediately for severe respiratory distress and a UAC was placed in the midthoracic aorta. She improved in her respiratory status until 5 days of age, when she developed a PDA. Initially the use of indomethacin was deferred because the infant had developed a grade III to IV intraventricular hemorrhage on the right. The intraventricular hemorrhage ultimately progressed to grade IV hemorrhages bilaterally. Because of deteriorating pulmonary status, one dose of indomethacin was later given. Subsequently, the infant developed an upper gastrointestinal hemorrhage with a bright red blood per nasogastric tube. This resolved with suction and intermittent Maalox therapy. On day 7, she developed a blue-discolored and distended abdomen. She became neutropenic and acidotic. Antibiotics were restarted. Over the next 2 days, the abdominal distension progressed to obvious perforation; as evidence by free air observed on x-ray.
Case 5 This 710-g infant boy was born at 24 weeks‘ gestation and had Apgar scores of 4 and 8 at 1 and 5 minutes, respectively. A UAC
Table 2. Patient Signs and Diagnostic Studies Falling Case No.
Blue Abdomen
Elevated WBC
Thrombocytopenia
Hematocrit
Free Air
Positive GI
Positive Abdominal
Positive
(x-we.)
Series
Ultrasound
Paracentesis ND
1
+
+
+
+
_
ND
2
+
+
+
+
_
ND
ND
ND
3
+
_
_
_
+
ND
ND
ND
4
+
_
+
+
ND
_
t
5
t
_
_
t
_
6
t
t
t
+
_
7
+
_
t
+
_
ND
ND
ND
Total
100% (7/7)
43% (3/7)
71% (5/7)
86% (6/7)
14% (l/7)
0
0
66% (2/3)
Abbreviations: WBC, white blood cells; GI, gastrointestinal: ND, not done.
_
_ +
716
was placed in the midthoracic aorta and mechanical ventilation was initiated for moderately severe respiratory distress. He did well, weaning to modest ventilator settings without developing clinical signs of a PDA until day 9 when he experienced a significant deterioration. He required increased ventilator support, inotropic agents, and received antibiotics after cultures of the blood, urine, and cerebrospinal fluid were obtained. The blood culture grew coagulase-negative staphylococci. On day 11, 2 days after the sudden deterioration, he developed a blue, discolored abdomen without distention and with minimal tenderness. Although his hematocrit decreased from 45% to 35%, his white blood cell count, platelet count, and base excess were normal. Abdominal x-rays showed a gasless abdomen and the abdominal ultrasound was negative for fluid or masses. Abdominal paracentesis was performed but did not yield any fluid. Metrizamide contrast study of the gastrointestinal tract was performed but showed only a slow transit time and no obvious obstruction or extraluminal contrast material. Because the infant failed to improve, an exploratory laparotomy was performed on day 13. He was found to have a moderate amount of blood mixed with meconium in the peritoneal cavity. The bowel was normal except for an isolated perforation in the terminal ileum. This perforation was exteriorized to create an ileostomy. The infant tolerated surgery well and was discharged on day 130.
Case 6 This 995-g infant girl was delivered at 26 weeks’ gestation and had Apgar scores of 4 and 7 at 1 and 5 minutes, respectively. She was ventilated immediately for severe respiratory distress and a UAC was placed in the midthoracic aorta. Her respiratory distress was complicated by bilateral pneumothoraces for which she received chest tubes. On days 5 and 6 she received 3 doses of Indomethacin for a significant PDA. (The PDA later recurred and was surgically ligated.) On day 7, the infant developed a blue discolored and distended abdomen. Abdominal x-rays showed a gasless abdomen with no evidence of pneumatosis intestinalis. Abdominal ultrasound showed no masses or significant fluid collection. Metrizimide gastrointestinal series showed simply delayed transit with no extravasation of dye. Paracentesis produced little fluid, but grew mixed flora and was felt to be a contaminant. Clinically, the infant also exhibited a falling hematocrit, hypotension, thrombocytopenia, and neutrophilia. In view of the negative diagnostic studies, the infant was felt to have a vascular accident rather than intestinal pathology, and the infant was supported medically. The UAC was removed. However, the infant developed a persistently positive blood culture for coagulase-negative staphylococci despite appropriate antibiotics for 2 weeks. She underwent an exploratory laparotomy on day 21 and was found to have an abscess from an old ileal perforation. After abscess drainage, her sepsis cleared. She ultimately did well, tolerated feedings when initiated, and was discharged on day 85.
Case 7 This 860-g infant boy was delivered at 26 weeks’ gestation and had Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. The infant was ventilated for mild to moderate respiratory distress and a UAC was placed in the midthoracic aorta. On day 4 he developed a significant PDA and was given 2 doses of Indomethacin. On day 6 he developed a blue-discolored and distended abdomen. At this time he also experienced a decrease in his hematocrit and thrombocytopenia. Abdominal x-ray was gasless. Antibiotics were restarted; because of continued deterioration, he underwent exploratory laparotomy the next day. He was found to have an isolated
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ileal perforation with no evidence of NEC according to the surgeon. He tolerated surgery well; however, postoperatively he developed overwhelming Can&da sepsis, renal failure, and an aortic thrombosis. Although the UAC had been removed, it was speculated that the clot had occluded his renal arteries. His renal failure progressed. He developed severe metabolic acidosis, hyperkalemia, and cardiac arrhythmias. He ultimately died of these complications despite maximal therapy. Autopsy was refused. Peritoneal cultures taken at surgery showed 4+ Candida albicans. RESULTS
Review of pathological and surgical findings showed that the perforations occurred in two sites: the terminal ileum (n = 4) or the transverse colon (n = 3). The perforations were described as isolated or “blowout” lesions either at the time of surgery, autopsy, or both. The remaining bowel was occasionally dilated and edematous but without evidence of NEC. Coagulase-negative staphylococci were cultured from blood (n = 5) or peritoneal fluid (n = 1) cultures at the time of diagnosis or surgery in 6 of 7 patients. Four patients died as a result of their intestinal perforation. Two patients died of overwhelming Candida sepsis despite surgical intervention. Due to their severe neurological injury, two additional patients did not receive surgical intervention and died. No late sequelae such as stricture formation or malabsorption were clinically evident in the three survivors. DISCUSSION
We report our experience only in patients with birth weights < 1,000 g because it is these patients in whom the diagnosis is most difficult and in whom surgical intervention is most likely to be delayed. Nonspecific signs of deterioration such as the need for inotropic agents and decreased perfusion were common (Table 1). However, the most characteristic and striking clinical finding was blue discoloration of the skin of the abdominal wall. This abnormality was present in all 7 patients and seemed at surgery to be due to spillage of meconium and blood into the peritoneal cavity. Two other patients had blue abdomens during the study period but were shown to have adrenal hemorrhage in one case and aortic thrombosis with a hematoma of the liver in the other, by abdominal ultrasound. Other clinical signs of intestinal perforation such as abdominal rigidity, tenderness, and erythema were not present. Radiological studies were not useful in identifying the perforation (Table 2) but abdominal ultrasound may serve to eliminate other possible diagnoses as noted previously. Laboratory abnormalities such as thrombocytopenia and decreasing hematocrit were
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common but not sufficiently specific to point to the diagnosis. Paracentesis, used in 3 patients, was diagnostic in 2 cases and might have been helpful in the third if a lavage had been carried out to obtain sufficient fluid for culture. Our recommendations for every VLBW infant with a blue abdomen are as follows: (1) a complete blood count; (2) abdominal x-ray; (3) abdominal ultrasound; and (4) paracentesis and/or lavage in those infants with unexplained thrombocytopenia and anemia. Histopathologic examination of the tissue immediately surrounding the perforations showed necrosis, ischemic changes, and in some cases localized inflammation. All patients had UACs. The possibility that ischemia caused these perforations is supported by the finding of 4 of 7 perforations in the terminal ileum, an area that receives its blood supply in a “watershed” fashion. However, perforations were also observed in the transverse and descending colon, areas that should have ample blood supply. It might be argued that these perforations are merely a manifestation of NEC.7,8If so, it is a form of NEC that is localized to an extremely small area of the bowel. Pathological specimens did not exhibit the widespread bowel ischemia and necrosis noted in
NEC. Similarly, the clinical signs of NEC such as abdominal tenderness, distention, hematochezia, and pneumatosis intestinalis were absent. Neither the etiology of NEC nor of these isolated intestinal perforations has been identified, and it is possible that the pathophysiology of these two clinically distinct syndromes overlap. This series of patients is similar to those reported by Aschner et al in that the patients were all extremely premature, lacked the usual clinical and radiographic signs of intestinal perforation and NEC, and always had a blue discoloration of the abdominal wa11.6That series of patients and the present series, combined, support the fact that spontaneous, isolated intestinal perforation is a definite clinical entity. A potentially significant difference in the present patients was the very high incidence of coagulasenegative staphylococcal infection. These bacteria may produce a delta-like toxin similar to the delta toxin of Staphylococcus aureus. ’ This coagulase-negative staphylococcal toxin or some other bacterial factor may be associated with NEC.9.10These perforations may be a toxin-mediated process or may simply reflect the most prominent species colonizing the gastrointestinal tract of these infants.
REFERENCES 1. Nagaraj HS, Sandhu AS, Cook LN, et al: Gastrointestinal perforation following indomethacin therapy in very-low-birthweight infants. J Pediatr Surg 16:1003-1007, 1981 2. Alpan G, Eyal F, Vinograd I, et al: Localized intestinal perforation after enteral indomethacin in premature infants. J Pediatr 106:277-281,1985 3. Lloyd JR: The etiology of gastrointestinal newborn. J Pediatr Surg 4:77-84,1969
perforations in the
4. Litwin A, Avidor I, Schujman E, et al: Neonatal intestinal perforation caused by congenital defects of the intestinal musculature. Am J Clin Pathol81:77-80,1984 5. Robbins SL, Keimar V: Pathologic Basis of Disease (ed 4). Philadelphia, PA, Saunders, 1989
6. Aschner JL, Deluga KS, Metlay LA, et al: Spontaneous focal gastrointestinal perforation in very low birth weight infants. J Pediatr 113:364-367,1988 7. Holzman IR, Brown DR: Necrotizing enterocolitis: A complication of prematurity. Semin Perinatol10:208-216. 1986 8. Kliegman RM, Fanaroff AA: Necrotizing enterocolitis. N Engl J Med 310:1093-1103,1984 9. Schiefele DW, Bjornson GL, Dyer RA, et al: Delta-like toxin produced by coagulase-negative staphylococci is associated with neonatal necrotizing enterocolitis. Infect Immun 55:2268-2273, 1987 10. Gruskay JA, Abbasi S, Anday E, et al: .Srqhylococcu.r epidemtis-associated necrotizing enterocolitis. J Pediatr 109:520525,1986
