- Email: [email protected]
Long-term Survival in Biliary Atresia
597
emerging. Early work points to better tolerability38 and perhaps an opportunity for formulation is only just
better seizure control. 37 More data are needed. Who should receive controlled-release carbamazepine ? It is worth trying in patients receiving high-dose carbamazepine, whether well or poorly controlled, who complain of intermittent diplopia, headache, nausea, dizziness, and tiredness. Many will be taking the drug in three or four divided doses. With the new formulation a twice-daily regimen is possible for all patients and once-daily administration may turn out to be suitable for some.39 In changing over, an identical daily dose can be substituted. Theoretically, controlled-release carbamazepine should also provide "gentler" introduction of the drug without the high peaks associated with the original formulation. Sustained or controlled-release formulations are invariably more expensive and the "new" carbamazepine is no exception. Nevertheless, there are real difficulties in formulating carbamazepine and care must be taken not to be seduced too readily by parsimony in prescribing when consistent absorption characteristics are essential for therapeutic efficacy. Epilepsy is too dangerous a condition to compromise patient care for a small financial saving. If the promise inherent in its improved kinetic profile is borne out by proper trials, the controlled-release formulation will be the one to use.
Long-term Survival
in
Biliary
Atresia LONG-TERM survival of patients who have undergone surgical treatment for extrahepatic biliary atresia in early infancy represents a major advance in paediatric surgery during the past 30 years. 1 in 14 000 infants are born with this sclerosing inflammatory lesion of the biliary tree,l which if untreated causes early death from cirrhosis and liver failure. The conventional surgical technique of biliary enteric anastomosis can achieve bile flow in the rare infant who proves at laparotomy to have residual segments of hepatic ducts, but in most infants the destruction of the extrahepatic bileducts extends up to the capsule of the liver. Intrahepatic damage with fibrosis or cirrhosis is always present at the time of diagnosis. Most cases of biliary atresia were believed to be uncorrectable until Kasai, beginning in the mid1950s, detected microscopic bile channels in the residual fibrous tissue of the porta hepatis and showed that some communicated with patent intrahepatic bileducts.2 He described the operation of 38. Aldencamp AP, Alpherts WCJ, Moerland MC, Ottevanger N, Van Parys JAP. Controlled release carbamazepine: cognitive side effects in patients with epilepsy. Epilepsia 1987; 28: 507-14. 39. Stefan
H, Schafer H, Kuhnen C, Schneider S. Clinical monitonng during carbamazepine slow-release, once-daily monotherapy. Epilepsia 1988; 29: 571-77. 1. Howard ER, Tan KC. Biliary atresia. Br J Hosp Med 1989; 41: 123-30. 2. Kasai M, Kimura S, Asakura Y, et al. Surgical treatment of biliary atresia. J Pediatr Surg 1968; 3: 665-75.
a Roux-en-Y loop of is anastomosed to the transected tissue of the jejunum porta hepatis, and reported the disappearance of jaundice in some of the children. Surgeons outside Japan were at first sceptical; in the United Kingdom the operation was not accepted as a standard procedure until after 1970. The development of liver transplantation techniques and immunosuppression in children, especially after the introduction of cyclosporin in 1980, increased still further the chances of cure for biliary atresia; this condition is now the commonest indication for liver replacement in children. Between 1980 and 1986, for example, biliary atresia was the reason for operation in 125 of the 244 patients under 18 years of age who underwent orthotopic liver transplantation in Pittsburgh,3and 67% were alive 2-5 years later. What, then, is the place of portoenterostomy in the management of biliary atresia, in the era of liver transplantation? Bile flow after portoenterostomy is often substantial at 300-800 ml a day,4and in Japan more than 80% of patients have become jaundice-free after surgery.s Many groups find that successful long-term bile flow depends on the age at surgery. Mieli-Vergani et al,9 for example, reported bile flow in 86% of infants treated before eight weeks of age, compared with 36% in older infants. Unfortunately, establishment of bile flow does not guarantee long-term survival. Cirrhosis, portal hypertension, and recurrent ascending cholangitis (which can further damage the liver) may all complicate the postoperative course. Variceal bleeding from portal hypertension can now be controlled satisfactorily with injection sclerotherapy, 10 but cholangitis has a pronounced adverse effect on long-term survival. In a series reported by Houwen et al8 five-year survival was only 54% in a group of patients with postoperative bile flow who had had episodes of infection, compared with 91% in a comparable group without infection. Efforts to prevent such intrahepatic infections have included surgical modifications to the Roux-en-Y loops, longterm antibiotics, and choleretics to increase bile flow but prospective randomised trials show no great benefit from these manoeuvres.11-15
portoenterostomy, in which
3. Iwatsuki S. Liver transplantation for children with biliary atresia. In: Ohi R, ed. Biliary atresia. Tokyo: Professional Postgraduate Services, 1987: 315-19. 4. Altman RP, Levy J. Biliary atresia. Pediatr Ann 1985; 14: 481-85. 5. Ohi R. Presentation at the British Association of Paediatric Surgeons 36th Congress, July, 1989. 6. Hays DM, Kimura K. Biliary atresia: new concepts of management. Curr Probl Surg 1981; 18: 541-608. 7. Kasai M, Ohi R, Chiba T. Long term survivors after surgery for biliary atresia. In: Ohi R, ed. Biliary atresia. Tokyo: Professional Postgraduate Services, 1987: 277-80. 8. Houwen RHJ, Zwierstra RP, Severijnen RS, et al. Prognosis of extrahepatic biliary atresia. Arch Dis Child 1989; 64: 214-18. 9. Mieli-Vergani G, Howard ER, Portmann B, Mowat AP. Late referral for biliary atresia—missed opportunities for effective surgery. Lancet 1989; i: 421-23 10. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management of esophageal varices in 61 children with biliary atresia. J Pediatr Surg 1989; 24: 438-42. 11. Ohi R, Hanamatsu M, Mochizuki I, Chiba T, Kasai M. Progress in the treatment of biliary atresia. World J Surg 1985; 9: 285-93. 12. Howard ER, Driver M, McClement JW, Mowat AP. Biliary atresia: the results of surgery in 88 consecutive cases. In: Daum F, ed. Extrahepatic biliary atresia. New York: Marcel Dekker, 1983: 99-103.
598
There are now substantial numbers of patients who have lived more than 10 years after portoenterosotomy. Of 26 such long-term survivors reported by Saeki et ap6 14 were over 15 years of age. Kasai et aF say that the chance of long-term survival has gradually improved: for the 149 children treated before 1976, overall 10-year survival was 26-8% whereas 13 (53%) of the 24 patients treated between 1971 and 1976 are still alive. The results again show the effect of age at operation, with 75% survival for those under 60 days at surgery compared with 10% for infants older than 90 days. About 40% of these long-term survivors do have abnormal liver function as measured by laboratory tests; all show abnormal intrahepatic bileducts on cholangiography; and 60% have evidence of oesophageal varices.1o Despite these findings many live a virtually normal life. It is therefore clear that the best results are obtained in infants who have earlier operation and who do not get cholangitis after surgery. For those who do not benefit from the Kasai operation or who go into liver failure when older, there is the option of liver transplantation. Andrews et al 17 report a 3-year survival of 73% after transplantation in 80 children operated on at an average of 5 years (44% for biliary atresia). Previous portoenterostomy did not complicate the procedures. Encouraging results in still younger children have been reported from Pittsburgh, with 12 of 20 children under 1 year surviving transplantation, at between 1 and 56 months, although a second transplant was necessary in 30%. The difficulties of transplant surgery in this age group are well illustrated by a series of 45 biliary atresia patients referred for transplantation.18 9 died on the waitinglist and 36 underwent surgery. A second transplant was required in 19%. Post-transplant surgery, for various complications, was necessary in 37% of the survivors and a third had infections. Interestingly, the six-month survival was better in those who had previously undergone portoenterostomy. The morbidity after transplantation will certainly be higher than that after portoenterostomy-Stewart and Lilly20 calculate a morbidity of 29% during the first year after the Kasai operation compared with 49% after transplantation. On existing evidence portoenterostomy is still a reasonable first-choice operation for extrahepatic 13. Burnweit CA, Coin D. Influence of diversion on the development of cholangitis after hepatoportoenterostomy for biliary atresia. J Pediatr Surg 1986; 21: 1143-46. 14. Vajro P, Couturier M, Lemmonier F, Odievre M. Effects of postoperative cholestyramine and phenobarbital administration on bile flow restoration in infants with extrahepatic biliary atresia. J Pediatr Surg 1986; 21: 362-65. 15. Ecoffey C, Rothman E, Bernard O, Hadchouel M, Valayer J, Alagille D. Bactenal cholangitis after surgery for biliary atresia. J Pediatr 1987; 111: 824-29. 16. Saeki M, Ogata T, Nakano M. Problems in long term survivors of biliary atresia. In: Ohi R, ed. Biliary atresia. Tokyo: Professional Postgraduate Services, 1987: 287-93. 17. Andrews WS, Wanek W, Fyock B, Grays S, Benser M. Pediatric liver transplantation: a 3-year experience. J Pediatr Surg 1989; 24: 77-82 18. Esquivel CO, Koneru B, Karrer F, et al. Liver transplantation before one year of age.
J Pediatr 1987; 110: 545-48. 19. Millis JM, Brems JJ, Hiatt JR, et al. Orthotopic liver transplantation for biliary atresia. Arch Surg 1988; 123: 1237-39. 20. Stewart BA, Hall RJ, Lilly JR. Liver transplantation and the Kasai operation in biliary atresia. J Pediatr Surg 1988; 23: 623-26
biliary atresia. Transplantation is not compromised by a previous portoenterostomy provided that complex loops-and enterostomies are avoided. Early diagnosis of biliary atresia before six weeks of age should be the goal.9 Transplantation should be considered for the infant in whom portoenterostomy fails completely or for the long-term survivor with deteriorating liver function or life-threatening portal
hypertension.
EPIDURAL MORPHINE, HYPERTENSION, AND
AORTIC SURGERY THE "stress" response that accompanies surgery leads to increases in blood concentrations of most catabolic hormones and a decrease in insulin secretion; many attempts have been made to reduce or block this response, but it is not clear whether total blockade is either necessary or desirable. In addition, increases in sympathetic nervous system activity and in catecholamine secretion may result in haemodynamic changes, including tachycardia and hypertension. These effects are most commonly seen after major operations, especially vascular or cardiac3 procedures. Patients who require peripheral vascular surgery often have associated cardiac or cerebrovascular disease, and increases in arterial pressure and heart rate may lead to myocardial ischaemia or infarction, cardiac failure, or cerebral haemorrhage. Intrathecal or epidural administration of opioids provides effective and sustained analgesia after many types of surgery by delivering high local concentrations of drug to the opioid receptors situated in the substantia gelatinosa in the spinal cord.4 Breslow and colleagues5 have now suggested that epidural morphine may reduce the frequency and severity of hypertension, and by implication the morbidity, after surgery to the abdominal aorta. Postoperative pain scores were significantly lower, and requirements for systemic morphine reduced, in patients who had received a single dose of epidural morphine 6 mg compared with those given epidural saline, and the administration of epidural morphine reduced mean arterial pressure and the need for antihypertensive drugs in the first 24 hours after operation. There were no differences between groups in perioperative adrenaline or antidiuretic hormone concentrations, but plasma noradrenaline concentration was lower in the epidural morphine group 6-24 hours postoperatively. The researchers suggest that the differences between groups with to arterial and noradrenaline respect pressure concentrations may be simply a secondary result of reduced pain, but propose that they might represent direct depression of the sympathetic nervous system, either centrally or within the spinal cord. 1. Frayn KN. Hormonal control of metabolism
m trauma and sepsis. Clin Endocrinol 1986; 24: 577-99. 2. Goldman L, Caldera DL. Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979; 50: 285-92 3. Wallach R, Karp RB, Reves JG, Oparil S, Smith LR, James TN. Pathogenesis of paroxysmal hypertension developing during and after coronary bypass surgery: a study of hemodynamic and humoral factors. Am J Cardiol 1980; 46: 559-65. 4. Morgan M. The rational use of intrathecal and extradural opioids. Br J Anaesth 1989;
63: 165-88. 5. Breslow MJ, Jordan
DA, Chnstopherson R, et al. Epidural morphine decreases hypertension by attenuating sympathetic nervous system hyperactivity. JAMA 1989; 261: 3577-81. postoperative
emerging. Early work points to better tolerability38 and perhaps an opportunity for formulation is only just
better seizure control. 37 More data are needed. Who should receive controlled-release carbamazepine ? It is worth trying in patients receiving high-dose carbamazepine, whether well or poorly controlled, who complain of intermittent diplopia, headache, nausea, dizziness, and tiredness. Many will be taking the drug in three or four divided doses. With the new formulation a twice-daily regimen is possible for all patients and once-daily administration may turn out to be suitable for some.39 In changing over, an identical daily dose can be substituted. Theoretically, controlled-release carbamazepine should also provide "gentler" introduction of the drug without the high peaks associated with the original formulation. Sustained or controlled-release formulations are invariably more expensive and the "new" carbamazepine is no exception. Nevertheless, there are real difficulties in formulating carbamazepine and care must be taken not to be seduced too readily by parsimony in prescribing when consistent absorption characteristics are essential for therapeutic efficacy. Epilepsy is too dangerous a condition to compromise patient care for a small financial saving. If the promise inherent in its improved kinetic profile is borne out by proper trials, the controlled-release formulation will be the one to use.
Long-term Survival
in
Biliary
Atresia LONG-TERM survival of patients who have undergone surgical treatment for extrahepatic biliary atresia in early infancy represents a major advance in paediatric surgery during the past 30 years. 1 in 14 000 infants are born with this sclerosing inflammatory lesion of the biliary tree,l which if untreated causes early death from cirrhosis and liver failure. The conventional surgical technique of biliary enteric anastomosis can achieve bile flow in the rare infant who proves at laparotomy to have residual segments of hepatic ducts, but in most infants the destruction of the extrahepatic bileducts extends up to the capsule of the liver. Intrahepatic damage with fibrosis or cirrhosis is always present at the time of diagnosis. Most cases of biliary atresia were believed to be uncorrectable until Kasai, beginning in the mid1950s, detected microscopic bile channels in the residual fibrous tissue of the porta hepatis and showed that some communicated with patent intrahepatic bileducts.2 He described the operation of 38. Aldencamp AP, Alpherts WCJ, Moerland MC, Ottevanger N, Van Parys JAP. Controlled release carbamazepine: cognitive side effects in patients with epilepsy. Epilepsia 1987; 28: 507-14. 39. Stefan
H, Schafer H, Kuhnen C, Schneider S. Clinical monitonng during carbamazepine slow-release, once-daily monotherapy. Epilepsia 1988; 29: 571-77. 1. Howard ER, Tan KC. Biliary atresia. Br J Hosp Med 1989; 41: 123-30. 2. Kasai M, Kimura S, Asakura Y, et al. Surgical treatment of biliary atresia. J Pediatr Surg 1968; 3: 665-75.
a Roux-en-Y loop of is anastomosed to the transected tissue of the jejunum porta hepatis, and reported the disappearance of jaundice in some of the children. Surgeons outside Japan were at first sceptical; in the United Kingdom the operation was not accepted as a standard procedure until after 1970. The development of liver transplantation techniques and immunosuppression in children, especially after the introduction of cyclosporin in 1980, increased still further the chances of cure for biliary atresia; this condition is now the commonest indication for liver replacement in children. Between 1980 and 1986, for example, biliary atresia was the reason for operation in 125 of the 244 patients under 18 years of age who underwent orthotopic liver transplantation in Pittsburgh,3and 67% were alive 2-5 years later. What, then, is the place of portoenterostomy in the management of biliary atresia, in the era of liver transplantation? Bile flow after portoenterostomy is often substantial at 300-800 ml a day,4and in Japan more than 80% of patients have become jaundice-free after surgery.s Many groups find that successful long-term bile flow depends on the age at surgery. Mieli-Vergani et al,9 for example, reported bile flow in 86% of infants treated before eight weeks of age, compared with 36% in older infants. Unfortunately, establishment of bile flow does not guarantee long-term survival. Cirrhosis, portal hypertension, and recurrent ascending cholangitis (which can further damage the liver) may all complicate the postoperative course. Variceal bleeding from portal hypertension can now be controlled satisfactorily with injection sclerotherapy, 10 but cholangitis has a pronounced adverse effect on long-term survival. In a series reported by Houwen et al8 five-year survival was only 54% in a group of patients with postoperative bile flow who had had episodes of infection, compared with 91% in a comparable group without infection. Efforts to prevent such intrahepatic infections have included surgical modifications to the Roux-en-Y loops, longterm antibiotics, and choleretics to increase bile flow but prospective randomised trials show no great benefit from these manoeuvres.11-15
portoenterostomy, in which
3. Iwatsuki S. Liver transplantation for children with biliary atresia. In: Ohi R, ed. Biliary atresia. Tokyo: Professional Postgraduate Services, 1987: 315-19. 4. Altman RP, Levy J. Biliary atresia. Pediatr Ann 1985; 14: 481-85. 5. Ohi R. Presentation at the British Association of Paediatric Surgeons 36th Congress, July, 1989. 6. Hays DM, Kimura K. Biliary atresia: new concepts of management. Curr Probl Surg 1981; 18: 541-608. 7. Kasai M, Ohi R, Chiba T. Long term survivors after surgery for biliary atresia. In: Ohi R, ed. Biliary atresia. Tokyo: Professional Postgraduate Services, 1987: 277-80. 8. Houwen RHJ, Zwierstra RP, Severijnen RS, et al. Prognosis of extrahepatic biliary atresia. Arch Dis Child 1989; 64: 214-18. 9. Mieli-Vergani G, Howard ER, Portmann B, Mowat AP. Late referral for biliary atresia—missed opportunities for effective surgery. Lancet 1989; i: 421-23 10. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management of esophageal varices in 61 children with biliary atresia. J Pediatr Surg 1989; 24: 438-42. 11. Ohi R, Hanamatsu M, Mochizuki I, Chiba T, Kasai M. Progress in the treatment of biliary atresia. World J Surg 1985; 9: 285-93. 12. Howard ER, Driver M, McClement JW, Mowat AP. Biliary atresia: the results of surgery in 88 consecutive cases. In: Daum F, ed. Extrahepatic biliary atresia. New York: Marcel Dekker, 1983: 99-103.
598
There are now substantial numbers of patients who have lived more than 10 years after portoenterosotomy. Of 26 such long-term survivors reported by Saeki et ap6 14 were over 15 years of age. Kasai et aF say that the chance of long-term survival has gradually improved: for the 149 children treated before 1976, overall 10-year survival was 26-8% whereas 13 (53%) of the 24 patients treated between 1971 and 1976 are still alive. The results again show the effect of age at operation, with 75% survival for those under 60 days at surgery compared with 10% for infants older than 90 days. About 40% of these long-term survivors do have abnormal liver function as measured by laboratory tests; all show abnormal intrahepatic bileducts on cholangiography; and 60% have evidence of oesophageal varices.1o Despite these findings many live a virtually normal life. It is therefore clear that the best results are obtained in infants who have earlier operation and who do not get cholangitis after surgery. For those who do not benefit from the Kasai operation or who go into liver failure when older, there is the option of liver transplantation. Andrews et al 17 report a 3-year survival of 73% after transplantation in 80 children operated on at an average of 5 years (44% for biliary atresia). Previous portoenterostomy did not complicate the procedures. Encouraging results in still younger children have been reported from Pittsburgh, with 12 of 20 children under 1 year surviving transplantation, at between 1 and 56 months, although a second transplant was necessary in 30%. The difficulties of transplant surgery in this age group are well illustrated by a series of 45 biliary atresia patients referred for transplantation.18 9 died on the waitinglist and 36 underwent surgery. A second transplant was required in 19%. Post-transplant surgery, for various complications, was necessary in 37% of the survivors and a third had infections. Interestingly, the six-month survival was better in those who had previously undergone portoenterostomy. The morbidity after transplantation will certainly be higher than that after portoenterostomy-Stewart and Lilly20 calculate a morbidity of 29% during the first year after the Kasai operation compared with 49% after transplantation. On existing evidence portoenterostomy is still a reasonable first-choice operation for extrahepatic 13. Burnweit CA, Coin D. Influence of diversion on the development of cholangitis after hepatoportoenterostomy for biliary atresia. J Pediatr Surg 1986; 21: 1143-46. 14. Vajro P, Couturier M, Lemmonier F, Odievre M. Effects of postoperative cholestyramine and phenobarbital administration on bile flow restoration in infants with extrahepatic biliary atresia. J Pediatr Surg 1986; 21: 362-65. 15. Ecoffey C, Rothman E, Bernard O, Hadchouel M, Valayer J, Alagille D. Bactenal cholangitis after surgery for biliary atresia. J Pediatr 1987; 111: 824-29. 16. Saeki M, Ogata T, Nakano M. Problems in long term survivors of biliary atresia. In: Ohi R, ed. Biliary atresia. Tokyo: Professional Postgraduate Services, 1987: 287-93. 17. Andrews WS, Wanek W, Fyock B, Grays S, Benser M. Pediatric liver transplantation: a 3-year experience. J Pediatr Surg 1989; 24: 77-82 18. Esquivel CO, Koneru B, Karrer F, et al. Liver transplantation before one year of age.
J Pediatr 1987; 110: 545-48. 19. Millis JM, Brems JJ, Hiatt JR, et al. Orthotopic liver transplantation for biliary atresia. Arch Surg 1988; 123: 1237-39. 20. Stewart BA, Hall RJ, Lilly JR. Liver transplantation and the Kasai operation in biliary atresia. J Pediatr Surg 1988; 23: 623-26
biliary atresia. Transplantation is not compromised by a previous portoenterostomy provided that complex loops-and enterostomies are avoided. Early diagnosis of biliary atresia before six weeks of age should be the goal.9 Transplantation should be considered for the infant in whom portoenterostomy fails completely or for the long-term survivor with deteriorating liver function or life-threatening portal
hypertension.
EPIDURAL MORPHINE, HYPERTENSION, AND
AORTIC SURGERY THE "stress" response that accompanies surgery leads to increases in blood concentrations of most catabolic hormones and a decrease in insulin secretion; many attempts have been made to reduce or block this response, but it is not clear whether total blockade is either necessary or desirable. In addition, increases in sympathetic nervous system activity and in catecholamine secretion may result in haemodynamic changes, including tachycardia and hypertension. These effects are most commonly seen after major operations, especially vascular or cardiac3 procedures. Patients who require peripheral vascular surgery often have associated cardiac or cerebrovascular disease, and increases in arterial pressure and heart rate may lead to myocardial ischaemia or infarction, cardiac failure, or cerebral haemorrhage. Intrathecal or epidural administration of opioids provides effective and sustained analgesia after many types of surgery by delivering high local concentrations of drug to the opioid receptors situated in the substantia gelatinosa in the spinal cord.4 Breslow and colleagues5 have now suggested that epidural morphine may reduce the frequency and severity of hypertension, and by implication the morbidity, after surgery to the abdominal aorta. Postoperative pain scores were significantly lower, and requirements for systemic morphine reduced, in patients who had received a single dose of epidural morphine 6 mg compared with those given epidural saline, and the administration of epidural morphine reduced mean arterial pressure and the need for antihypertensive drugs in the first 24 hours after operation. There were no differences between groups in perioperative adrenaline or antidiuretic hormone concentrations, but plasma noradrenaline concentration was lower in the epidural morphine group 6-24 hours postoperatively. The researchers suggest that the differences between groups with to arterial and noradrenaline respect pressure concentrations may be simply a secondary result of reduced pain, but propose that they might represent direct depression of the sympathetic nervous system, either centrally or within the spinal cord. 1. Frayn KN. Hormonal control of metabolism
m trauma and sepsis. Clin Endocrinol 1986; 24: 577-99. 2. Goldman L, Caldera DL. Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979; 50: 285-92 3. Wallach R, Karp RB, Reves JG, Oparil S, Smith LR, James TN. Pathogenesis of paroxysmal hypertension developing during and after coronary bypass surgery: a study of hemodynamic and humoral factors. Am J Cardiol 1980; 46: 559-65. 4. Morgan M. The rational use of intrathecal and extradural opioids. Br J Anaesth 1989;
63: 165-88. 5. Breslow MJ, Jordan
DA, Chnstopherson R, et al. Epidural morphine decreases hypertension by attenuating sympathetic nervous system hyperactivity. JAMA 1989; 261: 3577-81. postoperative