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Hypogammaglobulinemia complicating chylothorax after cardiac surgery in two infants
Hypogammaglobulinemia Complicating Chylothorax After Cardiac Surgery in Two Infants Mary E. McBride, BS, Joy C. Drass, MD, John W. Berkenbosch, MD, William R. Wilson, Jr, MD, and Joseph D. Tobias, MD
C
HYLOTHORAX is an uncommon event after cardiothoracic surgical procedures in children. It may be related to direct damage to the thoracic duct or its tributaries during surgical manipulation or the result of sustained, high central venous pressures.1 Because of its composition, ongoing losses of chyle can result in protein-calorie malnutrition with hypoalbuminemia, deficiency of fat-soluble vitamins, depletion of T lymphocytes, and electrolyte disturbances.2,3 Chyle also contains a high concentration of immunoglobulin and clinical experience has shown that ongoing chyle losses can lead to hypogammaglobulinemia. Despite the potential consequences of impairment of cellular and humoral immunity, the literature regarding the management of patients with chylothorax does not address the issue of immunoglobulin loss in chyle. The reviews of chylothorax and its management mention, without specific references, that immunoglobulin levels in chyle are equal to those of serum and that chronic chyle loss can lead to hypogammaglobulinemia.4 Two infants who developed chylothorax after cardiac surgery that resulted in hypogammaglobulinemia are reported. Treatment was instituted with intravenous immunoglobulin (IVIG). Gammaglobulin levels in serum and chyle during the course of their hospitalization are presented, and the potential role for gammaglobulin replacement in such patients is reviewed. CASE REPORTS
Case 1 A 16-day-old girl, born at 37 weeks’ gestational age, was diagnosed with truncus arteriosus with discontinuous pulmonary arteries and underwent a Rastelli procedure, reimplantation of the left pulmonary artery, and repair of a ventricular septal defect. The sternum was closed on postoperative day (POD) 11. Bilateral pleural effusions developed on POD 15, and chest tubes were placed for drainage. These effusions were diagnosed as chylothoraces owing to the high triglyceride concentration (782 and 383 mg/dL). Chest tube output averaged 40 to 50 mL/kg/d from POD 1 through 64. The pleural fluid and serum laboratory values and replacement therapy with IVIG are outlined in Table 1. Despite total parenteral nutrition, chylous drainage persisted, and on POD 32, a thoracotomy was performed with ligation of the thoracic duct. On POD 46, the serum gammaglobulin level was 33 mg/dL (normal, 150 to 250 mg/dL). The patient had persistent fever and respiratory insuf-
From the Departments of Child Health, Anesthesiology, and Cardiothoracic Surgery, The University of Missouri, Columbia, MO. Address reprint requests to Joseph D. Tobias, MD, Pediatric Critical Care/Pediatric Anesthesiology, Department of Child Health, The University of Missouri, M658 Health Sciences Center, One Hospital Drive, Columbia, MO 65212. Copyright © 2001 by W.B. Saunders Company 1053-0770/01/1503-0016$35.00/0 doi:10.1053/jcan.2001.23313 Key words: hypogammaglobulinemia, chylothorax, cardiac surgery 358
ficiency, which necessitated high-frequency jet ventilation and nitric oxide therapy. Renal function and urine output deteriorated, necessitating continuous peritoneal dialysis. Peritoneal fluid cultures subsequently became positive, and abdominal exploration revealed the entire midgut to be nonviable. Further therapy was withheld, and the child died on POD 72. Case 2 A 3-month-old boy, born at 33 weeks’ gestational age, was diagnosed with severe pulmonary and aortic stenosis. He underwent pulmonary outflow tract reconstruction with placement of a monocusp pulmonary valve, aortic commissurotomy, and ventricular septal defect repair at 92 days of age. Pleural effusions developed on POD 9. Chest tube output averaged 25 to 30 mL/kg/d from POD 1 through 25. Analysis of the pleural fluid revealed 21,000 total cells; 15,810 red blood cells; 5190 white blood cells (2% neutrophils, 96% lymphocytes); glucose, 83 mg/dL; and total protein, 3.7 g/dL. On POD 15, when enteral feedings were started, a pleural fluid triglyceride level of 169 mg/dL confirmed the suspicion of a chylothorax. The pleural fluid and serum laboratory values and replacement therapy with IVIG are outlined in Table 2. The patient was kept NPO, and total parenteral nutrition was started. The chest tube was removed on POD 26, and a medium-chain triglyceride formula was started on POD 28. IVIG was administered to achieve normal levels. With the resolution of the chylothorax, no further IVIG was administered, and serum IgG levels remained above normal values for age. DISCUSSION
Host defenses against infection require the normal function of several systems, including cellular and humoral immunity. Hypogammaglobulinemia may result from defective synthesis or accelerated losses of gammaglobulin (Table 3). Defective synthesis may occur in various genetic disorders. Excessive losses occur most commonly from renal or gastrointestinal causes; however, chylothoraces and traumatized skin can also be sites of immunoglobulin loss. Deficiency of any of the IgG subclasses is associated with increased susceptibility to infection. The response to polysaccharide antigens is especially decreased, resulting in a higher susceptibility to polysaccharide encapsulated organisms (eg, Escherichia coli, Haemophilus influenzae type b, Neisseria meningitidis, and Streptococcus pneumoniae). This problem is well documented by recurrent episodes of sepsis and infections in patients with the above-mentioned disorders. Current practice includes the administration of IVIG to patients with genetic production disorders of gammaglobulin to provide them exogenously with the capability to fight infections. By the same rationale, more recent evidence has shown decreased episodes of infections in preterm infants with low gammaglobulin levels treated with IVIG.5-9,11 Infants born before 32 weeks’ gestation have not received adequate amounts of IgG from maternal transmission. Endogenous synthesis does not begin until 24
Journal of Cardiothoracic and Vascular Anesthesia, Vol 15, No 3 (June), 2001: pp 358-361
HYPOGAMMAGLOBULINEMIA AND CHYLOTHORAX
359
Table 1. Summary of Chest Tube Output, Intravenous Immunoglobulin Administration and Serum/Pleural Fluid Values of Patient No. 1 Postoperative Day*
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72
CT Drainage (mL)
23 18 39 15 14 30 60 29 66 21 19 10 20 10 15 0 10 0
Lymphocytes (Serum) (%)
Absolute Lymph (1,000/L)
IgG Level (mg/dL)
IVIG Administration (g/kg)
4 3 5 11 4 1 8 6 4 2.7 1 22 28 23 4 2 6 2 20 22 16 1 1 3 23 22
1.68 1.33 1.94 4.3 0.5 0.16 1.36 2.4 1.8 1.5 0.5 0.4 7.9 6 1.2 0.5 1.65 0.7 5.2 5.5 2.2 0.1 0.08 0.36 2.6 5.1
se 33
0.4 0.4 0.4 0.4 0.4
se 278 pl 199
se 35 0.4 se 684 se 133
0.4
se 266
0.4 0.4 0.4 0.4 0.4
se 813
se 199
Abbreviations: CT, chest tube; IVIG, intravenous immunoglobulin; se, serum; pl, pleural fluid. *POD 32, thoracic duct ligation performed; POD 45, left pleurodesis performed; POD 46, right pleurodesis performed; POD 64, chest tubes were removed.
weeks after birth.10 At least 5 different studies have shown a significant protective advantage of IVIG in preventing infections in preterm infants.5-9 Jenson and Pollock11 reported a statistically significant benefit of prophylactic IVIG based on a 52-reference meta-analysis. Stiehm’s12 meta-analysis on the use of IVIG in primary as well as secondary antibody deficiencies, including protein-losing enteropathies and nephrotic syndrome, supported the use of IVIG when low serum immunoglobulin levels accompany secondary immunodeficiencies. Although it has been suggested in various review articles that hypogammaglobulinemia occurs with chylothoraces, there is limited documentation of this fact in the literature.3,13 Aside from the report of Mohan et al,13 the authors are unaware of documented reports of this problem. The 2 patients reported here showed hypogammaglobulinemia associated with chyle loss after cardiac surgery. The immunoglobulin concentration of pleural fluid was equivalent to that of the serum. Hypogammaglobulinemia resolved with the resolution of the chylothorax in the second patient. Mohan et al13 presented 2 children who developed chylothoraces after cardiac surgery. The first patient had undergone a pulmonary valvotomy followed by a modified Blalock-Taussig shunt. A large, left-sided pleural effusion developed on POD 7
that was identified as chyle. During 10 days, 50 to 200 mL/kg/d of chyle were drained. The patient developed bacteremia on POD 18. Blood cultures were positive for Staphylococcus epidermidis. Antibiotic treatment was supplemented with IVIG with a loading dose of 0.5 g/kg followed by a maintenance dose of 0.1 g/kg daily. Subsequent doses were adjusted to maintain a serum IgG level of 750 mg/dL. The chyle losses continued, and the infection was unresponsive to therapy. Further treatment was discontinued, and the patient died. The second patient at 4 months of age underwent a Blalock-Hanlon atrial septectomy and banding of the pulmonary artery. At 5 years of age, the patient underwent a cavopulmonary connection with fenestration of the atrial septum. A chylothorax developed on POD 10. Chest tube output was 60 to 130 mL/kg/d. On POD 21, bacteremia developed with a Staphylococcus species that responded to vancomycin. On POD 25, the patient underwent a tetracycline pleurodesis, which failed to control the chylothorax. IVIG was started on POD 37 with a loading dose of 0.5 g/kg and maintenance doses adjusted to serum levels. On POD 49, the chest tube drainage had ceased, and the drains were removed. Mohan et al13 suggested the potential benefit of administering IVIG as adjunctive therapy along with antibiotics to patients with chylothoraces after bacteremia has been diagnosed. Their rationale was that the prolonged loss of lymphocytes and gammaglobulin in chyle leads to a decrease in a patient’s immunologic response to infection. Antibodies of the IgG class augment host defenses against infection by activation of complement and complement-associated factors, increasing neutrophil counts and improving function and augmenting opsonin activity, endotoxin inhibition, and modulation of some of the proinflammatory cytokines. Conservative treatment of chylothoraces is a prolonged process typically consisting of 1 to 2 weeks of total parenteral nutrition necessitating vascular access, potentially predisposing a patient to infection and septicemia. Allen et al14 stated that despite aggressive nutritional support coupled with the selective use of surgery, mortality remained close to 10% in series involving pediatric patients with chylothorax after surgery for congenital heart disease. Most deaths are due to overwhelming bacterial or fungal infections. These patients are reported to be at an increased risk for infections because of loss of lymphocytes in chylous drainage. Although Allen et al14 found no correlation between the number of absolute circulating lymphocytes and infectious complications in 5 patients, they suggested that decreasing absolute lymphocyte counts may be an indication for prophylactic antimicrobial agents or surgical repair. They added that with lymphopenia these patients have several other factors that increase their risk of infectious complications, including hypogammaglobulinemia, malnutrition, prolonged intensive care unit stays, chronic illnesses, and central venous catheters. Despite the abundance of literature concerning management of chylothorax, the authors have noted little emphasis on the potential deleterious effects of excessive IgG losses in chyle. Two patients who developed hypogammaglobulinemia related to chyle losses were reported here. Serum and chyle IgG levels were equivalent. Because the actual losses depend on the concentration in the pleural fluid as well as the amount of drainage, which can vary significantly, specific recommendations as to
MCBRIDE ET AL
360
Table 2. Summary of Chest Tube Output, Intravenous Immunoglobulin Administration and Serum/Pleural Fluid Values of Patient No. 2 Postoperative Day
CT Drainage (mL)
10 11 12 13 14 15* 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
107 168 117 95 120 85 135 125 85 100 205 240 240 230 266 275 220 226 85 125 75 30 10 20
Lymphocytes (Serum) (%)
Absolute Lymph.s (1,000/L)
8 23 13 17 14
0.82 2.85 1.82 2.69 2.03
9
1.25
7 5
0.81 0.57
5
0.79
10
1.87
IgG Level (mg/dL)
90
IVIG Administration (g/kg)
Triglyceride (Pleural) (mg/dL)
1
pl 244, se 291 47 169 se 162 105 0.5 0.5
Abbreviations: CT, chest tube; IVIG, intravenous immunoglobulin; pl, pleural; se, serum. *Enteral feedings started with Enfamil with iron on POD 15.
how often IVIG should be administered cannot be made. Periodic sampling of serum concentrations is required with redosing of IVIG when specific serum concentrations are reached. Based on the treatment regimens of other causes of hypogammaglobulinemia and the potential beneficial therapeutic effect of IVIG, the authors recommend prophylactic treatment with IVIG in these patients when hypogammaglobulinemia develops. Future studies are needed, however, to clearly identify if this practice is cost-effective. Additionally, although the risks of adverse effects associated with IVIG are low, reported adverse effects include cardiovascular changes; anaTable 3. Causes of Hypogammaglobulinemia Production X-linked agammaglobulinemia (Bruton’s disease) Hyper-IgM syndrome Common variable immunodeficiency Immunoglobulin deficiency with transcobalamin II deficiency Selective IgA or IgM deficiencies Transient hypogammaglobulinemia of infancy Defective function/destruction HIV Splenectomized patients Myotonic dystrophy Excessive loss Protein-losing enteropathies Nephrotic syndrome Chylothorax Severe burns and dermatitis Abbreviation: HIV, human immunodeficiency virus.
phylactoid reactions; aseptic meningitis; acute renal failure; and although the product is heat-treated, the potential for the transmission of infectious agents, such as hepatitis C. REFERENCES 1. Beghetti M, La Scala G, Belli D, et al: Etiology and management of pediatric chylothorax. J Pediatr 136:653-658, 2000 2. Nguyen DM, Shum-Tim D, Dobell AR, Tchervenkov CI: The management of chylothorax/chylopericardium following pediatric cardiac surgery: A 10 year experience. J Card Surg 10:302-308, 1995 3. Buttiker V, Fanconi S, Burger R: Chylothorax in children: Guidelines for diagnosis and management. Chest 116:682-687, 1999 4. Paes ML, Powell H: Chylothorax: An update. Br J Hosp Med 51:482-490, 1994 5. Haque KN, Zaidi MH, Haque SK: Intravenous immunoglobulin for prevention of sepsis in preterm and low– birth-weight infants. Pediatr Infect Dis 5:622-625, 1986 6. Chirico G, Rondini G, Plebani A, et al: Intravenous gammaglobulin therapy for prophylaxis of infection in high-risk neonates. J Pediatr 110:437-442, 1987 7. Clapp DW, Kliegman RM, Baley JE, et al: Use of intravenously administered immune globulin to prevent nosocomial sepsis in low– birth-weight infants: Report of a pilot study. J Pediatr 115:973-978, 1989 8. Baker CJ, Melish ME, Hall RT, et al: Intravenous immune globulin for the prevention of nosocomial infection in low– birthweight neonates. N Engl J Med 327:213-219, 1992 9. Conway SP, Ng PC, Howel D, et al: Prophylactic intravenous immunoglobulin in pre-term infants: A controlled trial. Vox Sang 59:6-11, 1990 10. Lacy JB, Ohlsson A: Administration of intravenous immunoglobulins for prophylaxis or treatment of infection in preterm infants: Meta-analyses. Arch Dis Child Fetal Neonatal Ed 72:F151-155, 1995
HYPOGAMMAGLOBULINEMIA AND CHYLOTHORAX
11. Jenson HB, Pollock BH: The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis. Semin Perinatol 22:50-63, 1998 12. Stiehm ER: Human intravenous immunoglobulin in primary and secondary antibody deficiencies. Pediatr Infect Dis J 16:696-707, 1997 13. Mohan H, Paes ML, Haynes S: Use of intravenous immunoglobulins as an adjunct in the conservative management of chylothorax. Paediatr Anaesth 9:89-92, 1999
361
14. Allen EM, van Heeckeren DW, Spector ML, Blumer JL: Management of nutritional and infectious complications of postoperative chylothorax in children. J Pediatr Surg 26:1169-1174, 1991 15. Nowak-Wegrzyn A, Lederman HM: Supply, use, and abuse of intravenous immunoglobulin. Curr Opin Pediatr 11:533-539, 1999 16. Stangel M, Muller M, Marz P: Adverse events during treatment with high-dose intravenous immunoglobulins for neurological disorders. Eur Neurol 40:173-174, 1998
C
HYLOTHORAX is an uncommon event after cardiothoracic surgical procedures in children. It may be related to direct damage to the thoracic duct or its tributaries during surgical manipulation or the result of sustained, high central venous pressures.1 Because of its composition, ongoing losses of chyle can result in protein-calorie malnutrition with hypoalbuminemia, deficiency of fat-soluble vitamins, depletion of T lymphocytes, and electrolyte disturbances.2,3 Chyle also contains a high concentration of immunoglobulin and clinical experience has shown that ongoing chyle losses can lead to hypogammaglobulinemia. Despite the potential consequences of impairment of cellular and humoral immunity, the literature regarding the management of patients with chylothorax does not address the issue of immunoglobulin loss in chyle. The reviews of chylothorax and its management mention, without specific references, that immunoglobulin levels in chyle are equal to those of serum and that chronic chyle loss can lead to hypogammaglobulinemia.4 Two infants who developed chylothorax after cardiac surgery that resulted in hypogammaglobulinemia are reported. Treatment was instituted with intravenous immunoglobulin (IVIG). Gammaglobulin levels in serum and chyle during the course of their hospitalization are presented, and the potential role for gammaglobulin replacement in such patients is reviewed. CASE REPORTS
Case 1 A 16-day-old girl, born at 37 weeks’ gestational age, was diagnosed with truncus arteriosus with discontinuous pulmonary arteries and underwent a Rastelli procedure, reimplantation of the left pulmonary artery, and repair of a ventricular septal defect. The sternum was closed on postoperative day (POD) 11. Bilateral pleural effusions developed on POD 15, and chest tubes were placed for drainage. These effusions were diagnosed as chylothoraces owing to the high triglyceride concentration (782 and 383 mg/dL). Chest tube output averaged 40 to 50 mL/kg/d from POD 1 through 64. The pleural fluid and serum laboratory values and replacement therapy with IVIG are outlined in Table 1. Despite total parenteral nutrition, chylous drainage persisted, and on POD 32, a thoracotomy was performed with ligation of the thoracic duct. On POD 46, the serum gammaglobulin level was 33 mg/dL (normal, 150 to 250 mg/dL). The patient had persistent fever and respiratory insuf-
From the Departments of Child Health, Anesthesiology, and Cardiothoracic Surgery, The University of Missouri, Columbia, MO. Address reprint requests to Joseph D. Tobias, MD, Pediatric Critical Care/Pediatric Anesthesiology, Department of Child Health, The University of Missouri, M658 Health Sciences Center, One Hospital Drive, Columbia, MO 65212. Copyright © 2001 by W.B. Saunders Company 1053-0770/01/1503-0016$35.00/0 doi:10.1053/jcan.2001.23313 Key words: hypogammaglobulinemia, chylothorax, cardiac surgery 358
ficiency, which necessitated high-frequency jet ventilation and nitric oxide therapy. Renal function and urine output deteriorated, necessitating continuous peritoneal dialysis. Peritoneal fluid cultures subsequently became positive, and abdominal exploration revealed the entire midgut to be nonviable. Further therapy was withheld, and the child died on POD 72. Case 2 A 3-month-old boy, born at 33 weeks’ gestational age, was diagnosed with severe pulmonary and aortic stenosis. He underwent pulmonary outflow tract reconstruction with placement of a monocusp pulmonary valve, aortic commissurotomy, and ventricular septal defect repair at 92 days of age. Pleural effusions developed on POD 9. Chest tube output averaged 25 to 30 mL/kg/d from POD 1 through 25. Analysis of the pleural fluid revealed 21,000 total cells; 15,810 red blood cells; 5190 white blood cells (2% neutrophils, 96% lymphocytes); glucose, 83 mg/dL; and total protein, 3.7 g/dL. On POD 15, when enteral feedings were started, a pleural fluid triglyceride level of 169 mg/dL confirmed the suspicion of a chylothorax. The pleural fluid and serum laboratory values and replacement therapy with IVIG are outlined in Table 2. The patient was kept NPO, and total parenteral nutrition was started. The chest tube was removed on POD 26, and a medium-chain triglyceride formula was started on POD 28. IVIG was administered to achieve normal levels. With the resolution of the chylothorax, no further IVIG was administered, and serum IgG levels remained above normal values for age. DISCUSSION
Host defenses against infection require the normal function of several systems, including cellular and humoral immunity. Hypogammaglobulinemia may result from defective synthesis or accelerated losses of gammaglobulin (Table 3). Defective synthesis may occur in various genetic disorders. Excessive losses occur most commonly from renal or gastrointestinal causes; however, chylothoraces and traumatized skin can also be sites of immunoglobulin loss. Deficiency of any of the IgG subclasses is associated with increased susceptibility to infection. The response to polysaccharide antigens is especially decreased, resulting in a higher susceptibility to polysaccharide encapsulated organisms (eg, Escherichia coli, Haemophilus influenzae type b, Neisseria meningitidis, and Streptococcus pneumoniae). This problem is well documented by recurrent episodes of sepsis and infections in patients with the above-mentioned disorders. Current practice includes the administration of IVIG to patients with genetic production disorders of gammaglobulin to provide them exogenously with the capability to fight infections. By the same rationale, more recent evidence has shown decreased episodes of infections in preterm infants with low gammaglobulin levels treated with IVIG.5-9,11 Infants born before 32 weeks’ gestation have not received adequate amounts of IgG from maternal transmission. Endogenous synthesis does not begin until 24
Journal of Cardiothoracic and Vascular Anesthesia, Vol 15, No 3 (June), 2001: pp 358-361
HYPOGAMMAGLOBULINEMIA AND CHYLOTHORAX
359
Table 1. Summary of Chest Tube Output, Intravenous Immunoglobulin Administration and Serum/Pleural Fluid Values of Patient No. 1 Postoperative Day*
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72
CT Drainage (mL)
23 18 39 15 14 30 60 29 66 21 19 10 20 10 15 0 10 0
Lymphocytes (Serum) (%)
Absolute Lymph (1,000/L)
IgG Level (mg/dL)
IVIG Administration (g/kg)
4 3 5 11 4 1 8 6 4 2.7 1 22 28 23 4 2 6 2 20 22 16 1 1 3 23 22
1.68 1.33 1.94 4.3 0.5 0.16 1.36 2.4 1.8 1.5 0.5 0.4 7.9 6 1.2 0.5 1.65 0.7 5.2 5.5 2.2 0.1 0.08 0.36 2.6 5.1
se 33
0.4 0.4 0.4 0.4 0.4
se 278 pl 199
se 35 0.4 se 684 se 133
0.4
se 266
0.4 0.4 0.4 0.4 0.4
se 813
se 199
Abbreviations: CT, chest tube; IVIG, intravenous immunoglobulin; se, serum; pl, pleural fluid. *POD 32, thoracic duct ligation performed; POD 45, left pleurodesis performed; POD 46, right pleurodesis performed; POD 64, chest tubes were removed.
weeks after birth.10 At least 5 different studies have shown a significant protective advantage of IVIG in preventing infections in preterm infants.5-9 Jenson and Pollock11 reported a statistically significant benefit of prophylactic IVIG based on a 52-reference meta-analysis. Stiehm’s12 meta-analysis on the use of IVIG in primary as well as secondary antibody deficiencies, including protein-losing enteropathies and nephrotic syndrome, supported the use of IVIG when low serum immunoglobulin levels accompany secondary immunodeficiencies. Although it has been suggested in various review articles that hypogammaglobulinemia occurs with chylothoraces, there is limited documentation of this fact in the literature.3,13 Aside from the report of Mohan et al,13 the authors are unaware of documented reports of this problem. The 2 patients reported here showed hypogammaglobulinemia associated with chyle loss after cardiac surgery. The immunoglobulin concentration of pleural fluid was equivalent to that of the serum. Hypogammaglobulinemia resolved with the resolution of the chylothorax in the second patient. Mohan et al13 presented 2 children who developed chylothoraces after cardiac surgery. The first patient had undergone a pulmonary valvotomy followed by a modified Blalock-Taussig shunt. A large, left-sided pleural effusion developed on POD 7
that was identified as chyle. During 10 days, 50 to 200 mL/kg/d of chyle were drained. The patient developed bacteremia on POD 18. Blood cultures were positive for Staphylococcus epidermidis. Antibiotic treatment was supplemented with IVIG with a loading dose of 0.5 g/kg followed by a maintenance dose of 0.1 g/kg daily. Subsequent doses were adjusted to maintain a serum IgG level of 750 mg/dL. The chyle losses continued, and the infection was unresponsive to therapy. Further treatment was discontinued, and the patient died. The second patient at 4 months of age underwent a Blalock-Hanlon atrial septectomy and banding of the pulmonary artery. At 5 years of age, the patient underwent a cavopulmonary connection with fenestration of the atrial septum. A chylothorax developed on POD 10. Chest tube output was 60 to 130 mL/kg/d. On POD 21, bacteremia developed with a Staphylococcus species that responded to vancomycin. On POD 25, the patient underwent a tetracycline pleurodesis, which failed to control the chylothorax. IVIG was started on POD 37 with a loading dose of 0.5 g/kg and maintenance doses adjusted to serum levels. On POD 49, the chest tube drainage had ceased, and the drains were removed. Mohan et al13 suggested the potential benefit of administering IVIG as adjunctive therapy along with antibiotics to patients with chylothoraces after bacteremia has been diagnosed. Their rationale was that the prolonged loss of lymphocytes and gammaglobulin in chyle leads to a decrease in a patient’s immunologic response to infection. Antibodies of the IgG class augment host defenses against infection by activation of complement and complement-associated factors, increasing neutrophil counts and improving function and augmenting opsonin activity, endotoxin inhibition, and modulation of some of the proinflammatory cytokines. Conservative treatment of chylothoraces is a prolonged process typically consisting of 1 to 2 weeks of total parenteral nutrition necessitating vascular access, potentially predisposing a patient to infection and septicemia. Allen et al14 stated that despite aggressive nutritional support coupled with the selective use of surgery, mortality remained close to 10% in series involving pediatric patients with chylothorax after surgery for congenital heart disease. Most deaths are due to overwhelming bacterial or fungal infections. These patients are reported to be at an increased risk for infections because of loss of lymphocytes in chylous drainage. Although Allen et al14 found no correlation between the number of absolute circulating lymphocytes and infectious complications in 5 patients, they suggested that decreasing absolute lymphocyte counts may be an indication for prophylactic antimicrobial agents or surgical repair. They added that with lymphopenia these patients have several other factors that increase their risk of infectious complications, including hypogammaglobulinemia, malnutrition, prolonged intensive care unit stays, chronic illnesses, and central venous catheters. Despite the abundance of literature concerning management of chylothorax, the authors have noted little emphasis on the potential deleterious effects of excessive IgG losses in chyle. Two patients who developed hypogammaglobulinemia related to chyle losses were reported here. Serum and chyle IgG levels were equivalent. Because the actual losses depend on the concentration in the pleural fluid as well as the amount of drainage, which can vary significantly, specific recommendations as to
MCBRIDE ET AL
360
Table 2. Summary of Chest Tube Output, Intravenous Immunoglobulin Administration and Serum/Pleural Fluid Values of Patient No. 2 Postoperative Day
CT Drainage (mL)
10 11 12 13 14 15* 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
107 168 117 95 120 85 135 125 85 100 205 240 240 230 266 275 220 226 85 125 75 30 10 20
Lymphocytes (Serum) (%)
Absolute Lymph.s (1,000/L)
8 23 13 17 14
0.82 2.85 1.82 2.69 2.03
9
1.25
7 5
0.81 0.57
5
0.79
10
1.87
IgG Level (mg/dL)
90
IVIG Administration (g/kg)
Triglyceride (Pleural) (mg/dL)
1
pl 244, se 291 47 169 se 162 105 0.5 0.5
Abbreviations: CT, chest tube; IVIG, intravenous immunoglobulin; pl, pleural; se, serum. *Enteral feedings started with Enfamil with iron on POD 15.
how often IVIG should be administered cannot be made. Periodic sampling of serum concentrations is required with redosing of IVIG when specific serum concentrations are reached. Based on the treatment regimens of other causes of hypogammaglobulinemia and the potential beneficial therapeutic effect of IVIG, the authors recommend prophylactic treatment with IVIG in these patients when hypogammaglobulinemia develops. Future studies are needed, however, to clearly identify if this practice is cost-effective. Additionally, although the risks of adverse effects associated with IVIG are low, reported adverse effects include cardiovascular changes; anaTable 3. Causes of Hypogammaglobulinemia Production X-linked agammaglobulinemia (Bruton’s disease) Hyper-IgM syndrome Common variable immunodeficiency Immunoglobulin deficiency with transcobalamin II deficiency Selective IgA or IgM deficiencies Transient hypogammaglobulinemia of infancy Defective function/destruction HIV Splenectomized patients Myotonic dystrophy Excessive loss Protein-losing enteropathies Nephrotic syndrome Chylothorax Severe burns and dermatitis Abbreviation: HIV, human immunodeficiency virus.
phylactoid reactions; aseptic meningitis; acute renal failure; and although the product is heat-treated, the potential for the transmission of infectious agents, such as hepatitis C. REFERENCES 1. Beghetti M, La Scala G, Belli D, et al: Etiology and management of pediatric chylothorax. J Pediatr 136:653-658, 2000 2. Nguyen DM, Shum-Tim D, Dobell AR, Tchervenkov CI: The management of chylothorax/chylopericardium following pediatric cardiac surgery: A 10 year experience. J Card Surg 10:302-308, 1995 3. Buttiker V, Fanconi S, Burger R: Chylothorax in children: Guidelines for diagnosis and management. Chest 116:682-687, 1999 4. Paes ML, Powell H: Chylothorax: An update. Br J Hosp Med 51:482-490, 1994 5. Haque KN, Zaidi MH, Haque SK: Intravenous immunoglobulin for prevention of sepsis in preterm and low– birth-weight infants. Pediatr Infect Dis 5:622-625, 1986 6. Chirico G, Rondini G, Plebani A, et al: Intravenous gammaglobulin therapy for prophylaxis of infection in high-risk neonates. J Pediatr 110:437-442, 1987 7. Clapp DW, Kliegman RM, Baley JE, et al: Use of intravenously administered immune globulin to prevent nosocomial sepsis in low– birth-weight infants: Report of a pilot study. J Pediatr 115:973-978, 1989 8. Baker CJ, Melish ME, Hall RT, et al: Intravenous immune globulin for the prevention of nosocomial infection in low– birthweight neonates. N Engl J Med 327:213-219, 1992 9. Conway SP, Ng PC, Howel D, et al: Prophylactic intravenous immunoglobulin in pre-term infants: A controlled trial. Vox Sang 59:6-11, 1990 10. Lacy JB, Ohlsson A: Administration of intravenous immunoglobulins for prophylaxis or treatment of infection in preterm infants: Meta-analyses. Arch Dis Child Fetal Neonatal Ed 72:F151-155, 1995
HYPOGAMMAGLOBULINEMIA AND CHYLOTHORAX
11. Jenson HB, Pollock BH: The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis. Semin Perinatol 22:50-63, 1998 12. Stiehm ER: Human intravenous immunoglobulin in primary and secondary antibody deficiencies. Pediatr Infect Dis J 16:696-707, 1997 13. Mohan H, Paes ML, Haynes S: Use of intravenous immunoglobulins as an adjunct in the conservative management of chylothorax. Paediatr Anaesth 9:89-92, 1999
361
14. Allen EM, van Heeckeren DW, Spector ML, Blumer JL: Management of nutritional and infectious complications of postoperative chylothorax in children. J Pediatr Surg 26:1169-1174, 1991 15. Nowak-Wegrzyn A, Lederman HM: Supply, use, and abuse of intravenous immunoglobulin. Curr Opin Pediatr 11:533-539, 1999 16. Stangel M, Muller M, Marz P: Adverse events during treatment with high-dose intravenous immunoglobulins for neurological disorders. Eur Neurol 40:173-174, 1998