Esophageal variceal bleeding that does not resolve spon- taneously is frequently controlled with octreotide and/
or endoscopic therapy. Slowing or stopping the bleeding with octreotide while stabilizing the patient often makes endoscopic visualization and treatment much easier. If these measures are not successful, temporary control of bleeding may be achieved by balloon tamponade devices.3 This is infrequently required but may be life saving for the unstable patient. This is a delicate proce- dure performed in the ICU setting with sedation and control of the airway. As brisk bleeding makes endos- copy technically challenging, this maneuver can make endoscopic therapy more successful if the bleeding can be slowed or stopped. The balloon tamponade device is removed before endoscopy.
Treatment for bleeding varices includes sclero- therapy and band ligation. Both focus on obliterating esophageal varices at their most distal aspect near the lower esophageal sphincter (see Figure 6–3). Sclerother- apy has been used for decades and has a high success rate. An injection needle is introduced through the endoscope and small volumes of sclerosing agents are injected into the varix leading to obliteration of the ves- Intravenous Medications for Active GI Bleeding
Medications Class Dose*
Pantoprazole PPI 0.5–1 mg/kg/day (maximum 40 mg) divided once or twice daily Lansoprazole PPI 1–1.5 mg/kg/day (maximum 30 mg) divided once or twice daily Ranitidine H2 blocker Bolus: 2–4 mg/kg/day (maximum 200 mg) divided q 6–8 hours
Continuous: 1 mg/kg bolus, and then 2–4 mg/kg/day (maximum 200 mg/day) Octreotide* Vasoactive 1 mcg/kg bolus (maximum 50 mcg), and then 1 mcg/kg/hour
Titrate by 1 mcg/kg/hour q8 hours as needed (maximum 5 mcg/kg/hour) PPI = proton pump inhibitor; H2 blocker = histamine2 antagonist.
Note: PPI dosing is not based on stringent data. Some practitioners may use higher doses in select cases based on experience and available data.
*Octreotide dosing is based on limited data. Monitor for hyperglycemia.
Table 6–11.
sel and, hopefully, the smaller feeding vessels. Compli- cations are more common than with banding (ulcers, strictures, and perforation).
The concept of variceal banding is a simple one adapted from a proven treatment for hemorrhoids. The banding device is placed on the endoscope. Suction is applied to pull the varix into the device. An elastic band is released compressing the varix leading to obliteration.
Up to six bands can be placed in one session. Adult studies suggest banding is just as effective as sclerother- apy with less complications (no such comparative data exist in children). The major limitation is the size of the device which does not allow it to be introduced in smaller children and infants.
Rebleeding of varices is frequent (up to 50%).
However, sclerotherapy or banding can be repeated on an elective basis to eradicate varices and prevent rebleed- ing (multiple sessions may be required). Prophylaxis of rebleeding may include non-selective beta blockers to reduce portal pressures. They are effective in adult stud- ies but may signifi cantly limit exercise tolerance. Surgery to decompress the portal system or liver transplantation may be helpful in selected patients.
SUMMARY
GI bleeding in children is rarely life threatening but can be severe. The keys to approaching these patients are rapid assessment of severity and stabilization. In the majority of cases, this will allow a controlled evaluation yielding a diagnosis and/or consultation with a specialist.
REFERENCES
1. Gilger M, Whitfi eld K. Upper gastrointestinal bleeding. In:
Kleinman E, Walker WA, eds. Walker’s Pediatric Gastroin- testinal Disease: Physiology, Diagnosis, Management.
Hamilton, Ont./Lewiston, NY: BC Decker; 2008:1285.
2. Turck D, Michaud L. Lower gastrointestinal bleeding. In:
Kleinman E, Walker WA, eds. Walker’s Pediatric Gastroin- testinal Disease: Physiology, Diagnosis, Management.
Hamilton, Ont./Lewiston, NY: BC Decker; 2008:1309.
3. Boyle JT. Gastrointestinal bleeding in infants and chil- dren. Pediatr Rev. 2008;29:39–52.
4. Mas E, Olives JP. Toxic and traumatic injury of the esopha- gus. In: Kleinman E, Walker WA, eds. Walker’s Pediatric
Gastrointestinal Disease: Physiology, Diagnosis, Manage- ment. Hamilton, Ont./Lewiston, NY: BC Decker;
2008:105.
5. Applegate KE. Evidence-based diagnosis of malrotation and volvulus. Pediatr Radiol. 2009;39(suppl 2):
S161–S163.
6. Deerojanawon J, Peongsujarit D, Vivatvakin B, Prapphal N. Incidence and risk factors of upper gastrointestinal bleeding in mechanically ventilated children. Pediatr Crit Care Med. 2009;10(1):91–95.
7. Maloney J, Nowak-Wegrzyn A. Educational clinical case series for pediatric allergy and immunology: allergic proc- tocolitis, food protein-induced enterocolitis syndrome and allergic eosinophilic gastroenteritis with protein-los- ing gastroenteropathy as manifestations of non-IgE- mediated cow’s milk allergy. Pediatr Allergy Immunol.
2007;18(4):360–367.
8. Arvola T, Ruuska T, Keranen J, et al. Rectal bleeding in infancy: clinical, allergological, and microbiological exam- ination. Pediatrics. 2006;117(4):e760–e768.
9. Lewis NA, Levitt MA, Zallen GS, et al. Diagnosing Hirschsprung’s disease: increasing the odds of a positive rectal biopsy result. J Pediatr Surg. 2003;38(3):412–416.
10. Walker TM. Ileocolonoscopy and enteroscopy. In: Klein- man E, Walker WA, eds. Walker’s Pediatric Gastrointestinal Disease: Physiology, Diagnosis, Management. Hamilton, Ont./Lewiston, NY: BC Decker; 2008:1291.
11. Thurley PD, Halliday KE, Somers JM. Radiological fea- tures of Meckel’s diverticulum and its complications. Clin Radiol. 2009;64(2):109–118.
12. Waseem M, Rosenberg HK. Intussusception. Pediatr Emerg Care. 2008;24(11):793–800.
13. Schappi M, Mougenot JF, Belli D. Upper gastrointestinal endoscopy. In: Kleinman E, Walker WA, eds. Walker’s Pediatric Gastrointestinal Disease: Physiology, Diagnosis, Management. Hamilton, Ont./Lewiston, NY: BC Decker;
2008:1265.
14. Kay MH, Wyllie R. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding.J Pediatr Gastroenterol Nutr.
2007;45(2):157–171.
15. Melmed GY, Lo SK. Capsule endoscopy: practical applications. Clin Gastroenterol Hepatol. 2005;3(5):
411–422.
16. Kiratli PO, Aksoy T, Bozkurt MF, Orhan D. Detection of ectopic gastric mucosa using 99mTc pertechnetate: review of the literature. Ann Nucl Med. 2009;23(2):97–105.
17. Siafakas C, Fox VL, Nurko S. Use of octreotide for the treatment of severe gastrointestinal bleeding in children.
JPGN. 1998;26(3):356–359.
DEFINITIONS AND EPIDEMIOLOGY
Jaundice comes from the French word “jaune,” meaning yellow. Jaundice refers to the yellow staining of the sclera, mucous membranes, and skin by bilirubin. It is not a disease by itself but rather a manifestation that accompa- nies different diseases. Jaundice is caused by elevated serum bilirubin levels with subsequent tissue deposition.
In infants, it is usually apparent with bilirubin levels above 4–5 mg/dL (68–86 mmol/L). In older children, jaundice can be noted at levels above 2–3 mg/dL (34–51 mmol/L). The color of the sclera and skin varies depend- ing on the serum bilirubin level. Jaundice involves the head fi rst and progresses caudally with higher levels.
Total serum bilirubin is the sum of the unconju- gated (or indirect) and conjugated (or direct) bilirubin fractions. The terms direct and conjugated hyperbiliru- binemia are often used interchangeably, but this is not always accurate. Direct bilirubin is measured in the labo- ratory using a diazo dye-binding assay, and, depending on the method used, can include both conjugated biliru- bin and delta bilirubin. Delta bilirubin is formed by cova- lent bond formation between serum conjugated bilirubin and albumin. Clearance of delta bilirubin can therefore be prolonged, refl ecting the half-life of albumin, and may lag behind other signs of clinical improvement.
Cholestasis is defi ned as diminished bile forma- tion or fl ow, and is manifested by conjugated hyper- bilirubinemia. The guidelines of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN)1 defi ne an abnormal conju- gated bilirubin level as:
■ a conjugated bilirubin ⬎1.0 mg/dL, if the total biliru- bin is ⬍5 mg/dL, or
■ a conjugated bilirubin level ⬎20% of the total bilirubin, if the total bilirubin is ⬎5 mg/dL.
Neonatal jaundice is common, observed in the fi rst week of life in about 50% of term infants and 80% of preterm infants. This is usually harmless, often related to physiological jaundice or breastfeeding, and is char- acterized by unconjugated hyperbilirubinemia. Rarely, however, severe unconjugated hyperbilirubinemia can lead to bilirubin encephalopathy or kernicterus.2 On the contrary, cholestasis (or conjugated hyperbilirubine- mia) is much less commonly seen but often results from conditions with serious hepatobiliary dysfunction.
Cholestatic jaundice affects approximately 1 in every 2500 infants.3 The challenge for physicians is to identify infants with cholestasis who will need additional evalu- ation and treatment. Early detection of cholestatic jaun- dice and accurate diagnosis of its etiology are vital for successful treatment and a favorable prognosis.
PATHOGENESIS
Bilirubin is the end product of heme moiety metabo- lism from hemoglobin and other heme-containing pro- teins (Figure 7–1). After unconjugated bilirubin is formed, it is transported with albumin in blood to the liver. Inside hepatocytes, unconjugated bilirubin is con- jugated with glucuronic acid by uridine diphosphate glucuronosyltransferase (UGT) to increase water solu- bility. Conjugated bilirubin, along with cholesterol, bile acids, and phospholipids, is transported through the bile canalicular system to the gallbladder and later into the small intestine. Conjugated bilirubin cannot be reabsorbed by enterocytes and is degraded by the intes- tinal fl ora into colorless urobilinogen, which is excreted with feces. Urobilinogen is oxidized to urobilin and ster- cobilin, which are responsible for the brown color of stools. A portion of conjugated bilirubin is deconju- gated by beta-glucuronidase and is reabsorbed into the
Jaundice and
Neonatal Cholestasis
Riad M. Rahhal
CHAPTER 7
portal circulation and liver, a normal process called the enterohepatic bilirubin circulation. In the liver, this can be conjugated again and excreted into the bile.4
Any disease process that leads to increased biliru- bin production and/or limits bilirubin excretion can potentially manifest by visible jaundice from underlying hyperbilirubinemia. Depending on the etiology and pathogenesis, this can lead to unconjugated or conju- gated hyperbilirubinemia.
Hyperbilirubinemia in healthy, full-term infants is often attributed to physiological immaturity of bilirubin metabolism, leading to elevated unconjugated bilirubin levels. In actuality, neonatal jaundice is often due to a com- bination of one or more of the following (Table 7–1):
■ increased bilirubin production;
■ decreased bilirubin clearance;
■ increased enterohepatic circulation.
Increased bilirubin production is seen with hemo- lytic disease processes such as ABO incompatibility, inherited membrane defects or enzyme abnormalities of red blood cells, hyperviscosity (polycythemia)
syndrome, or resorption of a large hematoma. Decreased bilirubin conjugation is seen in Crigler–Najjar syn- drome and Gilbert’s syndrome that are due to the absence or reduction of UGT activity, leading to uncon- jugated hyperbilirubinemia.5 Delayed intestinal transit can enhance the enterohepatic circulation of unconju- gated bilirubin contributing to unconjugated hyperbili- rubinemia. This can be seen in breast milk jaundice, inadequate breastfeeding, and impaired intestinal motil- ity or intestinal obstruction. In neonates, the inade- quately developed anaerobic intestinal fl ora may also enhance the enterohepatic circulation as less bilirubin is converted to urobilinogen for excretion.6
Cholestasis, or conjugated hyperbilirubinemia, results from diminished bile fl ow or excretion. In infants, the etiologies vary and can be divided into two main categories: obstructive/structural and hepatocellular (Table 7–2). The category of obstructive/structural cholestasis includes biliary atresia and choledochal cysts.
The etiology of biliary atresia is unknown, but several mechanisms (infectious, genetic, and immunologic) have been proposed to explain the infl ammatory process
Albumin +
Albumin Unconjugated
bilirubin
Unconjugated bilirubin
Conjugated bilirubin
Conjugated bilirubin Small intestine
Bile canalicular system Hepatocyte Blood
stream
Glucuronic acid
Enterohepatic circulation
Bacteria Urobilinogen and related
products UGT
Unconjugated bilirubin Heme
metabolism
Feces
FIGURE 7–1 ■ Bilirubin metabolism: following transport from the blood stream into the hepatocytes, unconjugated bilirubin is converted by the action of uridine diphosphate glucuronosyltransferase (UGT) to mono- and diglucuronide that are excreted into the small intestine.
that leads to bile duct obliteration.7 Biliary atresia is described in more detail in Chapter 23. Choledochal cysts are rare congenital anomalies of the bile ducts characterized by cystic dilatation of the biliary tree.8 Conditions that lead to hepatocellular cholestasis are numerous and include idiopathic neonatal hepatitis, infections, metabolic, genetic, and endocrine disorders.