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Thrombocytopenia with actinomycin-D therapy
Volume 108 Number 6
E d i t o r i a l correspondence
nocturnal tube feeding in patients with cystic fibrosis is not entirely resolved. Our initial studies 9 used nasogastric tube feeding, as advocated by Dr. Shepherd and his group, and others. Our patients were able to tolerate nasogastric geeding for a m a x i m u m of 3 to 5 weeks: when they developed an upper respiratory tract infection, the nasogastric tube was intolerable. Vomiting became a significant problem. Placement of a gastrostomy tube was by incisionless technique, and the patients could be discharged home within 2 to 3 days; keeping them in hospital for a longer period of time was to train them in the techniques necessary to administer nocturnal feeds at home. We have had 5 years' experience with home enteral feeding programs for a variety of conditions, and find that the training time is the same whether the child is sent home with nasogastrie feedings or gastrostomy tube feedings. The principal advantage of jejunal feedings is that they may reduce gastroesophageal reflux. [n patients in whom gastroesophageal reflux is a problem, we have used the gastrostomy site for the placement of gastrojejunal tubes. Thus. once the gastrostomy site is established, it can be used either for intragastric or intrajejunal feeds. We agree with Dr. Shepherd that prevention of undernutrinon is essential. We suggest that for the reasons given above, for the majority of patients, until the lung disease becomes quite advanced, an effective preventive measure is to use high-fat diets. Only in those patients in whom diet therapy is ineffective is tube feeding necessary.
L. Levy, M.B.. Ch.B. P. Durie. M.D. P. Peneharz. M.B.. Ch.B. M. Corey, M.Sc. Departments o f Pediatrics and Nutritional Sciences University o f Toronto Research Institute The Hospital for Sick Children 555 University Ave. Toronto. Ontario. Canada M5G 1X8
REFERENCES
1.
2.
3. 4.
5. 6.
7.
Shepherd RW. Thomas BJ. Bennett D, et al. Changes in body composition and muscle protein degradation during nutritional supplemental in nutritionally growth retarded children with cystic fibrosis. J Pediatr Gastroenterol Nutr 1983:2:439-446. Pencharz PB. Energy intakes and low fat diets in children with cystic fibrosis. J Pediatr Gastroenterol N u t r 1983: 2:400. Crozier DN. Cystic fibrosis: a not so fatal disease. Pediatr Clin North A m 1974:21:935 Bell L, Linton W [ . Corey ML, et al. Nutrient intakes of adolescents with cystic fibrosis. J Can Diet Assoc 1981: 42:62. Gurwitz D. Corey M. Francis PWJ. et al. Perspective in cystic fibrosis. Pediatr Clin North A m 1979:26:603. Shepherd R W , Holt TL. Thomas BJ. et al. Malnutrition and cystic fibrosis: the nature of the nutritional deficit and optimal management. Nutr Abstr Rev 1984;54:1009. Kraemer R. Rudeberg A. Adorn R. et al. Relative under-
10 3 9
weight in cystic fibrosis and its prognostic value. Acta Paediatr Scand 1978:67:3. Shepherd R W , Cooksley W G E . Cook WBD. Improved growth and clinical nutritional and respiratory char~ged in response to nutritional therapy in cystic fibrosis. J PBmATR 1980:97:351. Pencharz P. Hill R. Archibald E, et al. Energy needs and nutritional rehabilitation in undernourished adolescents and young adult patients with cystic fibrosis. J Pediatr Gastroenterol N u t r 1984:3:S147. Editor's note: The above correspondence has been abbreviated
because of space limitations.
J.M.G.
Thrombocytopenia with
actinomycin-D therapy To the Editor: We read the article by Hodder et aM with great interest. We had a similar experience with thromboeytopenia associated with VAV therapy (vincristine 2 mg/m2/dose, day 1 and 7: aetinomycin-D 15 # g / k g / d o s e , days 2 through 6 per course, every 12 weeks) in a 4-year-old boy with Wilms tumor. Severe thrombocytopenia (60,000 !- 25.000/#1) occurred without any severe granuIocytopenia or anemia, with nadirs 1 to 4 days after completion of each course except one. During the eighth and tenth courses of VAV therapy, fever and thrombocytopenia (45,000/~1 and 37,000,~tl, respective!y) developed after the second and third infusions of actinomyein-D. In addition, sudden thrombocytopenia (12.000/ul) developed 10 weeks after the eighth course of VAV therapy, which returned to a normal level (275,000/#1) in a week without therapy. The patient completed 10 courses of VAV therapy in June 1985, and was seen regularly without treatment. Again. in December 1985. thrombocytopenia (44,000//4) developed. Bone marrow examination revealed that megakaryocytes were all immature, with normal other precursors. Because the thromboeytopenia persisted for 2 weeks, prednisone 2 m g / k g / d a y was prescribed. Four days after initiation of prednisone therapy the platelet count increased to 409.000/#1, and remained al a normal level after cessation of prednisone. The Wilms tumor has also been in complete remission. Thus. the thrombocytopenia developed during, shortly after, and long after aetinomycin-D therapy. Inasmuch as actinomycin-D is an antibiotic agent, it is conceivable that immune thromboeytopenia long a,fter actinomycin-D therapy could result from exposure to an antigen similar to or cross-reactive with actinomycin-D. Therefore. careful follow-up of thrombocytopeni~t might be recommended, even after therapy, in patients in whom thrombocytopenia develops associated with actinomycin-D therapy.
Toshiro Hara. M.D. Eiiehi Ishii. M.D. Kohji Ueda. M.D. Department o f Pediatrics Faculty o f Medicine Kyushu University Maidashi 3-1-1. Higashi-ku Fukuoka 812. Japan
10 4 0
Editorial correspondence
REFERENCES
1.
Hodder F S, Kempert P, McCormack S, et al. Immune thr0mboeytopenia following actinomycin-D therapy. J PEDI: ATR 1985;107:6! 1.
Reply
The Journal of Pediatrics June 1986
one infant given theophylline and in four given placebo the tubes were not removed during the study period. At first glance, xanthines appea~" useful in the periextubation period. We encourage Viscardi et al. to address the issues we have raised so that clinicians can decide whether the rules of evidence have been satisfied and the value of theophylline has been firmly established.
William F. Powers, M.D., M.P.H. Assistant Clinical Professor of Pediatrics University of Illinois College of Medicine at Peoria Peoria, IL 61656 Robert J. Anderson, M.P.H., Ph.D. Associate Professor Epidemiology-Biometry Program School of Publ(c Health University of Illinois at Chicago Chicago, IL 60680
TO the Editor: We have subsequently followed the five patients reported in The Journal, a n d none has developed thrombocytopenia either shortly after or long after chemotherapy. It is speculative to assume that the patient reported by Hara et al. developed immune thrombocytopenia from an antigen cross-reactive with actinomycin-D many months after therapy. It would be of interest to go back in this patient's history and review the type of exposures that may have occurred 2 to 4 weeks prior to this last episode of immune thromboeytopenia. It would also be interesting to measure antiplatelet antibodies during the course of actinomycin-D therapy or during the subsequent episode of immune thrombocytopenla. This letter suggests that we should continue to observe patients in whom this syndrome develops during the course of actinomycin-D therapy, and especially document any subsequent episodes of therapy while these patients are receiving antibiotics that may have cross-reactive antigens. Mitchell S. Cai~'o, M.D. Director, Hematology-Oncology Research Childrens Hospital of Orange County P.O. Box 5700 Orange, CA 92667-0700 Assistant Professor o f Pediatric s University of California, Irvine
Theophylline to prevent post-extubation respiratory failure To the Editor: The recent report by Viscardi et al. 1 on the use of theophylline for prevention o f post-extubation respiratory failure raises the question: Were the accumulating data subjected to more than one statistical analysis'? It is unclear what criterion was used for evaluating and terminating the study. The Fisher exact test is reasonable for the data as presented in Table II in the context of a fixed sample size or a fixed time interval study, but it is not clear whether this procedure was used as a monitoring mechanism to determine when to stop the study. If the Fisher-exact test was indeed used for monitoring the study, there is no indication of the method used for overall protection against a type 1 error. Failure to make such an adjustment may lead to inappropriately low P values. A few fine points also need clarification. The preliminary abstract 2 says that five maintenance doses of theophylline were given, whereas the report mentions six. The text mentions that in three infants in each group the endotracheal tubes were not removed during the 72-hour study, whereas Table 11 states that in
REFERENCES
1.
2.
Viscardi RM, Faix RG, Nicks J J, Grasela TH. Efficacy of theophylline for prevention of post-extubation respiratory failure in very 10w birth weight infants. J PEDIATR 1985;107;469. Viscardi RM, Faix RG, Grasela TH, Nicks JJ. Efficacy of the0Phyltine for prevention of post-extubation respiratory failure in infants less than 1250 grams. Pediatr Res 1985;19:396A.
Reply To the Editor: The accumulating data were subjected to two statistical analyses. Sample size was originally determined using a review of all infants weighing <1250 gm during the 2 years preceding the study. Comparison of the frequency of successful post-extubation courses in those infants who had received empirical theophylline treatment at the discretion of their caretakers and those Who had not, enabled us to calculate that a sample siz e of 30 (15 in each group) would be necessary if the retrospectively observed frequencies continued, using c~ <0.05 and/3 <0.20. Treatment assignment was decoded during the study only for infants in whom treatment had failed. With treatment assignment for the Successfully extubated patients remaining unknown, we could not have analyzed after every patient even if we had so desired. One analysis was conducted for submission of an abstract to the Midwest Society for Pediatric Research (Clin Res 1984;32:508A) after 19 patients had completed the study; theophylllne resulted in successful extubation for at least 5 days significantly more Often than placebo, with P = 0.0049 at that time. The second analysis was performed after all of the predetermined 30 prepackaged treatment courses had been expended: 25 patients had completed the studY; one patient had been excluded because of protocol violations; four prepackaged courses were unusable for a variety of reasons. Results of the second ana!ysis were reporte d in The Journal, P = 0.007 at that time (rounded offto 0.01 in the article). Powers and Anderson are correct that adjustments need to be
E d i t o r i a l correspondence
nocturnal tube feeding in patients with cystic fibrosis is not entirely resolved. Our initial studies 9 used nasogastric tube feeding, as advocated by Dr. Shepherd and his group, and others. Our patients were able to tolerate nasogastric geeding for a m a x i m u m of 3 to 5 weeks: when they developed an upper respiratory tract infection, the nasogastric tube was intolerable. Vomiting became a significant problem. Placement of a gastrostomy tube was by incisionless technique, and the patients could be discharged home within 2 to 3 days; keeping them in hospital for a longer period of time was to train them in the techniques necessary to administer nocturnal feeds at home. We have had 5 years' experience with home enteral feeding programs for a variety of conditions, and find that the training time is the same whether the child is sent home with nasogastrie feedings or gastrostomy tube feedings. The principal advantage of jejunal feedings is that they may reduce gastroesophageal reflux. [n patients in whom gastroesophageal reflux is a problem, we have used the gastrostomy site for the placement of gastrojejunal tubes. Thus. once the gastrostomy site is established, it can be used either for intragastric or intrajejunal feeds. We agree with Dr. Shepherd that prevention of undernutrinon is essential. We suggest that for the reasons given above, for the majority of patients, until the lung disease becomes quite advanced, an effective preventive measure is to use high-fat diets. Only in those patients in whom diet therapy is ineffective is tube feeding necessary.
L. Levy, M.B.. Ch.B. P. Durie. M.D. P. Peneharz. M.B.. Ch.B. M. Corey, M.Sc. Departments o f Pediatrics and Nutritional Sciences University o f Toronto Research Institute The Hospital for Sick Children 555 University Ave. Toronto. Ontario. Canada M5G 1X8
REFERENCES
1.
2.
3. 4.
5. 6.
7.
Shepherd RW. Thomas BJ. Bennett D, et al. Changes in body composition and muscle protein degradation during nutritional supplemental in nutritionally growth retarded children with cystic fibrosis. J Pediatr Gastroenterol Nutr 1983:2:439-446. Pencharz PB. Energy intakes and low fat diets in children with cystic fibrosis. J Pediatr Gastroenterol N u t r 1983: 2:400. Crozier DN. Cystic fibrosis: a not so fatal disease. Pediatr Clin North A m 1974:21:935 Bell L, Linton W [ . Corey ML, et al. Nutrient intakes of adolescents with cystic fibrosis. J Can Diet Assoc 1981: 42:62. Gurwitz D. Corey M. Francis PWJ. et al. Perspective in cystic fibrosis. Pediatr Clin North A m 1979:26:603. Shepherd R W , Holt TL. Thomas BJ. et al. Malnutrition and cystic fibrosis: the nature of the nutritional deficit and optimal management. Nutr Abstr Rev 1984;54:1009. Kraemer R. Rudeberg A. Adorn R. et al. Relative under-
10 3 9
weight in cystic fibrosis and its prognostic value. Acta Paediatr Scand 1978:67:3. Shepherd R W , Cooksley W G E . Cook WBD. Improved growth and clinical nutritional and respiratory char~ged in response to nutritional therapy in cystic fibrosis. J PBmATR 1980:97:351. Pencharz P. Hill R. Archibald E, et al. Energy needs and nutritional rehabilitation in undernourished adolescents and young adult patients with cystic fibrosis. J Pediatr Gastroenterol N u t r 1984:3:S147. Editor's note: The above correspondence has been abbreviated
because of space limitations.
J.M.G.
Thrombocytopenia with
actinomycin-D therapy To the Editor: We read the article by Hodder et aM with great interest. We had a similar experience with thromboeytopenia associated with VAV therapy (vincristine 2 mg/m2/dose, day 1 and 7: aetinomycin-D 15 # g / k g / d o s e , days 2 through 6 per course, every 12 weeks) in a 4-year-old boy with Wilms tumor. Severe thrombocytopenia (60,000 !- 25.000/#1) occurred without any severe granuIocytopenia or anemia, with nadirs 1 to 4 days after completion of each course except one. During the eighth and tenth courses of VAV therapy, fever and thrombocytopenia (45,000/~1 and 37,000,~tl, respective!y) developed after the second and third infusions of actinomyein-D. In addition, sudden thrombocytopenia (12.000/ul) developed 10 weeks after the eighth course of VAV therapy, which returned to a normal level (275,000/#1) in a week without therapy. The patient completed 10 courses of VAV therapy in June 1985, and was seen regularly without treatment. Again. in December 1985. thrombocytopenia (44,000//4) developed. Bone marrow examination revealed that megakaryocytes were all immature, with normal other precursors. Because the thromboeytopenia persisted for 2 weeks, prednisone 2 m g / k g / d a y was prescribed. Four days after initiation of prednisone therapy the platelet count increased to 409.000/#1, and remained al a normal level after cessation of prednisone. The Wilms tumor has also been in complete remission. Thus. the thrombocytopenia developed during, shortly after, and long after aetinomycin-D therapy. Inasmuch as actinomycin-D is an antibiotic agent, it is conceivable that immune thromboeytopenia long a,fter actinomycin-D therapy could result from exposure to an antigen similar to or cross-reactive with actinomycin-D. Therefore. careful follow-up of thrombocytopeni~t might be recommended, even after therapy, in patients in whom thrombocytopenia develops associated with actinomycin-D therapy.
Toshiro Hara. M.D. Eiiehi Ishii. M.D. Kohji Ueda. M.D. Department o f Pediatrics Faculty o f Medicine Kyushu University Maidashi 3-1-1. Higashi-ku Fukuoka 812. Japan
10 4 0
Editorial correspondence
REFERENCES
1.
Hodder F S, Kempert P, McCormack S, et al. Immune thr0mboeytopenia following actinomycin-D therapy. J PEDI: ATR 1985;107:6! 1.
Reply
The Journal of Pediatrics June 1986
one infant given theophylline and in four given placebo the tubes were not removed during the study period. At first glance, xanthines appea~" useful in the periextubation period. We encourage Viscardi et al. to address the issues we have raised so that clinicians can decide whether the rules of evidence have been satisfied and the value of theophylline has been firmly established.
William F. Powers, M.D., M.P.H. Assistant Clinical Professor of Pediatrics University of Illinois College of Medicine at Peoria Peoria, IL 61656 Robert J. Anderson, M.P.H., Ph.D. Associate Professor Epidemiology-Biometry Program School of Publ(c Health University of Illinois at Chicago Chicago, IL 60680
TO the Editor: We have subsequently followed the five patients reported in The Journal, a n d none has developed thrombocytopenia either shortly after or long after chemotherapy. It is speculative to assume that the patient reported by Hara et al. developed immune thrombocytopenia from an antigen cross-reactive with actinomycin-D many months after therapy. It would be of interest to go back in this patient's history and review the type of exposures that may have occurred 2 to 4 weeks prior to this last episode of immune thromboeytopenia. It would also be interesting to measure antiplatelet antibodies during the course of actinomycin-D therapy or during the subsequent episode of immune thrombocytopenla. This letter suggests that we should continue to observe patients in whom this syndrome develops during the course of actinomycin-D therapy, and especially document any subsequent episodes of therapy while these patients are receiving antibiotics that may have cross-reactive antigens. Mitchell S. Cai~'o, M.D. Director, Hematology-Oncology Research Childrens Hospital of Orange County P.O. Box 5700 Orange, CA 92667-0700 Assistant Professor o f Pediatric s University of California, Irvine
Theophylline to prevent post-extubation respiratory failure To the Editor: The recent report by Viscardi et al. 1 on the use of theophylline for prevention o f post-extubation respiratory failure raises the question: Were the accumulating data subjected to more than one statistical analysis'? It is unclear what criterion was used for evaluating and terminating the study. The Fisher exact test is reasonable for the data as presented in Table II in the context of a fixed sample size or a fixed time interval study, but it is not clear whether this procedure was used as a monitoring mechanism to determine when to stop the study. If the Fisher-exact test was indeed used for monitoring the study, there is no indication of the method used for overall protection against a type 1 error. Failure to make such an adjustment may lead to inappropriately low P values. A few fine points also need clarification. The preliminary abstract 2 says that five maintenance doses of theophylline were given, whereas the report mentions six. The text mentions that in three infants in each group the endotracheal tubes were not removed during the 72-hour study, whereas Table 11 states that in
REFERENCES
1.
2.
Viscardi RM, Faix RG, Nicks J J, Grasela TH. Efficacy of theophylline for prevention of post-extubation respiratory failure in very 10w birth weight infants. J PEDIATR 1985;107;469. Viscardi RM, Faix RG, Grasela TH, Nicks JJ. Efficacy of the0Phyltine for prevention of post-extubation respiratory failure in infants less than 1250 grams. Pediatr Res 1985;19:396A.
Reply To the Editor: The accumulating data were subjected to two statistical analyses. Sample size was originally determined using a review of all infants weighing <1250 gm during the 2 years preceding the study. Comparison of the frequency of successful post-extubation courses in those infants who had received empirical theophylline treatment at the discretion of their caretakers and those Who had not, enabled us to calculate that a sample siz e of 30 (15 in each group) would be necessary if the retrospectively observed frequencies continued, using c~ <0.05 and/3 <0.20. Treatment assignment was decoded during the study only for infants in whom treatment had failed. With treatment assignment for the Successfully extubated patients remaining unknown, we could not have analyzed after every patient even if we had so desired. One analysis was conducted for submission of an abstract to the Midwest Society for Pediatric Research (Clin Res 1984;32:508A) after 19 patients had completed the study; theophylllne resulted in successful extubation for at least 5 days significantly more Often than placebo, with P = 0.0049 at that time. The second analysis was performed after all of the predetermined 30 prepackaged treatment courses had been expended: 25 patients had completed the studY; one patient had been excluded because of protocol violations; four prepackaged courses were unusable for a variety of reasons. Results of the second ana!ysis were reporte d in The Journal, P = 0.007 at that time (rounded offto 0.01 in the article). Powers and Anderson are correct that adjustments need to be