Meconium Disease Flashcards

Question

How does cystic fibrosis result in meconium disease?

Answer 1

Cystic fibrosis is thought to result in abnormally thick, viscid, tenacious meconium by two mechanisms: 1) a pancreatic exocrine enzyme deficiency and, 2) more importantly, secretion of hyperviscous mucus by abnormal intestinal glands.

Answer 2

Obstruction begins in utero and typically occurs in the mid- to distal ileum. Bowel begins to dilate and thicken and may be seen as echogenic bowel on fetal ultrasound.

Answer 3

Polyhydramnios may be seen in approximately 20% of cases of meconium ileus. Echogenic bowel may be a transient finding in many normal fetuses, with no implications. However, if echogenic bowel is persistent or seen in combination with bowel dilatation, polyhydramnios, calcifications, absence of the gallbladder, or a cystic abdominal mass, screening the parents for the cystic fibrosis gene should be offered, if not done routinely. The fetal diagnosis of cystic fibrosis can also be established by genetic testing of fetal cells obtained from amniocentesis or chorionic villus sampling.

Answer 4

The obstruction may manifest early, and the baby may in fact be born with distended loops that are palpable with a doughy consistency on physical examination.

Answer 5

Abdominal films will typically show distended loops without air-fluid levels, as the “fluid” is replaced by thick meconium that does not layer out. Plain films shows a distal obstruction with multiple distended loops but absence of air-fluid levels. A water-soluble contrast enema shows a microcolon with multiple filling defects in the distal small bowel. A contrast enema may be diagnostic and therapeutic, if it succeeds in dislodging the thick meconium and relieving the obstruction. Classically, the enema was done with hyperosmotic gastrografin contrast to encourage fluid exudation into the bowel lumen. However, due to concern for major fluid shifts with this contrast agent, most radiologists now use iso-osmotic water-soluble contrast. This may have actually resulted in the lower therapeutic success rates reported in more recent studies. If the patient remains stable, the enema may be repeated up to three times at daily intervals. The mucolytic agent, N-acetylcysteine, can be added to the contrast agent, although there is no strong evidence that this actually improves success rates. Failure of the enemas to succeed in relieving the obstruction or any signs of worsening obstruction or clinical deterioration should prompt the surgeon to proceed with laparotomy.

Answer 6

Once bowel function returns in cases of meconium ileus, patients are typically placed on supplemental pancreatic enzymes. If not already made by prenatal testing, the diagnosis of cystic fibrosis should be confirmed. A sweat chloride test with a chloride level more than 60 mmol/L is diagnostic of cystic fibrosis. However, the test requires the collection of 100 mg of sweat, which is possible only at a few weeks of age. Presently, the diagnosis is typically established earlier by genetic analysis. All laboratories test for the F508del, which is responsible for approximately 75% of cases of cystic fibrosis. A number of other mutations are also usually tested for using population characteristics, yielding a false-negative rate below 10% in most cases. At discharge, follow-up should be arranged in a multidisciplinary cystic fibrosis clinic. A sweat chloride test should be done at 6–8 weeks of age if genetic testing was negative. it is important to understand that meconium peritonitis does not immediately imply a complicated meconium ileus. In fact, cystic fibrosis is responsible for less than one-third of cases of meconium peritonitis, with other obstructive etiologies or idiopathic intestinal perforation responsible for the remainder.

Answer 7

Meconium plug syndrome is distinctly different from meconium ileus. The obstruction is usually in the proximal or transverse colon due to a long, serpentine-like meconium plug that can extend from the rectosigmoid junction to the splenic flexure. Operative intervention is rarely required for this anomaly, as the baby almost always passes the meconium plug during or immediately after a water-soluble contrast enema. The syndrome was traditionally thought to affect mostly infants of diabetic mothers, but more recent evidence shows a much lower association with maternal diabetes. Cystic fibrosis is also rarely associated with this syndrome, and routine testing of these infants for cystic fibrosis is not necessary if the obstruction is quickly relieved. There is also concern for Hirschsprung’s disease, which may occur in 10%–15% of patients with meconium plug syndrome. Some have recommended a rectal biopsy in all patients with meconium plug syndrome, but clearly this will be negative in the majority of patients. I typically biopsy patients who do not immediately recover following the contrast enema or who show any residual or recurrent signs of intestinal obstruction on close follow-up.

Answer 8

Small left colon syndrome is a rare cause of neonatal distal intestinal obstruction, with no clear etiology. The clinical presentation closely mimics meconium plug syndrome. The contrast enema may raise concern for Hirschsprung’s disease with a transition zone in the distal transverse or proximal descending colon. However, in these cases, the rectosigmoid is typically larger than the descending colon, which is not consistent with Hirschsprung’s. Like meconium plug syndrome, the obstruction is typically immediately relieved by a contrast enema. Again, if any concern persists, a suction rectal biopsy should be performed.

Answer 9

A meconium obstruction syndrome particular to premature, extremely low birth weight neonates, has been well defined in recent years and is best called meconium obstruction of prematurity. Like meconium ileus, the obstruction is typically in the distal ileum. However, the syndrome has no association with cystic fibrosis. In addition, the obstruction in these babies is usually due to a discrete ileal meconium plug and not the thick, tenacious meconium seen in meconium ileus. The obstruction typically presents during the first week of life in a premature neonate who experiences perinatal stress, such as preeclampsia, tocolysis with magnesium sulfate, premature rupture of membranes, or stat C-section. Uniform distention of bowel loops is seen with no air-fluid levels. Diagnosis does not require contrast studies and can be made using abdominal films in the appropriate clinical context. Although the obstruction is almost always benign at onset, cases of intussusception, perforation, and gangrene have been reported. Treatment can be instituted in an escalating manner, starting with rectal irrigations and prograde N-acetylcysteine administered by nasogastric tube, followed by therapeutic contrast enemas, followed by surgical exploration if the obstruction is persistent or becomes complicated. In non-complicated cases, an enterotomy proximal to the obstruction and gentle evacuation of the meconium plug with warm saline irrigation is enough. If perforation or gangrene has occurred, bowel resection will be necessary. (Figure 33.9 shows a patient who responded to medical treatment with 10 mL/kg warm saline irrigations every 4 hours and 1 mL of 10% N-acetylcysteine solution by nasogastric tube every 6 hours. Figure 33.10 shows a patient who underwent surgical treatment for persistent obstruction, not responding to irrigation, N-acetylcysteine, or contrast enema.)

Answer 10

The surgeon should be aware that any mechanical or functional obstructive syndrome can produce inspissated meconium consisting of thick, discrete, meconium pellets resembling rabbit droppings. This is often erroneously described as meconium ileus and may lead to an incorrect diagnosis and intervention. The surgeon should therefore question the diagnosis of meconium ileus if this type of meconium is encountered, and specifically if it is encountered in the jejunum or proximal ileum. (An example is shown in Figure 33.11. A proximal jejunal obstruction was found with luminal patency but complete occlusion of the distal bowel with hundreds of these meconium pellets. The patient had near-total intestinal Hirschsprung’s disease, sparing only 20 cm of jejunum.)

Answer 11

Meconium ileus (MI) is one of the most common causes of intestinal obstruction in the newborn, accounting for 9–33% of neonatal intestinal obstructions. It is characterized by extremely viscid, protein-rich, inspissated meconium causing an intraluminal obstruction in the distal ileum, usually at the ileocecal valve. It is often the earliest clinical manifestation of cystic fibrosis (CF), occurring in approximately 16% of patients with CF. Although MI can occur with other uncommon conditions such as pancreatic aplasia and total colonic aganglionosis, it is often considered pathognomonic for CF. MI may be an early indication of a more severe phenotype of CF, as suggested by significantly diminished pulmonary function found in children with a history of MI compared with age- and gendermatched children with CF who did not have MI.

Answer 12

Due to abnormalities of exocrine mucous secretion and pancreatic enzyme deficiency, the meconium in MI differs from normal meconium. Meconium in MI has less water content (65% vs 75%) when compared with normal meconium, lower sucrase and lactase levels, increased albumin, and decreased pancreatic enzymes. Additionally, concentrations of sodium, potassium, magnesium, heavy metals, and carbohydrates in MI meconium are reduced in CF with or without MI. Concentrations of protein nitrogen are increased and composed of abnormal mucoproteins. Therefore, more viscous intestinal mucous in the absence of degrading enzymes results in thick, dehydrated meconium that obstructs the intestine.

Answer 13

In 1989, the CF locus was localized through linkage analysis to human chromosome 7q31, and it was discovered that mutations in the CF transmembrane (conductance) regulator (CFTR) gene result in CF. The cell membrane protein coded by CFTR is a 3′-5′-cyclic adenosine monophosphate (cAMP)-induced chloride channel, which also regulates the flow of other ions across the apical surface of epithelial cells. The alteration in CFTR results in an abnormal electrolyte content in the environment external to the apical surface of epithelial membranes. This leads to desiccation and reduced clearance of secretions from tubular structures lined by affected epithelia. The most common mutation of the CFTR gene, F508del (previously known as ΔF508), is a three-base-pair deletion that results in the removal of a phenylalanine residue at amino acid position 508 of the CFTR. Although there are currently 2012 mutations listed in the CFTR database, the F508del mutation is responsible for approximately 70% of abnormal CF genes. In families with MI, there is a significantly higher occurrence rate than the expected 25% for an autosomal recessive genetic disorder according to Mendelian genetics. In one series, 79% of CF patients with the F508del mutation presented with abdominal complaints (including MI) rather than pulmonary complaints. However, there is no evidence of distinct allelic frequencies or haplotypic variants in CF patients with MI compared with those without, or in CF patients with significant liver disease.

Answer 14

CF is characterized by mucoviscidosis of exocrine secretions throughout the body resulting from abnormal transport of chloride ions across apical membranes of epithelial cells via calcium-activated chloride channels. The role of intracellular Ca 2+ concentration on these channels may impact the pathophysiology of CF. Abnormal bicarbonate transport also affects mucin formation in CF. The clinical result is chronic obstruction and infection of the respiratory tract, insufficiency of the exocrine pancreas, and elevated sweat chloride levels. Other clinical variants, such as patients with chronic sinusitis or adult males with congenital bilateral absence of the vas deferens (CBAVD), who typically have little other clinical involvement, have been described (Fig. 32.2). In patients with CBAVD, the CFTR genotype usually includes at least one mild mutation not typical of CF patients. The mild-mutation allele is frequently associated with a severe mutation on the other allele, such as the F508del mutation. CBAVD has been described in a patient with F508del and G551D mutations, both of which were categorized as severe. The allele G551D is the third most common CF-associated mutation, and patients affected by this mutation may have pancreatic insufficiency, pulmonary symptoms, and an episode of MI equivalent, indicating CBAVD may be associated with a more severe CF phenotype. Development of both the pancreas and intestinal tract in fetuses with CF is abnormal. In patients with CF, abnormal pancreatic secretions obstruct the ductal system leading to autodigestion of the acinar cells, fatty replacement of pancreatic parenchyma, and fibrosis. Although this process begins in utero, it occurs variably over time. Regardless, pancreatic insufficiency is prevalent in young infants with CF and has a significant impact on growth and nutrition. Pancreatic insufficiency plays a central role in the pathogenesis of MI. Congenital stenosis of the pancreatic ducts is associated with meconium-induced bowel obstruction. This is further supported by the fact that two-thirds of infants found to have CF by neonatal screening are pancreatic insufficient at birth. However, approximately 10% of patients with CF are pancreatic sufficient and tend to have a milder course. Also, pancreatic lesions are variable at birth and become more severe in CF children older than 1 year of age. This finding suggests that pancreatic insufficiency is not the leading cause of abnormal meconium in MI. It appears that a prevalence of intestinal glandular abnormalities contribute more significantly to the production of abnormal meconium. The lack of concordance between MI and the severity of pancreatic disease and the preponderance of intestinal glandular lesions implies that intraluminal intestinal factors contribute more to the development of MI than the absence of pancreatic secretions. Abnormal intestinal motility may also contribute to the development of MI. Some patients with CF have prolonged small intestinal transit times. Also, the CFTR ion channel defect results in an exocrine secretion that is rich in sodium and chloride that can lead to further dehydration of the intraluminal contents, resulting in impaired clearance. Non-CF diseases associated with abnormal gut motility, such as Hirschsprung disease and chronic intestinal pseudoobstruction, have been associated with MI-like disease, signifying that decreased peristalsis may allow for increased reabsorption of water thus favoring the development of abnormal meconium. One of the authors recently cared for a patient with MI and no genetic nor clinical diagnosis of CF. Although rare, this has been described.

Answer 15

The antenatal diagnosis of MI can be made in two different groups: a high-risk group and a low-risk group. In the low-risk group, the diagnosis is suspected when the sonographic appearances of MI are found on routine prenatal ultrasound (US) in a mother with a negative CF carrier screen. Sonographic findings consistent with MI in a fetus with parents who are known carriers of CF, and pregnancies subsequent to the birth of a CF-affected child, are considered high-risk. CF was associated with increased relative risk (95% CI) of 3.5 (2.5–4.9), 1.6 (1.1–2.4), 3.0 (2.2–4.0), and 6.8 (1.7–26.5) for low birth weight (LBW) neonates, small-for-gestational-age (SGA) neonates, preterm birth, and infant death, respectively. Parents of a child with CF are considered to be obligate carriers of a CF mutation. An algorithm has been established that may be useful in decision making and management of the fetus suspected of having MI. The algorithm has been updated to include newer recommendations discussed below. If both parents are carriers, evaluation of the fetus should be made by chorionic villus sampling or amniocentesis. In a pregnancy where CF is suspected, sonographic examinations are performed monthly until delivery. This evaluation allows the early detection of potential complications and prepares the clinicians for special or urgent medical or surgical needs on delivery.

Answer 16

Sonographic characteristics associated with MI include a hyperechoic, intra-abdominal mass (inspissated meconium), dilated bowel, and nonvisualization of the gallbladder. Normal fetal meconium, when visualized in the second and third trimesters, is usually hypoechoic or isoechoic to adjacent abdominal structures. The sensitivity of intra-abdominal echogenic masses in the detection of MI/CF is reported to be between 30% and 70%. In addition to MI, hyperechoic bowel has been reported with Down syndrome, intrauterine growth retardation, prematurity, in utero cytomegalovirus infection, intestinal atresia, abruptio placenta, and fetal demise. The importance of hyperechoic fetal bowel is related to gestational age at detection, ascites, calcification, volume of amniotic fluid, and the presence of other fetal anomalies. The positive predictive value of hyperechoic masses in a high-risk fetus is estimated to be 52%, but is only 6.4% in the low-risk fetus. It is important to note that hyperechoic bowel has been found to be a normal variant in both the second and third trimesters. The finding of dilated bowel on prenatal US, in association with a family history of CF, has been reported less frequently than that of hyperechoic bowel. In MI, bowel dilation is caused by obstruction from meconium, but mimics findings in midgut volvulus, congenital bands, intestinal atresia, intestinal duplication, internal hernia, meconium plug syndrome, and Hirschsprung disease. The correlation of dilated fetal bowel and MI suggests that dilated fetal bowel warrants parental testing for CF and continued sonographic surveillance of the fetus. The inability to visualize the gallbladder on fetal US has also been associated with CF. Combined with other sonographic features, nonvisualization of the gallbladder can be useful in the prenatal detection of the disease. However, caution should be exercised in the interpretation of an absent gallbladder as the differential diagnosis also includes biliary atresia, omphalocele, diaphragmatic hernia, chromosomal abnormalities, and a normal pregnancy. Recently magnetic resonance imaging (MRI) was compared with US and found to provide useful additional information regarding meconium distribution in the small bowel helping to clarify the level of obstruction. MRI was additionally useful in the assessment of colon and rectal contents, serving as essentially a “fetal enema.” Abnormally diminished meconium in the rectum suggested CF or combined small-bowel and colonic obstruction, information that was useful in parenteral counseling and preparation for postnatal care. — Simple MI is characterized by a pattern of unevenly dilated loops of bowel on an abdominal radiograph with the variable presence of air–fluid levels. The absence of air–fluid levels is due to the viscosity of the meconium not allowing an air interface with the fluid. As swallowed air mixes with the tenacious meconium, bubbles of gas may be seen. This soap bubble or ground-glass appearance depends on the viscosity of the meconium and is not a constant feature. While each of these features alone is not diagnostic of MI, collectively with a family history of CF, they strongly suggest the diagnosis. Radiographic findings in complicated MI vary with the complication. Prenatal US findings include ascites, intraabdominal cystic masses, dilated bowel, and calcification. Neonatal radiographs may show peritoneal calcifications, free air, and/or air–fluid levels (related to atresia). Airfluid levels may be minimally present or absent, misleading the clinician to make an incorrect diagnosis of uncomplicated meconium ileus. Speckled calcification on abdominal plain films is highly suggestive of intrauterine intestinal perforation and meconium peritonitis. Radiographic findings of obstruction and a large dense mass with a rim of calcification imply a pseudocyst. These calcium deposits are linear and course along the parietal peritoneum and serosal surface of the visceral organs. Interestingly, one-third of cases of complicated MI have no radiologic findings that suggest a complication. A contrast enema should be performed in all cases of low intestinal obstruction in the newborn. We advocate an initial water-soluble contrast enema for both diagnosis and treatment. In MI, contrast instillation is monitored fluoroscopically and demonstrates a colon of small caliber, described as the “microcolon of disuse,” often containing small, inspissated rabbit pellets (scybala) of meconium. The enema also identifies cecal position, indicating whether malrotation is present. In complicated cases, such as atresia, a microcolon with reflux into a decompressed terminal ileum may be noted. If contrast cannot be refluxed into the dilated small bowel, operative exploration is required for diagnosis and therapy.

Answer 17

The thickened meconium begins to form in utero. As it obstructs the mid-ileum, proximal bowel dilatation and thickening along with congestion occur. Approximately one-half of these neonates present with simple uncomplicated obstruction. The remaining patients present with complications of MI, including volvulus, gangrene, atresia, and/or perforation, which may result in meconium peritonitis and giant cystic meconium peritonitis.

Answer 18

In simple MI, the terminal ileum is filled with firm concretions. The bowel in this area is small in diameter and molds around the inspissated lumps of meconium. The ileum becomes dilated and is filled with thick sticky meconium with gas and fluid found within the small bowel proximal to this area. Newborns with uncomplicated MI often appear healthy immediately after birth. However, within 1–2 days, they develop abdominal distension and bilious emesis. Normal meconium will not be passed. Eventually, dilated loops of bowel become visible on exam and have a “doughy” character that indent on palpation. The rectum and anus are often narrow, a finding that may be misinterpreted as anal stenosis. The presentation of the baby with MI is similar to many types of neonatal small bowel obstruction. Therefore, the clinician should simultaneously consider malrotation, small intestinal atresia, colonic atresia, and meconium plug syndrome. The history, physical examination, and contrast enema help distinguish between these entities.

Answer 19

Infants with complicated MI present with symptoms within 24 hours of birth. Some newborns are symptomatic immediately after birth as a result of in utero perforation or bowel compromise. Signs of peritonitis, including distension, tenderness, abdominal wall edema and erythema, and clinical evidence of sepsis, may be found on the initial neonatal exam. Abdominal distension can be so severe as to cause immediate respiratory distress. A palpable mass suggests pseudocyst formation, which results from in utero bowel perforation. The neonate may present in extremis and need urgent resuscitation and operative exploration. Historically, segmental volvulus was reported to be the most common complication of MI. Prenatal volvulus of the meconium-distended segment of ileum may lead to interruption of the mesenteric blood flow and results in ischemic necrosis, intestinal atresia with an associated mesenteric defect, or perforation. When an in utero perforation occurs, most of the sterile meconium is reabsorbed with trace amounts becoming calcified. Atretic segments are common in MI, and the affected bowel may appear viable, showing no evidence of perforation or gangrene. Twelve percent to 17% of neonates born with jejunoileal atresia have CF. Therefore, all neonates with jejunoileal atresia and an abnormal meconium presentation (MI, meconium plug syndrome, giant cystic meconium peritonitis, etc.) should undergo testing for CF. The incidence of CF in neonates with meconium peritonitis is reported to be 15–40%. Four types of meconium peritonitis have been recognized including: 1) adhesive meconium peritonitis 2) giant cystic meconium peritonitis or pseudocyst 3) meconium ascites, and 4) infected meconium peritonitis. In addition to MI, other causes of in utero bowel perforation must also be considered (atresia, stenosis, colonic disorders, imperforate anus) in this clinical setting. The differences in clinical presentation are secondary to the timing of the perforation and whether or not the perforation sealed spontaneously. The site of perforation is usually closed by birth. Not surprisingly, mortality is increased in cases where the perforation remains open. Initially, meconium peritonitis is a nonbacterial, chemical, and foreign body peritonitis occurring during gestation. As meconium escapes the obstructed bowel, a sterile chemical peritonitis ensues. After delivery, bacterial superinfection may occur with colonization of the gastrointestinal tract. It is important to note that meconium peritonitis may also occur without MI and is not pathognomonic for CF.

Answer 20

Diagnosis of CF requires two clinical indicators of CF and an objective measure of CFTR dysfunction. The three options for this are abnormal sweat chloride, two identified disease-causing CFTR mutations, or nasal potential difference testing consistent with CF. However, sweat testing remains the gold standard, and most CF centers will not diagnose CF without sweat testing. There is a “rule of 2s” with respect to sweat testing: 32 weeks EGA, 2 weeks chronologic age, and 2 kg to increase the likelihood of a successful sweat test. Many centers use a 3-kg weight, however. In most newborn infants sweat testing is done between 2 and 4 weeks of age. A sodium concentration of 60 mmol/L in 100 mg of sweat is diagnostic of CF, with 40–60 mmol/L being intermediate (but more likely to be diagnostic in infants) and <40 mmol/L being normal. The test is typically performed at several weeks of life to obtain an adequate sample size. Neonatal CF screening programs using the Guthrie blood spot test for raised concentrations of immunoreactive trypsinogen is available in many countries, but must be confirmed in a two-stage approach incorporating CFTR mutation analysis. Genetic testing for CFTR mutations is available; however, commercial assays test for a limited number of mutations. Most regional laboratories will provide the results for the four or five most common mutations for the relevant ethnic group or geographic region in their area using the amplification refractory mutation system (ARMS) technique. Stool analyses for albumin, trypsin, and chymotrypsin are available, and abnormal values coupled with the operative findings suggest CF.

Answer 21

Neonates should initially be managed as any other newborn with intestinal obstruction. This management should include volume resuscitation and ventilator support as necessary. Gastric decompression to prevent progressive abdominal distension, aspiration, and pulmonary compromise is important. In addition, correction of any coagulation disorders and empiric broad-spectrum antibiotic coverage should be initiated. The majority of newborns with MI can be managed nonoperatively. As noted earlier, the initial management should include an isotonic water-soluble contrast enema under fluoroscopic control. The water-soluble enema will also exclude other causes of neonatal intestinal obstruction. Prior to performing the water soluble enema, the neonate should receive adequate intravenous fluid to correct and avoid hypovolemia, receive appropriate electrolyte repletion, and be normothermic. Under fluoroscopic control, the water-soluble contrast material is slowly infused at a low hydrostatic pressure through a catheter inserted into the rectum. Inflation of the catheter balloon should be avoided to minimize the risk of perforation. On completion, the catheter is withdrawn and an abdominal radiograph is obtained to evaluate for perforation. The infant is then returned to the NICU for intensive monitoring and fluid resuscitation. Usually there is rapid passage of meconium pellets followed by semiliquid meconium, which continues in the ensuing 24–48 hours. On instillation of the enema, extraluminal fluid is drawn into the intestinal lumen, hydrating and softening the meconium mass. Warm saline enemas containing 1% N-acetylcysteine (Mucomyst; Apothecon, Princeton, NJ) may be given to help complete the evacuation. Radiographs should be obtained as clinically indicated to confirm evacuation of the obstruction and to exclude late perforation. If evacuation is incomplete, or if the first attempt at contrast enema evacuation does not reflux contrast into dilated bowel, a second enema may be necessary. However, if progressive distension, signs of peritonitis, or clinical deterioration occur, operative exploration is indicated. After two failed attempts at nonoperative watersoluble enemas, operative intervention is likely warranted. Following successful evacuation and resuscitation, 5 mL of a 10% N-acetylcysteine solution may be administered every 6 hours through a nasogastric tube to liquefy the upper gastrointestinal secretions. Feedings with supplemental pancreatic enzymes for those infants confirmed with CF may be initiated when signs of obstruction have subsided. In the past, the success rate of patients with uncomplicated MI, treated with Gastrografin enemas, has ranged between 63% and 83%. However, more recent reports indicate a much lower success rate likely secondary to the use of isotonic enema fluid. Several potential complications exist with the use of enemas in treating MI. The risk of rectal perforation can be avoided by careful placement of the catheter under fluoroscopic guidance and by not inflating the balloon-tipped catheter. A 23% perforation rate has been reported in patients when inflated balloon catheters were used, and the risk of perforation increases with repeated enemas. Late perforation, occurring between 12 and 48 hours following the enema, can occur as well. Potential causes for late perforation include severe bowel distension by fluid osmotically drawn into the intestine or by injury to the bowel mucosa by the contrast medium. Lower perforation rates have been reported more recently, possibly related to less aggressive enema attempts and isotonic enema agents. Hypovolemic shock is a risk when delivering hypertonic enemas. Ischemia caused by overdistension is worsened by hypoperfusion caused by hypovolemia due to inadequate fluid resuscitation.

Answer 22

The indications for operative management in patients with simple MI are inadequate meconium evacuation or a complication from the contrast enema (e.g., perforation). Failure of nonoperative treatment with the contrast enema may result from the inability to advance the column of enema fluid into the ileum or from an unsuspected associated intestinal atresia. If the enema fails to promote passage of meconium within 24–48 hours, or two attempts at washout are unsuccessful, operative intervention is indicated. Neonates with MI who fail to respond to nonoperative measures may be treated by appendectomy and irrigation with water-soluble contrast into the small bowel via the small bowel or the appendiceal stump at operation. Manual evacuation of the inspissated meconium can be aided by intraoperative instillation of 2% or 4% N-acetylcysteine or saline solutions. These fluids can be passed antegrade through a nasogastric tube, retrograde through the appendiceal stump, or directly into the meconium through an enterotomy. If an appendectomy is chosen, the appendix (or other intestinal biopsy) may be sent for histologic analysis. Pathognomonic findings or histology for CF include goblet cell hyperplasia and accumulated secretions within crypts or lumen. If an enterotomy is performed, a purse-string suture is placed in the antimesenteric wall of the bowel and a silicone catheter is inserted through a small incision within the purse-string. This is followed by gentle instillation of the solution into the proximal bowel and terminal ileum to avoid perforation. Often the thick tenacious meconium can be removed directly through the enterotomy. The dissolved meconium and pellets can be either removed directly or milked into the colon. It is important that the surgeon avoids exposure of the meconium to the peritoneum. Once the meconium is cleared, the enterotomy or appendiceal stump is closed. If necessary, an indwelling intestinal catheter or a T-tube may be left through the enterotomy for the purpose of postoperative bowel irrigation, decompression, pancreatic enzyme instillation, and/or feeding. The enterostomy tube should be positioned at the junction of the proximal dilated bowel and collapsed distal ileum. The irrigations are begun in the early postoperative period. After successful clearance of the meconium, the tubes are removed and the enterocutaneous fistula is allowed to close spontaneously. Although uncommon, resection with primary anastomosis is occasionally required and was first described in 1962. Anastomotic leakage complicated early attempts with this approach, but improved results have been reported. Successful outcome following resection with primary anastomosis depends on adequate resection of compromised bowel, complete proximal and distal evacuation of meconium, and preservation of an adequate blood supply. Nevertheless, a recent report showed that primary anastomosis still results in complication rates between 21% and 31% higher than those noted with delayed anastomosis. Other options at operation involve resection, anastomosis, and temporary enterostomy through which postoperative irrigations may be delivered. Several stomas have been used: the Mikulicz double-barreled enterostomy, the Bishop–Koop distal chimney enterostomy, and the Santulli and Blanc proximal enterostomy. Disadvantages of these and other procedures employing resection and stoma(s) include potential high volume stoma output, bowel length loss due to resection, and the need for a second procedure to reestablish intestinal continuity. However, recent experiences with the Bishop–Koop stoma have reaffirmed it as a safe operative choice with minimal stoma complications such as stoma care problems or electrolyte imbalances being reported.

Answer 23

Operative management is almost always required in patients with complicated MI. One exception is the rare in utero spontaneously sealed perforation with intact intestinal continuity and extraluminal intraperitoneal calcified meconium. Late findings include calcified meconium identified in a patent processus vaginalis during herniorrhaphy or incidentally on abdominal radiographs. Indications for operation include peritonitis, persistent intestinal obstruction, enlarging abdominal mass, and ongoing sepsis. Surgical management includes debridement of necrotic material, pseudocyst resection, diverting stoma(s), antibiotics, and meticulous postoperative care. Creation of an ostomy is usually the fastest and safest operative course, alleviating concern over bowel size discrepancy, anastomotic leak/obstruction, and return of bowel activity. However, neonates and infants with CF are at risk for total body sodium depletion from a combinations of their stoma output and sweating, and sodium chloride and possibly sodium bicarbonate repletion may be indicated in certain patients. In cases with pseudocyst formation, decortication of the cyst wall is recommended if possible. Although meconium peritonitis is best managed with an enterostomy, segmental volvulus and intestinal atresia (without peritoneal contamination) in stable patients may be managed with resection, bowel irrigation, and primary anastomosis depending on the state of the intestine, although complications are still reported. Ultimately, the goal of operative management is the relief of intestinal obstruction and the preservation of maximal intestinal length.

Answer 24

1) Double barrel ileostomy (Mikulicz enterostomy) 2) Bishop-Koop ileostomy 3) Santulli ileostomy 4) Tube enterostomy Both the Bishop-Koop and Santulli ileostomies require an intra-abdominal anastomosis.

Answer 25

Postoperative management requires ongoing resuscitation, including maintenance fluids and replacement of insensible and gastrointestinal fluid losses (nasogastric suction and ileostomy). Instillation of 2% or 4% N-acetylcysteine via a nasogastric tube, enterostomy tube, or via an ileostomy or mucous fistula will help solubilize residual meconium. In the patient with fetal or neonatal bowel obstruction, diagnostic tests to evaluate for CF should be performed. Stomas should be closed when possible (4–6 weeks) to avoid prolonged problems with fluid, electrolyte, nutritional losses, and cholestatic jaundice. In a recent review, the incidence of reoperations was noted to be high (22%) in MI irrespective of the type of management.

Answer 26

Enteral feeds in infants with uncomplicated MI and CF may be initiated with breast milk or infant formula, along with supplemental pancreatic enzymes and vitamins. Caution must be used when prescribing enteric enzyme medication to patients with MI/CF. Treatment failures and complications include fibrosing colonopathy from excessive enzyme doses and MI equivalent, or distal intestinal obstruction syndrome (DIOS) from inadequate enzyme therapy or generic substitutions for proprietary medications. Often patients with a complicated postoperative course will require either continuous enteral feeds or total parenteral nutrition (TPN). Dilation of the small bowel by the obstructing meconium may lead to mucosal damage that can contribute to poor peristalsis or malabsorption. In patients with complicated MI or in those with significant loss of intestinal length, initiating the enteral feeding with a predigested, diluted formula at low continuous volumes is best. If this is well tolerated, the concentration should be increased followed by the volume. Pancreatic enzymes should be given with enteral feedings (even with predigested formula) starting at 2000–4000 lipase units per 120 mL of full-strength formula. Capsules containing enteric-coated microspheres can be opened and the contents mixed with formula or applesauce in older infants. The microcapsules should not be crushed as this will expose the enzymes to the acid of the stomach where they will be destroyed. Uncrushed pancreatic enzymes should be given even with MCT-oil-containing formulas. Infants with MI are at increased risk for cholestasis, particularly if they have had or are receiving TPN. Alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be monitored weekly. The fluid and nutritional status of infants who have had significant bowel resection (greater than one-third) may be difficult to manage. In addition, the presence of an ileostomy may lead to excessive losses of fluid and sodium. If access to the distal, defunctionalized bowel is feasible, drip feeds of glutamine-enriched formula or instillation of the effluent from the proximal stoma may be given at low volumes to enhance bowel growth and help prevent bacterial translocation. Gastric acid hypersecretion is seen in patients who have short bowel syndrome. An acidic intestinal environment inactivates pancreatic enzymes and prevents dissolution of enteric-coated microcapsules. H2 -receptor antagonists or proton pump inhibitors may be used as an adjunct with pancreatic enzyme therapy in patients who have had significant bowel resections. Patients with excessive sweat and intestinal sodium losses may develop a total body sodium deficit. Urine sodium should be measured in infants with ileostomies, especially when there is growth failure, even if serum sodium levels are normal. Those with a urine sodium <10 mEq/L will need sodium (and possibly bicarbonate) supplementation.

Answer 27

Although clinical lung disease is usually a delayed complication, mucous plugging and atelectasis can be seen. Prophylactic pulmonary care with chest physiotherapy should be initiated early in the postoperative period. The headdown position should not be used as this increases the risk of gastroesophageal reflux (GER) and aspiration. Infants should receive nebulized albuterol twice daily followed by chest physiotherapy. Prophylactic antibiotics are contraindicated, and antibiotic therapy should be directed by respiratory cultures, if needed.

Answer 28

The prognosis for infants with MI was uniformly poor despite operative treatment prior to the mid-1900s. Early series reported mortality rates of 50–67%. The improved survival in infants with MI can be attributed to many factors. Advances in prenatal diagnosis, pulmonary and neonatal intensive care, nutrition, antibiotics, anesthesia, operative management, and an improved understanding of the pathophysiology and treatment of the CF complications have resulted in dramatic prognostic improvement for infants with both complicated and simple MI. Survival rates of 85–100% have been reported in uncomplicated MI, and up to 93% in complicated cases. Previously, it was thought that patients with CF presenting with MI had worse outcomes than those without MI. However, it is no longer clear if this is true. Several longterm follow-up studies of patients with CF report pulmonary function at age 13 years to be no different between those born with and those without MI. One prospective study found children with MI have worse lung function and more obstructive lung disease than those with CF without MI, but a recent review noted pulmonary function for patients with CF and MI at 15 and 25 years old is similar to those without MI, although height and weight percentiles may be lower. In another study, comparison of the nutritional status of a similar population of patients with CF suggests that those who presented with MI suffer more long-term nutritional complications and other problems.

Answer 29

The meconium plug syndrome (MPS) was first described in 1956 by Clatworthy et al. It was hypothesized initially that either colonic motility or the character of the meconium was altered, thereby preventing its normal passage and subsequent decompression of the colon in the newborn period. Under normal conditions, the terminal two centimeters of neonatal meconium is firm in texture, forming a whitish cap. Most newborns pass this meconium cap before, during, or shortly after delivery. One in 500 newborns will have a longer, more tenacious obstructive plug. Failure to pass this plug results in MPS, and the term “plugged-up babies” was coined. The presentation of MPS is similar to that of MI. Signs and symptoms include failure to pass meconium, bilious vomiting, and abdominal distention with an obstructive pattern on plain abdominal films. Often, the meconium plug becomes dislodged following digital stimulation of the anus and rectum. In a recent study, approximately 30% of patients had spontaneous resolution of the meconium plug without any treatment. Fortunately, colon function is generally preserved and returns to normal following passage of the plug. Ultimately, most of these infants are found to be healthy. Historically, causes of MPS have been thought to include CF, small left colon syndrome, and Hirschsprung disease. However, in a recent study of 61 infants, CF was found in 7 patients (11%), and Hirschsprung disease was found in 2 patients (3.2%). Ten (16%) mothers of infants with MPS had received magnesium tocolysis for for pre-eclampsia, but up to 30% of mothers are reported to receive tocolysis during their pregnancy. Less common causes include congenital hypothyroidism, maternal narcotic addiction, and neuronal intestinal dysplasia. A contrast enema may be therapeutic as well as diagnostic. Contrast barium enema had a recently reported 97% success, and it was still successful in 94% of patients with a gestational age of <36 weeks. Following resolution, a sweat test should be performed to exclude CF and a TSH level should be obtained. A rectal biopsy should be performed to evaluate for Hirschsprung disease if there is a dysfunctional stooling pattern after resolution of the plug.

Answer 30

C After delivery, uncomplicated meconium ileus is characterised by a typical plain obstruction series on radiographic assessment of the abdomen. In addition to the supine and erect films appearing remarkably similar, the characteristic findings include the following: (1) great disparity in the size of the intestinal loops because of the configuration of the different segments of the bowel; (2) no or few air–fluid levels on the erect film because swallowed air cannot layer above the thickened inspissated meconium; and (3) a granular, ‘soap-bubble’, or ‘groundglass’ appearance seen frequently in the right half of the abdomen, a finding that requires swallowed air bubbles to intermix within the sticky meconium. This ‘soap-bubble’ appearance was described by Neuhauser in 1946, and is also known as ‘Neuhauser’s sign’. Each of these features alone is not exclusively diagnostic of meconium ileus and may be seen with other causes of intestinal obstruction. Collectively, however, they strongly suggest meconium ileus. Plain radiography done for differential diagnosis will include any cause of a distal small bowel obstruction, including ileal atresia, Hirschsprung’s disease, or the meconium plug/small left colon syndrome. SPSE 1

Answer 31

D The diagnosis of CF is aided by the finding of pathognomonic changes in appendiceal and intestinal specimens, including goblet cell hyperplasia and accumulation of secretions within the crypts or within the lumen. If operation is done for putative meconium ileus and an appendicostomy is used as a bowel intraluminal irrigation site, appendicectomy may be warranted to obtain such a diagnostic pathological specimen. SPSE 1

Answer 32

A A confirming study that may support the plain radiographic diagnosis of meconium ileus is the contrast enema. A contrast enema (whether with barium, Gastrografin, or any water-soluble contrast agent like Cysto-Conray II will outline a normally positioned colon of appropriate length but of small calibre. It will be empty or will contain pellets of inspissated meconium. The colon will be the typical ‘unused’ colon or ‘microcolon’. If reflux of contrast agent into the terminal ileum occurs, it will outline pellets of inspissated meconium. If the contrast agent refluxes more proximally into the ileum, the transition into dilated loops of small bowel will be encountered. Failure to reflux contrast medium into the proximal dilated small bowel will neither prove the diagnosis of meconium ileus nor determine the exact level of the intestinal obstruction; and with this failure of the contrast medium to reflux into the dilated segment, operative intervention for diagnosis and treatment becomes necessary. The differential diagnosis at this point would include meconium ileus and distal small-bowel (ileal) atresia. SPSE 1

Answer 33

C A Gastrografin enema has been the standard non-operative treatment. Gastrografin (meglumine diatrizoate + sodium diatrizoate) is a hyperosmolar, water-soluble, radio-opaque solution containing 0.1% polysorbate 80 (Tween 80), a solubilising or wetting agent, and 37% organically bound iodine. The meglumine is a 76% aqueous solution of sodium-methyl-glucamine salt of N,N1-diacetyl-3,5diamino-2,4,6-triiodobenzoic acid, and this hypertonic solution has an osmolality of 1900 mosm/l, a property that draws fluid into the intestinal lumen and aids in the release of the inspissated meconium. Because of the risk of dehydration it is recommended that the enema solution be diluted before use. After administration, both a transient osmotic diarrhoea and a putative osmotic diuresis occur, factors that emphasise the importance of aggressive fluid resuscitation. In addition, the product is radio-opaque, which enables a safe fluoroscopically monitored administration. Polysorbate 80 (Tween 80) is a non-ionic surface-active emulsifier that not only may better define the bowel mucosal pattern radiographically but may also facilitate passage of the hypertonic Gastrografin between the mucosa and the adherent meconium at the site of the obstruction. Polysorbate 80 as a 10% solution has been administered intraoperatively by way of an enterostomy to liquefy meconium. other hypertonic water-soluble agents (e.g. 40% sodium diatrizoate (40% Hypaque), with or without polysorbate 80, or Cysto-Conray) are also effective in relieving the obstruction and preclude the potential adverse mucosal effects of Gastrografin on the colon. SPSE 1

Answer 34

E The definitive study to confirm the diagnosis of CF is the sweat test. With the use of pilocarpine iontophoresis method, sweat is collected from the infant’s forearm, leg or back; the amount is quantified, and the concentration of sodium and chloride in the sample is measured. The minimum amount of sweat to be collected is 100 mg, and a measured concentration of sweat chloride in excess of 60 mEq/l is diagnostic of CF. The adequacy of the size of the sweat sample is the factor that usually precludes the application of this test to the newborn, despite reports to the contrary. Genetic testing for CF can be done by analysing cellular DNA for CFTR, thus establishing the carrier status of parents of a child with putative CF presenting with features of meconium ileus. However, because of the minimum number of mutations tested by these commercial analyses, negative results become less meaningful. If a family has known CFTR mutations, then amniocentesis with fetal DNA restriction fragment length polymorphism analysis may predict a fetal CF diagnosis. The pathophysiologic alteration of an increased albumin concentration of meconium may prove useful as a diagnostic screening tool for meconium ileus. This test, which uses a tetrabromophenolethylester blue indicator, detects meconium albumin concentration in excess of 20 mg/g of stool; however, a persisting incidence of false-positive results was seen from such factors as prematurity, melaena, gastroschisis and intrauterine infection. meconium from normal neonates has an albumin concentration of less than 5.0 mg/g of stool, whereas meconium from neonates with CF has values at times in excess of 80 mg/g. Stool trypsin and chymotrypsin analysis has historically been a popular screening test for meconium ileus. A trypsin level less than 80 mg/g of stool, coupled with operative findings, supports the diagnosis of meconium ileus. SPSE 1

Answer 35

A meconium ileus may occur in the absence of CF in term or pre-term infants with pancreatic or intestinal insufficiency from a variety of causes. These intraluminal obstructions result from accumulation of inspissated sticky meconium in the terminal ileum or right colon, but the meconium is neither tar-like nor resistant to conventional enema irrigation that usually proves to be therapeutic. Whether intestinal secretion insufficiency or a pancreatic achylia is aetiologic is variable, but rarely has pancreatic insufficiency been documented. Definitive exclusion of CF clinically requires a sweat chloride analysis, DNA analysis, or both. A series of 44 infants in Amsterdam identified only 53.5% of these patients as having CF. Although the clinical manifestations of meconium ileus are the same, some differences exist in the patients with and without CF. Patients with CF presenting with meconium ileus are more likely to be born at term, whereas those with meconium ileus and prematurity or low birthweight do not have CF. Additionally, those patients with complex meconium ileus or meconium peritonitis were likely not to have CF, a small comfort to the parents of these children. other series have described higher than expected incidence of meconium ileus in patients without CF, anywhere from 21.6% to 53.5%. These findings highlight the diversity of genetic mutations and influence of modifiers on this disease. SPSE 1

Answer 36

C In 1989, the genetic mutation that codes for the cell membrane protein termed the CF transmembrane regulator (CFTR) was identified by Francis Collins as the locus associated with the diagnosis of CF. This locus was identified on the long arm of chromosome 7, band q31. The protein was identified as a cyclic adenosine monophosphate-induced chloride channel that regulates ion flow across the apical surface of epithelial cells. There are more than 1300 identified mutations of the CFTR gene that ultimately produces abnormal electrolyte content along the external apical environment of epithelial membranes. Tubular structures lined by such affected epithelia will be characterised by desiccation and reduced clearance of their secretions, and include epithelial cells of respiratory, gastrointestinal, biliary, pancreatic and reproductive systems. The clinical correlate of this pathophysiology has included pancreatic insufficiency (90%), meconium ileus (10%–20%), diabetes mellitus (20%), obstructive biliary disease (15%–20%) and azoospermia (nearly 100%). There are varying mechanisms for the epithelial glandular abnormality to be expressed, and the elaboration of a hyperviscous mucin is the result of such mutations. The tenacious meconium protein and water content and its increased viscosity have been described long before the genetic factors were identified. The delta F508 mutation is the most common of the many CFTR gene mutations, occurring as a homozygous pair in almost 50% of CF patients, whereas another 25%–30% of patients will carry one copy of this mutation. Thus, up to more than 70% of patients with CF have this mutation resulting in the in-frame deletion of a phenylalanine residue at position 508 of the polypeptide chain. Homozygous individuals nearly always phenotypically express pancreatic exocrine insufficiency, and they also present with a higher incidence of meconium ileus. A similar higher frequency of meconium ileus is also seen in delta F508 patients who also carry the G542X mutation. SPSE 1

Answer 37

B Neonates with meconium ileus often are born with abdominal distension. In fact, meconium ileus is the only variety of neonatal intestinal obstruction that produces abdominal distension at birth before the neonate swallows air. Visible peristaltic waves and palpable, doughy bowel loops are often present. Finger pressure over a firm loop of bowel may hold the indentation, the so-called ‘putty sign’. In simple or uncomplicated meconium ileus, no findings of peritoneal irritation are present. The findings on rectal examination are unremarkable, and characteristically on withdrawal of the examining finger a spontaneous expulsion of meconium does not follow. In the presence of an in utero perforation with meconium peritonitis and ‘cyst’ formation, a palpable abdominal mass, discolouration of the abdominal wall, and signs of peritoneal irritation are often observed. Physical evidence of hypovolaemia may rapidly develop in infants with peritonitis. on passage of a nasogastric tube the quantity of bile-stained gastric fluid usually exceeds 20 ml. SPSE 1

Answer 38

C Non-operative management of meconium ileus depends on the dissolution of the inspissated intraluminal meconium in an otherwise patent and uncompromised ileocolon. Although various solubilising agents historically have been administered by mouth, intraoperatively or by rectum, the mainstay of meconium ileus treatment remained an operative procedure. In 1969 several additional reports suggested that solvents were effective and the value of non-operative application of such solvents was suggested both clinically and experimentally. Noblett reported the successful use of a hypertonic contrast enema in four neonates with uncomplicated meconium ileus. Since that report, a Gastrografin enema has been the standard of non-operative treatment. The success of non-operative treatment is variable. The initial report of Noblett suggested that as many as two-thirds of patients were successfully treated by this technique. Advantages of the non-operative therapy include a reduction in pulmonary morbidity and a reduced length of hospital stay. Disadvantages of therapy include a delay in operative intervention for those unsuccessfully treated by the enema, the risk of immediate and delayed intestinal injury or perforation, and the induction of hypovolaemia. Bowel injury leading to a potential perforation may be a product of repeated enemas, injudicious inflation of an enema catheter balloon, or a direct mucosal injury induced by the enema agent. The mechanism of such an injury may be related to bowel distension or to the polysorbate 80 content. The latter injury may be prevented by using a solubilising enema agent containing 1%–2% polysorbate 80 with isotonic Gastrografin diluted with water to a final osmolality of 320–340 mosm/l or by using an alternative isotonic contrast agent. Reports have been published of diminishing success of the contrast enema in simple meconium ileus. one retrospective analysis compared a contemporary group of neonates receiving enemas with a historical control. The success rate for relieving the obstruction in the historical group was 39%, whereas the success in the contemporary group was only 5.5%. This discrepancy in success rates was because of fewer attempts at contrast enema compared with the historical control. Also there was a wider use of other contrast agents like Cysto-Conray (400 mosm/kg water) and non-Tween 80–containing agents, compared with the highly osmotically active Gastrografin (1940 mosm/kg water). The conclusion was that in stable patients, repeated enemas should be attempted prior to surgical exploration. SPSE 1

Answer 39

C In the presence of an in utero perforation with meconium peritonitis and ‘cyst’ formation, a palpable abdominal mass, discolouration of the abdominal wall, and signs of peritoneal irritation are often observed. Physical evidence of hypovolaemia may rapidly develop in infants with peritonitis. on passage of a nasogastric tube the quantity of bile-stained gastric fluid usually exceeds 20 ml. meconium peritonitis may be seen as one of several varieties. A meconium pseudocyst is a result of meconium accumulating in the peritoneal cavity for weeks to months. A calcified ‘pseudocyst’ fibrous wall forms around an accumulation of meconium, and spared bowel loops are peripheral to this cyst. Adhesive meconium peritonitis follows meconium contamination of the peritoneal cavity for days to weeks before delivery. Dense and vascular adhesions make operative relief of the adhesive intestinal obstruction difficult. Scattered calcifications may be present. When intestinal perforation occurs only a few days before delivery, an abdomen filled with meconium ascites results and calcification is absent. The fourth variant of meconium peritonitis is bacterially infected ascites, which occurs when colonised intestinal organisms penetrate from the perforated intestine into the peritoneal cavity. SPSE 1

Answer 40

C Irrigating solutions may include warmed saline, a 50% diatrizoate solution, a 1% solution of pancreatic enzymes (Viokase; AH Robbins Co, Richmond, VA), hydrogen peroxide, and, most commonly, either a 2% or a 4% solution of N-acetylcysteine (mucomyst; Apothecon, Princeton, NJ). more concentrated solutions of N-acetylcysteine or Gastrografin, or the use of hydrogen peroxide with its attendant risk of air embolism, may produce greater risk than benefit. After solubilisation by the irrigant, injected through the enterotomy catheter, the meconium is gently milked distally into the colon or evacuated through the enterotomy. The enterotomy and the abdomen may then either be closed and an enterostomy created; or the site can be controlled by insertion of a T-tube. This last treatment has been designed to be located at the junction of proximal distended ileum with distal (more collapsed) ileum where intraluminal balls of inspissated meconium are found. leaving this tube in place and attaching the enterotomy site to the anterior abdominal wall ensures a controlled fistula as well as a route of gastrointestinal access for the instillation of pancreatic enzyme solutions beginning on the first postoperative day. By postoperative days 7–14, the irrigant should pass freely into the colon, the obstruction should be relieved, and therefore the catheter can be removed. This avoids the need for reoperation and enterostomy closure. A 40-year experience with T-tube ileostomy use has been reviewed. once the patient was on adequate oral intake and had spontaneous stooling, the T-tube could be removed at bedside without significant problems. Eighty-seven per cent of the patients with a T-tube had relief of the obstruction with T-tube solubilising irrigations. An alternative technique is appendicectomy with appendicostomy, with meconium evacuation or irrigation through this route. A temporary indwelling tube caecostomy may alternatively be left in place. For such an irrigant technique to be successful, the bowel must be handled gently, not overdistended, and not excessively massaged or ‘milked’ in an effort to evacuate the inspissated meconium. Additionally, there have been case reports of N-acetylcysteine-associated liver injury after oral or rectal administration. SPSE 1

Answer 41

D The enterostomy site can be controlled by insertion of a T-tube, which is used for instillation of pancreatic enzyme solutions. An alternative operation to enterotomy irrigation is placement of a temporary obstruction-relieving stoma with or without an associated partial resection. Gross initially advocated placement of the mikulicz’s double-barreled enterostomy, which could be performed quickly and which did not require intraoperative meconium evacuation. The exteriorised bowel loop can be opened and/or resected after the abdominal incision has been closed, thereby minimising intraperitoneal contamination. After the obstruction is relieved and the infant has recovered, a spur-crushing mikulicz’s clamp can be applied externally at the stoma to complete a side-to-side enteral anastomosis. It may be necessary to return to the operating room to close the stoma: after the clamp-induced anastomosis the residual enterocutaneous fistula may not spontaneously close. An alternative to such an ‘extraabdominal resection’ and delayed stoma closure is primary resection and anastomosis. After meconium had been evacuated, a primary intraperitoneal anastomosis could be performed, or the infant could be allowed to recover more fully, after which the stoma could be closed in a delayed fashion by an end-to-end anastomosis. An alternative operation is resection coupled with a distal chimney enterostomy, the so-called Bishop–Koop’s procedure. Intraoperatively, a No 8 French rubber catheter is passed through the ostomy chimney into the distal ileum. Within 12–24 hours after the operation, catheter irrigations are commenced with a pancreatic enzyme solution (1 teaspoon Viokase per 30 ml water) repeated every 4–6 hours until the distal intraluminal obstruction is relieved, at which time the catheter is removed. After an initial large volume of enterostomy output, the ostomy drainage will diminish as the more distal obstruction is relieved. The transcolonic passage of stool will follow. Thereafter, the output from the stoma may cease altogether. Eventually the chimney may be treated by one of two techniques. At the bedside the ‘stoma’ may be ligated. If the result of this non-invasive technique is a persistent enterocutaneous fistula, then a formal intraperitoneal or extraperitoneal stomal closure can be performed with the patient under a general anaesthetic. The latter procedure is necessary in approximately 75% of patients treated by this technique. Santulli described a proximal chimney enterostomy, an operation that in essence is the reverse of the resection coupled with a distal chimney enterostomy. The distal ileal end is anastomosed end-to-side to the proximal ileum at a level corresponding to an immediate subfascial plane, and the proximal ileum is exited as an end enterostomy. With this stoma arrangement, irrigation and decompression of the proximal ileum is enhanced. As with Bishop–Koop’s procedure, an intraoperative catheter passed through the stoma is positioned into the distal ileum for the postoperative instillation of solubilising agent. Because a high-output functional end enterostomy has been created, it is necessary to close such a stoma early to avoid the complications induced by excessive fluid and electrolyte losses. SPSE 1

Answer 42

B Non-operative management of meconium ileus depends on the dissolution of the inspissated intraluminal meconium in an otherwise patent and uncompromised ileocolon. Although various solubilising agents historically have been administered by mouth, intraoperatively, or by rectum, the mainstay of meconium ileus treatment remained an operative procedure. In 1969, several additional reports suggested that solvents were effective and the values of non-operative application of such solvents was suggested both clinically and experimentally. Noblett reported the successful use of a hypertonic contrast enema in four neonates with uncomplicated meconium ileus. She described the need to fulfil the following criteria before applying such therapy: (1) an initial diagnostic contrast enema should exclude other causes of distal intestinal obstruction; (2) the complications of volvulus, atresia, perforation or peritonitis must be excluded; (3) the enema must be performed with careful fluoroscopic control; (4) intravenous antibiotics should be administered; (5) the patient should be attended by a paediatric surgeon during the procedure; (6) the patient should have a full fluid resuscitation with fluids given aggressively (one to three times maintenance) during the procedure; and (7) the patient should be prepared for imminent operation should complications develop. Since that report, a Gastrografin enema has been the standard of non-operative treatment. After administration, both a transient osmotic diarrhoea and a putative osmotic diuresis occur, factors that emphasise the importance of aggressive fluid resuscitation. In addition, the product is radio-opaque, which enables a safe fluoroscopically monitored administration. Polysorbate 80 is a non-ionic surface-active emulsifier that not only may better define radiographically the bowel mucosal pattern but also may facilitate the passage of the hypertonic Gastrografin between the mucosa and the adherent meconium at the site of the obstruction. Polysorbate 80 as a 10% solution has been administered intraoperatively by way of an enterostomy to liquefy meconium. Complications can arise from enema use and include hypovolaemic shock from the osmotic fluid shifts, inflammation, perforation and ischaemic enterocolitis. The technique of solubilising enema treatment of meconium ileus continues to use the aforementioned guidelines of Noblett. After fluid resuscitation and nasogastric decompression have been performed, and after physical examination and plain abdominal radiographs have excluded the diagnosis of peritonitis or perforation, the diagnostic contrast enema with barium or water-soluble agent is administered. When the preliminary diagnostic study has been completed, an enema-tip, non-balloon catheter is inserted into the anorectum and the buttocks are taped together around the catheter. With fluoroscopic guidance and an initial solution of 50% Gastrografin in water, the contrast agent is slowly injected via the catheter-tipped syringe. When contrast medium traverses the colon and reaches the dilated meconium-impacted ileum, the study is terminated and the infant is returned to a bed for monitoring, fluid administration (two times maintenance) and normalisation of body temperature. Spontaneous passage of the inspissated meconium per rectum should follow. An abdominal radiograph should be repeated in 8–12 hours to determine whether the obstruction has been relieved. If instead the evacuation is incomplete and obstruction persists, the enema may be repeated with the same concentration of Gastrografin. If either no evacuation occurs after a successfully refluxing enema or if contrast medium cannot be refluxed into dilated bowel, then this technique should be abandoned and operative intervention planned. Similarly, signs of worsening obstruction, clinical distension, greater distension of loops on radiograph, or signs of peritonitis resulting from a possible perforation are also indication for operative intervention. Noblett suggests that after a successful enema, 5 ml of a 10% N-acetylcysteine solution should be administered every 6 hours through a nasogastric tube to liquefy upper gastrointestinal secretions. Furthermore, when formula feedings are begun, supplemental pancreatic enzymes must be administered with each feeding. SPSE 1

Answer 43

A The outcome of the treatment of patients with meconium ileus, whether the condition is complicated or simple, has steadily improved over the last 3 decades; the most recently reported survival rates approaching 100%. In a series of patients treated both non-operatively and operatively, survival rate at 5 and 10 years for the two categories improved steadily from the 1960s (30% and 70%, respectively) through the 1970s (80% and 70%, respectively) and 1980s (100% at 5-year follow-up). In the past, non-operative treatment contributed to an improved survival rate, but in the past decade the survival rate for both operative and non-operative treatment was 100%. The significant improvement in operative survival has come since the 1960s when the 6-month survival rate was only 33%. The operative survival rate had improved to 60% before 1979 and to 100% after 1979 and 1989. No significant overall differences in outcomes were observed with regard to the patient gender, whether complication of meconium ileus was present, or with regard to the type of operation performed (ileostomy, resection with primary anastomosis, resection and mikulicz’s ileostomy, and Bishop–Koop’s enterostomy). Additionally, the long-term survival rates (measured at 6 years) of patients treated with Bishop–Koop’s procedure (62% survival) did not differ from those of patients with other operations. Furthermore, all deaths in patients older than 6 months of age were cardiopulmonary or pneumonitic deaths related to underlying CF and not to complications of operation. Interestingly, both simple and complicated cases of meconium ileus had 72% 10-year survival rates. Death occurs from multiple causes, which include intraperitoneal sepsis from unrecognised leakage, pulmonary sepsis and bronchopneumonia, or short bowel syndrome with complicating liver failure. SPSE 1

Answer 44

A Two simultaneous pathogenetic events in meconium ileus appear to begin in utero and result in intraluminal accumulation of a highly viscid and tenacious meconium: (1) the development of pancreatic exocrine enzyme deficiency and (2) the secretion of hyperviscous mucus by pathologically abnormal intestinal glands. The thickened meconium accumulates and begins in utero to obstruct the intestine intraluminally. This accounts for the complications of meconium ileus (i.e. a twist of a heavy loop with perforation, peritonitis and cyst or atresia) seen in the neonate. The proximal ileum dilates, and its wall thickens as it becomes filled with the tenacious and tarry meconium. Concomitantly, the narrowed distal small bowel, and at times the colon, contains beaded or ‘boxcar’ concretions of grey-white, putty-like inspissated meconium. The more distal colon is small or unused, a microcolon. The past 2 decades have seen continued progress. The genetic lesion of a mutation in the CF transmembrane regulator (CFTR) gene was defined as the causal lesion of CF, and it is now recognised that patients with meconium ileus likely represent a distinct phenotype with earlier presentation and worse pulmonary function. Yet, the outcome of the treatment of patients with meconium ileus, whether the condition is complicated or simple, has steadily improved over the last three decades. SPSE 1