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Circulating endotoxins during orthotopic liver transplantation and post-reperfusion syndrome
Letters to the Editor
Haemophilus influenzae immunisation and timing of cardiac transplantation SIR-Haemophilus influenzae is a major cause of morbidity and mortality in children. The conjugate H influenzae type b (Hib) vaccines are safe and immunisation in infancy can protect against disease.1,2 Children on the waiting list for cardiac transplantation in our unit are now routinely immunised with Hib if under the age of 5 years. The timing of transplantation in any child on the active waiting list is unpredictable and we have had two children transplanted shortly after vaccine administration. Case 1 (2-day-old girl in cardiac failure)-Hypoplastic left heart syndrome was diagnosed. She had several palliative procedures to ensure that the right ventricle could supply the systemic circulation and would hopefully maintain her until she received a heart transplant some time in infancy. She was discharged home at age 8 weeks to await transplantation. She received the Hib (Merieux Pasteur) vaccine at age 6 months. A month later she underwent cardiac transplantation with the usual immunosuppressive regimen of intravenous cyclosporin, azathioprine, and equine antithymocyte globulin. She died soon after operation as a result of primary dysfunction of the donor heart, but there was a heavy growth of H influenzae type b in the tracheal aspirate. Case 2 (4-year-old boy with severe dilated cardiomyopathy, admitted for transplant assessment)-since he was severely incapacitated he was placed on the active waiting list and went home to await transplantation. He had the Hib vaccine (Merieux Pasteur) at age 4 years 4 months, and 8 days later underwent cardiac transplantation. On the next day H influenzae type b was cultured from tracheal aspirates, but was not treated initially as he had no clinical signs of infection. However, 48 hours later, when an episode of rejection required treatment with methylprednisolone and the growth of the organism had become profuse, he was given amoxycillin. He made a good postoperative recovery and was discharged well from intensive care 16 days after transplantation. H influenzae is an important pathogen, especially in children under 2 years old. The organism is a normal commensal of the upper respiratory tract and bacteraemia occurs when the encapsulated serotype b invades the respiratory epithelium. In children about to undergo cardiac transplantation with its obvious long-term use of immunosuppressive drugs, we are keen to immunise before transplantation because it takes several weeks to achieve immunity. Our policy is not to delay transplantation after immunisation because the vaccine is not live. Our two patients were transplanted soon after immunisation and were subsequently shown to have extensive colonisation of the upper airways with H influenzae type b. The heavy growth of haemophilus may not have been related to recent vaccination. However, local nasopharyngeal immunity may be affected by vaccination in a similar way to that postulated after the meningococcal vaccine.3 The combination of recent vaccination with the profound immunosuppression associated with transplantation may especially predispose to colonisation with haemophilus type b.
We have not changed our policy of transplantation after immunisation with Hib but, if the clinical situation permits, it may be prudent to delay transplantation for about 6 weeks. John
O’Sullivan, John H Dark, Kate Gould
Cardiopulmonary Transplant Unit and Department of Microbiology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK 1 2
3
Moxon ER, Rappuoli R. Modern vaccines. Lancet 1990; 335: 1324-29. Eskola J, Peltola H, Takala AK et al. Efficacy of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy. N Engl J Med 1987; 317: 717-22. Gotschlich E, Goldschneider I, Arstein S. Human immunity to the meningococcus: the effect of immunisation with meningococcal group c polysaccharide on the carrier state. J Exp Med 1969; 129: 1385-95.
Circulating endotoxins during orthotopic liver transplantation and post-reperfusion syndrome SiR-Liver revascularisation during orthotopic liver transplantation (OLT) has been associated with an unexplained and unpredictable cardiovascular depression,l which shares some analogies with septic shock, in which the role of endotoxins is established.2 We have prospectively evaluated the relation between circulating endotoxins during OLT and this post-reperfusion syndrome (PRS). Fifteen consecutive adult patients without documented infection and undergoing OLT were studied. In every patient a radial artery catheter was inserted for the continuous measurement of systemic arterial pressure. At the revascularisation of the newly grafted liver, the PRS was noted as "a decrease in MAP greater than or equal to 30% from baseline for at least one minute within five minutes of reperfusion".3 Blood samples were collected from arterial catheter and portal vein in sterile pyrogen-free heparinised glass-tubes before restoring graft circulation. A kinetic chromogenic limulus amoebocyte lysate assay was used to measure endotoxins, in duplicate by one technician blinded to clinical data (sensitivity, 0-1endotoxin U/mL in plasma). The relation between endotoxins at the end of the anhepatic phase and the PRS was assessed.
Table: Plasma endotoxins
(U/mL) and development of PRS. 859
The endotoxaemias observed are shown in the table. Only four recipients had detectable endotoxaemia in the anhepatic phase (patients 5, 8, and 10) and four (4,5,12,14) demonstrated typical PRS as defined above. Only patient 5 had both. No correlation was found between plasma endotoxins and the
PRS. PRS occurs in about 30% of OLTs.3 Acidosis, hypothermia, and hyperkalaemia did not seem to be responsible for this syndrome, as initially suspected. A myocardial depressant factor was isolated from the plasma of patients who underwent OLT with PRS,4but this syndrome remains unexplained.
Stephane Blanot, Marie Christine Gillon, Claude Ecoffey Département d’Anesthésie-Réanimation, Hôpital Paul Brousse, Université Paris-Sud, 94804 Villejuif, France
Isabelle Lopez Laboratoire BioWhittaker
1
2 3
4
Lindop MJ, Farman JV. Anesthesia for hepatic transplantation: cardiovascular and metabolic alterations and their management. Anesth Analg 1985; 64: 108-16. Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE. Endotoxemia in human septic shock. Chest 1991; 99: 169-75. Aggarwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc 1987; 10: 54. Jayais P, Chemla D, Ecoffey C, Descorpe Declere A, Samii K, Lecarpentier Y. Myocardial depressant effect of plasma from liver transplanted patients with post reperfusion syndrome: an in-vitro study. Anesthesiology 1991; 75: A554. Carmichael FJ,
Renal
transplantation granulomatosis
In
Wegener’s
SIR-Although Wegener’s granulomatosis (WG) associated glomerulonephritis may result in end-stage renal failure, only anecdotal data are available about the long-term outcome of renal transplantation1,2 and the course with standard immunosuppression (cyclosporin and prednisolone). 3 . We report on 20 WG patients (15 males, 5 females, mean age 38-1 years) who received renal transplant between 1982 and 1993. All patients met ACR-1990 criteria for WG,4 19 were histologically confirmed for anti-neutrophil cytoplasmic antibodies (cANCA). In addition to renal involvement, typical symptoms occurred in the upper and/or lower respiratory tract. Treatment before transplantation consisted of oral cyclophosphamide plus prednisolone in 19 patients, and azathioprine plus prednisolone in 1. 12 patients had had 27 relapses before or during haemodialysis (0-2 and 0-3 relapses per patient per year, respectively) (figure). At transplantation, 6 patients showed symptoms of active disease (5 upper and 1 lower respiratory tract, 1 eye involvement). cANCA titres, available in 12, were positive in 8. The immunosuppressive regimen and frequency of relapse after transplantation are shown in the figure. During a mean follow-up of 48 months (range 4-114), 5 of the 20 patients had 7 relapses (0-1 relapses per patient per year) of the upper (5) and lower (2) respiratory tract, the eyes (1), and the gut (1). 1 patient on cyclosporin plus prednisolone died 46 months after transplantation during a severe relapse involving the lungs and gut, but not the kidneys. All other patients who relapsed were treated successfully. 6 patients with active disease at transplantation achieved remission for 29 (3-60) months (2 relapses only, after 3 and 54 months, respectively). It should be stressed, however, that after transplantation 5 of 6 were given azathiopine (3) or cyclophosphamide (2) in addition to with
Figure: Frequency of relapse In WG before and after transplantation (upper) with respect to treatment modalities (below) institutions. 1 patient lost graft function due to biopsy-proven chronic rejection. Our remaining 18 patients have functioning grafts with a mean creatinine of 150-3 (imoI/L (range 53-0282-9). 16 patients are in complete remission; 2 display signs of active WG in the upper respiratory tract (2) and the eyes (1) without progressive features. These data demonstrate that survival rate and graft function in patients with WG are similar to those of other transplanted groups. According to our results, patients with symptoms of active disease at time of allograft availability do not have to be excluded from transplantation, since no immediate exacerbation has been observed after the operation. Relapse rate is reduced to one-third compared with the time before transplantation, even in patients receiving cyclosporin plus
prednisolone only. Thus, post-transplant therapy must not necessarily include cyclophosphamide. Recurrence of WG in the allograft is rares and does not cause additional graft loss. Therefore, renal transplantation should be offered to patients with WG and end-stage renal disease. Because late and life-threatening relapses may occur, follow-up has to include short-term control of vasculitic activity. Wilhelm H Schmitt, Marion Haubitz, Nouhad Mistry, Reinhard Brunkhorst, Brigitte Erbslöh-Möller, Wolfgang L Gross Departments of Rheumatology and Internal Medicine, University of Lubeck, Rheumaklinik Bad Bramstedt, 24576 Bad Bramstedt, Germany; and Department of Nephrology, University of Hannover 1
2
3
860
108-11. Kuross S, Davin T, Kjellstrand CM. Wegener’s granulomatosis with severe renal failure: clinical course and results of dialysis and transplantation. Clin Nephrol 1991; 16: 172-80. Schollmeyer P, Grotz W. Cyclosporin in the treatment of Wegener’s granulomatosis (WG) and related diseases. APMIS 1990; 98
(suppl 19): 4
cyclosporin/prednisolone. The frequency of rejection and infectious complications was similar to that of the total population transplanted in our
Tzardis PJ, Gruessner RWG, Matas AJ, et al. Long-term follow-up of renal transplantation for Wegener’s disease. Clin Transplant 1990; 4:
5
54-55.
Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990; 33: 1101-07. Lowance DC, Vosatka K, Whelchel J, et al. Recurrent Wegener’s granulomatosis. Am J Med 1992; 92: 573-75.
Haemophilus influenzae immunisation and timing of cardiac transplantation SIR-Haemophilus influenzae is a major cause of morbidity and mortality in children. The conjugate H influenzae type b (Hib) vaccines are safe and immunisation in infancy can protect against disease.1,2 Children on the waiting list for cardiac transplantation in our unit are now routinely immunised with Hib if under the age of 5 years. The timing of transplantation in any child on the active waiting list is unpredictable and we have had two children transplanted shortly after vaccine administration. Case 1 (2-day-old girl in cardiac failure)-Hypoplastic left heart syndrome was diagnosed. She had several palliative procedures to ensure that the right ventricle could supply the systemic circulation and would hopefully maintain her until she received a heart transplant some time in infancy. She was discharged home at age 8 weeks to await transplantation. She received the Hib (Merieux Pasteur) vaccine at age 6 months. A month later she underwent cardiac transplantation with the usual immunosuppressive regimen of intravenous cyclosporin, azathioprine, and equine antithymocyte globulin. She died soon after operation as a result of primary dysfunction of the donor heart, but there was a heavy growth of H influenzae type b in the tracheal aspirate. Case 2 (4-year-old boy with severe dilated cardiomyopathy, admitted for transplant assessment)-since he was severely incapacitated he was placed on the active waiting list and went home to await transplantation. He had the Hib vaccine (Merieux Pasteur) at age 4 years 4 months, and 8 days later underwent cardiac transplantation. On the next day H influenzae type b was cultured from tracheal aspirates, but was not treated initially as he had no clinical signs of infection. However, 48 hours later, when an episode of rejection required treatment with methylprednisolone and the growth of the organism had become profuse, he was given amoxycillin. He made a good postoperative recovery and was discharged well from intensive care 16 days after transplantation. H influenzae is an important pathogen, especially in children under 2 years old. The organism is a normal commensal of the upper respiratory tract and bacteraemia occurs when the encapsulated serotype b invades the respiratory epithelium. In children about to undergo cardiac transplantation with its obvious long-term use of immunosuppressive drugs, we are keen to immunise before transplantation because it takes several weeks to achieve immunity. Our policy is not to delay transplantation after immunisation because the vaccine is not live. Our two patients were transplanted soon after immunisation and were subsequently shown to have extensive colonisation of the upper airways with H influenzae type b. The heavy growth of haemophilus may not have been related to recent vaccination. However, local nasopharyngeal immunity may be affected by vaccination in a similar way to that postulated after the meningococcal vaccine.3 The combination of recent vaccination with the profound immunosuppression associated with transplantation may especially predispose to colonisation with haemophilus type b.
We have not changed our policy of transplantation after immunisation with Hib but, if the clinical situation permits, it may be prudent to delay transplantation for about 6 weeks. John
O’Sullivan, John H Dark, Kate Gould
Cardiopulmonary Transplant Unit and Department of Microbiology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK 1 2
3
Moxon ER, Rappuoli R. Modern vaccines. Lancet 1990; 335: 1324-29. Eskola J, Peltola H, Takala AK et al. Efficacy of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy. N Engl J Med 1987; 317: 717-22. Gotschlich E, Goldschneider I, Arstein S. Human immunity to the meningococcus: the effect of immunisation with meningococcal group c polysaccharide on the carrier state. J Exp Med 1969; 129: 1385-95.
Circulating endotoxins during orthotopic liver transplantation and post-reperfusion syndrome SiR-Liver revascularisation during orthotopic liver transplantation (OLT) has been associated with an unexplained and unpredictable cardiovascular depression,l which shares some analogies with septic shock, in which the role of endotoxins is established.2 We have prospectively evaluated the relation between circulating endotoxins during OLT and this post-reperfusion syndrome (PRS). Fifteen consecutive adult patients without documented infection and undergoing OLT were studied. In every patient a radial artery catheter was inserted for the continuous measurement of systemic arterial pressure. At the revascularisation of the newly grafted liver, the PRS was noted as "a decrease in MAP greater than or equal to 30% from baseline for at least one minute within five minutes of reperfusion".3 Blood samples were collected from arterial catheter and portal vein in sterile pyrogen-free heparinised glass-tubes before restoring graft circulation. A kinetic chromogenic limulus amoebocyte lysate assay was used to measure endotoxins, in duplicate by one technician blinded to clinical data (sensitivity, 0-1endotoxin U/mL in plasma). The relation between endotoxins at the end of the anhepatic phase and the PRS was assessed.
Table: Plasma endotoxins
(U/mL) and development of PRS. 859
The endotoxaemias observed are shown in the table. Only four recipients had detectable endotoxaemia in the anhepatic phase (patients 5, 8, and 10) and four (4,5,12,14) demonstrated typical PRS as defined above. Only patient 5 had both. No correlation was found between plasma endotoxins and the
PRS. PRS occurs in about 30% of OLTs.3 Acidosis, hypothermia, and hyperkalaemia did not seem to be responsible for this syndrome, as initially suspected. A myocardial depressant factor was isolated from the plasma of patients who underwent OLT with PRS,4but this syndrome remains unexplained.
Stephane Blanot, Marie Christine Gillon, Claude Ecoffey Département d’Anesthésie-Réanimation, Hôpital Paul Brousse, Université Paris-Sud, 94804 Villejuif, France
Isabelle Lopez Laboratoire BioWhittaker
1
2 3
4
Lindop MJ, Farman JV. Anesthesia for hepatic transplantation: cardiovascular and metabolic alterations and their management. Anesth Analg 1985; 64: 108-16. Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE. Endotoxemia in human septic shock. Chest 1991; 99: 169-75. Aggarwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc 1987; 10: 54. Jayais P, Chemla D, Ecoffey C, Descorpe Declere A, Samii K, Lecarpentier Y. Myocardial depressant effect of plasma from liver transplanted patients with post reperfusion syndrome: an in-vitro study. Anesthesiology 1991; 75: A554. Carmichael FJ,
Renal
transplantation granulomatosis
In
Wegener’s
SIR-Although Wegener’s granulomatosis (WG) associated glomerulonephritis may result in end-stage renal failure, only anecdotal data are available about the long-term outcome of renal transplantation1,2 and the course with standard immunosuppression (cyclosporin and prednisolone). 3 . We report on 20 WG patients (15 males, 5 females, mean age 38-1 years) who received renal transplant between 1982 and 1993. All patients met ACR-1990 criteria for WG,4 19 were histologically confirmed for anti-neutrophil cytoplasmic antibodies (cANCA). In addition to renal involvement, typical symptoms occurred in the upper and/or lower respiratory tract. Treatment before transplantation consisted of oral cyclophosphamide plus prednisolone in 19 patients, and azathioprine plus prednisolone in 1. 12 patients had had 27 relapses before or during haemodialysis (0-2 and 0-3 relapses per patient per year, respectively) (figure). At transplantation, 6 patients showed symptoms of active disease (5 upper and 1 lower respiratory tract, 1 eye involvement). cANCA titres, available in 12, were positive in 8. The immunosuppressive regimen and frequency of relapse after transplantation are shown in the figure. During a mean follow-up of 48 months (range 4-114), 5 of the 20 patients had 7 relapses (0-1 relapses per patient per year) of the upper (5) and lower (2) respiratory tract, the eyes (1), and the gut (1). 1 patient on cyclosporin plus prednisolone died 46 months after transplantation during a severe relapse involving the lungs and gut, but not the kidneys. All other patients who relapsed were treated successfully. 6 patients with active disease at transplantation achieved remission for 29 (3-60) months (2 relapses only, after 3 and 54 months, respectively). It should be stressed, however, that after transplantation 5 of 6 were given azathiopine (3) or cyclophosphamide (2) in addition to with
Figure: Frequency of relapse In WG before and after transplantation (upper) with respect to treatment modalities (below) institutions. 1 patient lost graft function due to biopsy-proven chronic rejection. Our remaining 18 patients have functioning grafts with a mean creatinine of 150-3 (imoI/L (range 53-0282-9). 16 patients are in complete remission; 2 display signs of active WG in the upper respiratory tract (2) and the eyes (1) without progressive features. These data demonstrate that survival rate and graft function in patients with WG are similar to those of other transplanted groups. According to our results, patients with symptoms of active disease at time of allograft availability do not have to be excluded from transplantation, since no immediate exacerbation has been observed after the operation. Relapse rate is reduced to one-third compared with the time before transplantation, even in patients receiving cyclosporin plus
prednisolone only. Thus, post-transplant therapy must not necessarily include cyclophosphamide. Recurrence of WG in the allograft is rares and does not cause additional graft loss. Therefore, renal transplantation should be offered to patients with WG and end-stage renal disease. Because late and life-threatening relapses may occur, follow-up has to include short-term control of vasculitic activity. Wilhelm H Schmitt, Marion Haubitz, Nouhad Mistry, Reinhard Brunkhorst, Brigitte Erbslöh-Möller, Wolfgang L Gross Departments of Rheumatology and Internal Medicine, University of Lubeck, Rheumaklinik Bad Bramstedt, 24576 Bad Bramstedt, Germany; and Department of Nephrology, University of Hannover 1
2
3
860
108-11. Kuross S, Davin T, Kjellstrand CM. Wegener’s granulomatosis with severe renal failure: clinical course and results of dialysis and transplantation. Clin Nephrol 1991; 16: 172-80. Schollmeyer P, Grotz W. Cyclosporin in the treatment of Wegener’s granulomatosis (WG) and related diseases. APMIS 1990; 98
(suppl 19): 4
cyclosporin/prednisolone. The frequency of rejection and infectious complications was similar to that of the total population transplanted in our
Tzardis PJ, Gruessner RWG, Matas AJ, et al. Long-term follow-up of renal transplantation for Wegener’s disease. Clin Transplant 1990; 4:
5
54-55.
Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990; 33: 1101-07. Lowance DC, Vosatka K, Whelchel J, et al. Recurrent Wegener’s granulomatosis. Am J Med 1992; 92: 573-75.