Letter to the Editor
PARENTERAL ACETYLSALICYLIC ACID TREATMENT IN CHILDREN WITH SICKLE CELL PAIN CRISIS: A Preliminary Report
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
A. Koren, MD 0 Pediatric Department “B,” Central Emek Hospital, Afula 18101, Israel
Bone vasocclusive crisis (VOC) is a frequent reason for hospitalization of children with sickle cell disease. In spite of significant efforts, no effective antisickling agent has been found, and hydration and analgesia are the recommended modes of treatment.’ Oral aspirin, acetaminophen, or codeine is recommended for mild pain, as is a parented narcotic for moderate or severe crises. P a r e n t e d acetylsalicylic acid (ASA) has been proved a potent analgesic with minimal side We describe the use of parented acetylsalicylic acid in 59 episodes of vasocclusive crisis in a group of 11 children with sickle cell disease treated in our department. Patients with mild bone pain were treated as outpatients with acetaminophen or dypirone, and were not included in the study. Patients with moderate pain were admitted to the ward and treated with hydration and oral analgesics (dypirone or acetaminophen) on request. Patients with severe bone pain received intravenous hypotonic fluids and intravenous acetylsalicylic acid. Acetylsalicylic acid (lysine acetylsalicylate, Lysoprin, RAFA Laboratories, Tel Aviv, Israel) was given as 15 mg/kg/ dose, limited to 0.5 g/dose and 2.0 g/day. In the first 48 hours of VOC 244 doses of acetylsalicylic acid were given. A mean of 4.1 doses per episode (range 1-8) was given in the first 2 days of VOC. During the period between 48 and 96 hours after admission, 77 doses of ASA were given in 24 episodes (mean 3.2 doses per episode). In 35 episodes ASA was not needed after 458 hours and a less potent analgesic was used. After each injection/infusion of ASA patient comfort was achieved in a mean time of 20 minutes. Usually the patients fell asleep for 4-5 hours. No adverse side effects or hemorrhagic tendencies were observed during ASA treatment. Acute chest syndrome (ACS) was present on admission in two episodes and developed during the hospitalization period in eight (13.8%). In those Pediatric Hematology and Oncolow, 9:373-376, 1992 Copykht 0 1992 by Hemisphere Publishins Corporation
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Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
374
A. KOREN
episodes the ACS developed after 3-7 days. Central nervous system VOC was not present. In all but six of the episodes the patients were discharged in good general condition after a mean of 5.8 f 3.3 days (range 2-17 days). Six episodes who developed ACS necessitated a longer hospitalization of 10 days or more. The pain of severe sickle cell crisis was described to be “equal or greater in magnitude than that suffered in the postoperative state.”’ Inadequate pain management may lead to severe mental instability and, as we observed in one case, to a nearly psychotic behavior. The specific analgesic and supportive management of sickle cell vasocclusive crisis have received little attention in the literature. Hydration, oxygen, and analgesics are usually recommended. Prompt relief of pain is recommended to avoid adverse psychological reactions and patient anxiety; otherwise pain management becomes a traumatic experience to the patient and the physician. Beutler recommended the use of nonnarcotic analgesics such as aspirin or propoxyphene “whenever they provide effective pain relief.’’ He also states that “it is often necessary to use narcotics” and that “many patients with sickle cell disease have become addicted to narcotics, and those ” ~ possible risk of addiction becomes more who have not may become ~ 0 . The significant when we treated young patients. One pediatric textbook stated that “regular administration of narcotics should be avoided to prevent addiction.’’6 A textbook of pediatric hematology recommended that acetaminophen be used in mild cases and codeine in more severe cases, and that narcotics should be used only when pain is extreme.’ Serjeant stated: “Addictive preparations should be avoided if at all possible since their frequent use in a recurring problem such as the painful crisis may lead to drug dependence.”’ In 1986 Cole et a19 reported their experience in using intravenous narcotic therapy for children with severe sickle cell pain crisis. Good pain relief was achieved after 3 hours of morphine infusion. On three occasions an overdose was given because of dosing errors. Severe respiratory distress developed in three patients, two of whom died and one of whom suffered severe hypoxic encephalopathy. They stated that narcotic therapy may not be the precipitating factor for these events. No addiction was observed. Mallouh’o’l’stated that administration of intravenous narcotics is an effective but unsafe treatment protocol for sickle cell patients, and that this mode of therapy should not be encouraged by physicians who do not closely follow up sickle cell patients. also suggested the use of narcotics in the manVichinsky et al” and Shapi1-0’~ agement of VOC. They stated that drug addiction is infrequent in patients with sickle cell anemia and is overshadowed by the prevalence of inadequate analgesic therapy.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
ACETYLSALICYLIC ACID A N D SICKLE CELL PAIN
375
Parenteral acetylsalicylic acid is a potent analgesic which was successfully compared with several known narcotic analgesics in experimental and clinical studies.‘ Several reports, including a double-blind study, have shown that ASA was as effective as pethidine or morphine hydr~chloride.*-~ During prolonged treatment with ASA no significant alteration in blood coagulation or hemorrhagic tendency was observed. I’ ASA given intravenously has a prompt onset of action (5-15 minutes) and the effect lasts about 5-6 hours. In our experience ASA provides good pain control in sickle cell patients with VOC. No side effects or hemorrhagic complications were observed. The incidence of ACS is similar to that in previous reports. Acetylsalicylic acid decreases endothelial cell prostacyclin production and some authors suggested that low prostacyclin levels may play a pathogenic role in the development of VOC in sickle cell The average length of crises observed by us 13 (5.8 days) is not different from that reported in the literature. Therefore we did not believe that the antiprostacyclin effect of ASA aggravates the severity of an already present VOC. We suggest that ASA may be a good alternative to narcotics in the management of VOC. Future controlled studies and pharmacokinetic investigations may be useful to assess the effect of acetylsalicylic acid in vasoocclusive crisis in sickle cell anemia patients.
REFERENCES 1. Vichinsky EP, Lubin BH. Sickle cell anemia and related hemoglobinopathies. Pediatr Clin North Am. 1980;27:429-447. 2. Kweekel de Vries WJ, Spierdisk J, Mattie H, et al. A new soluble acetylsalicylicacid derivative in the treatment of postoperative pain. Br J Anacsthesiol. 1974;46:133-135. 3. Cattaneo AD, Rivara A, Laund C. Valutazione clinica dell’ acetylsalicilate di lisina nel controllo del dolore postoperatorio [Clinical evaluation of lysine acetylsalycilate in the control of postoperative pain]. M i w v a Arusthesiol. 1975;41:599-606. 4. Papatheodossiou N. Traitement de la doleur post operatoire par I’acetylsalicylate de lysine injectable. Comparison d’eflicacite de I’ASL injectable et de la pentazocine [Parenteral treatment of postoperative pain with cysine acetylsalicylic acid (ASL). Comparison between ASL and pentazocline]. Med Hyg. 1976;1206:1262- 1263. 5. Beutler E. The sickle cell diseases and related disorders. In: Williams WJ, Beutler E, Erslev AJ, et al. eds. Hmtolou, 3rd Ed. New York: McGraw-Hill, 1983;583-609. 6. Pearson HA. Sickle cell hemoglobinopathies. In: Behrman RE, Vaughan VC, Eds. Nelson Zxtbook .f Pediatrics, 13th Ed. Philadelphia: W. B. Saunders, 1987;1049-1051. 7. Pearson H. Sickle cell syndromes and other hemoglobinopathies. In: Miller DR, Baehner RL, McMilIon CW, et al, eds. Blood Diseases of Infan9 and Childhood, 5th Ed. St. Louis: C . V. Mosby, 1984;402438. 8. Cole TB, Sprinkle RH, Smith SJ, Buchanan GR. Intravenous narcotic therapy for children with severe sickle cell pain crisis. AJDC. 1986;140:1255-1259. 9. Serjeant GR. Sickle Cell Disease. Oxford: Oxford Medical Publications, 1989;204. 10. Mallouh AA. Intravenous narcotics in sickle cell crises. AJDC. 1987;141:1039-1040. 11. Mallouh AA. Use of narcotics in sickle cell disease. AJDC. 1988;142:483-484. 12. Vichinsky E, Lubin BH. Suggested guidelines for the treatment of children with sickle cell anemia. HmtoUOncol Clin North Am. 1987;1:483-501. 13. Shapiro BS. The management of pain in sickle cell disease. Pediatr Clin North Am. 1989;36:1029-1045.
376
A. KOREN
14. Josue P. Utilisation de I’Acetylsalicylate de lysine en perfusion continue postoperative. A p r o p s de 42 malades de chirurgie generale. [Postoperative infusion of lysine acetylsalicylic acid. A report in 42 general surgery patients]. 721-Egic. 1973;174:11-13. 15. Stuart MJ, Sills RH. Deficiency of plasma prostacyclin or PGI, regenerating ability in sickle cell anemia. BrJ H m f o l . 1981;48:545-550. 16. Koren A, Halevi R. Decreased prostacyclin levels in sickle cell disease. Pediafr H m f o l Oncol. 1988;6:5 1-54.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
Receiucd November 13, 1991 Accepted January 22, 1992 Address correspondence to A . Koren.
PARENTERAL ACETYLSALICYLIC ACID TREATMENT IN CHILDREN WITH SICKLE CELL PAIN CRISIS: A Preliminary Report
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
A. Koren, MD 0 Pediatric Department “B,” Central Emek Hospital, Afula 18101, Israel
Bone vasocclusive crisis (VOC) is a frequent reason for hospitalization of children with sickle cell disease. In spite of significant efforts, no effective antisickling agent has been found, and hydration and analgesia are the recommended modes of treatment.’ Oral aspirin, acetaminophen, or codeine is recommended for mild pain, as is a parented narcotic for moderate or severe crises. P a r e n t e d acetylsalicylic acid (ASA) has been proved a potent analgesic with minimal side We describe the use of parented acetylsalicylic acid in 59 episodes of vasocclusive crisis in a group of 11 children with sickle cell disease treated in our department. Patients with mild bone pain were treated as outpatients with acetaminophen or dypirone, and were not included in the study. Patients with moderate pain were admitted to the ward and treated with hydration and oral analgesics (dypirone or acetaminophen) on request. Patients with severe bone pain received intravenous hypotonic fluids and intravenous acetylsalicylic acid. Acetylsalicylic acid (lysine acetylsalicylate, Lysoprin, RAFA Laboratories, Tel Aviv, Israel) was given as 15 mg/kg/ dose, limited to 0.5 g/dose and 2.0 g/day. In the first 48 hours of VOC 244 doses of acetylsalicylic acid were given. A mean of 4.1 doses per episode (range 1-8) was given in the first 2 days of VOC. During the period between 48 and 96 hours after admission, 77 doses of ASA were given in 24 episodes (mean 3.2 doses per episode). In 35 episodes ASA was not needed after 458 hours and a less potent analgesic was used. After each injection/infusion of ASA patient comfort was achieved in a mean time of 20 minutes. Usually the patients fell asleep for 4-5 hours. No adverse side effects or hemorrhagic tendencies were observed during ASA treatment. Acute chest syndrome (ACS) was present on admission in two episodes and developed during the hospitalization period in eight (13.8%). In those Pediatric Hematology and Oncolow, 9:373-376, 1992 Copykht 0 1992 by Hemisphere Publishins Corporation
3 73
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
374
A. KOREN
episodes the ACS developed after 3-7 days. Central nervous system VOC was not present. In all but six of the episodes the patients were discharged in good general condition after a mean of 5.8 f 3.3 days (range 2-17 days). Six episodes who developed ACS necessitated a longer hospitalization of 10 days or more. The pain of severe sickle cell crisis was described to be “equal or greater in magnitude than that suffered in the postoperative state.”’ Inadequate pain management may lead to severe mental instability and, as we observed in one case, to a nearly psychotic behavior. The specific analgesic and supportive management of sickle cell vasocclusive crisis have received little attention in the literature. Hydration, oxygen, and analgesics are usually recommended. Prompt relief of pain is recommended to avoid adverse psychological reactions and patient anxiety; otherwise pain management becomes a traumatic experience to the patient and the physician. Beutler recommended the use of nonnarcotic analgesics such as aspirin or propoxyphene “whenever they provide effective pain relief.’’ He also states that “it is often necessary to use narcotics” and that “many patients with sickle cell disease have become addicted to narcotics, and those ” ~ possible risk of addiction becomes more who have not may become ~ 0 . The significant when we treated young patients. One pediatric textbook stated that “regular administration of narcotics should be avoided to prevent addiction.’’6 A textbook of pediatric hematology recommended that acetaminophen be used in mild cases and codeine in more severe cases, and that narcotics should be used only when pain is extreme.’ Serjeant stated: “Addictive preparations should be avoided if at all possible since their frequent use in a recurring problem such as the painful crisis may lead to drug dependence.”’ In 1986 Cole et a19 reported their experience in using intravenous narcotic therapy for children with severe sickle cell pain crisis. Good pain relief was achieved after 3 hours of morphine infusion. On three occasions an overdose was given because of dosing errors. Severe respiratory distress developed in three patients, two of whom died and one of whom suffered severe hypoxic encephalopathy. They stated that narcotic therapy may not be the precipitating factor for these events. No addiction was observed. Mallouh’o’l’stated that administration of intravenous narcotics is an effective but unsafe treatment protocol for sickle cell patients, and that this mode of therapy should not be encouraged by physicians who do not closely follow up sickle cell patients. also suggested the use of narcotics in the manVichinsky et al” and Shapi1-0’~ agement of VOC. They stated that drug addiction is infrequent in patients with sickle cell anemia and is overshadowed by the prevalence of inadequate analgesic therapy.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
ACETYLSALICYLIC ACID A N D SICKLE CELL PAIN
375
Parenteral acetylsalicylic acid is a potent analgesic which was successfully compared with several known narcotic analgesics in experimental and clinical studies.‘ Several reports, including a double-blind study, have shown that ASA was as effective as pethidine or morphine hydr~chloride.*-~ During prolonged treatment with ASA no significant alteration in blood coagulation or hemorrhagic tendency was observed. I’ ASA given intravenously has a prompt onset of action (5-15 minutes) and the effect lasts about 5-6 hours. In our experience ASA provides good pain control in sickle cell patients with VOC. No side effects or hemorrhagic complications were observed. The incidence of ACS is similar to that in previous reports. Acetylsalicylic acid decreases endothelial cell prostacyclin production and some authors suggested that low prostacyclin levels may play a pathogenic role in the development of VOC in sickle cell The average length of crises observed by us 13 (5.8 days) is not different from that reported in the literature. Therefore we did not believe that the antiprostacyclin effect of ASA aggravates the severity of an already present VOC. We suggest that ASA may be a good alternative to narcotics in the management of VOC. Future controlled studies and pharmacokinetic investigations may be useful to assess the effect of acetylsalicylic acid in vasoocclusive crisis in sickle cell anemia patients.
REFERENCES 1. Vichinsky EP, Lubin BH. Sickle cell anemia and related hemoglobinopathies. Pediatr Clin North Am. 1980;27:429-447. 2. Kweekel de Vries WJ, Spierdisk J, Mattie H, et al. A new soluble acetylsalicylicacid derivative in the treatment of postoperative pain. Br J Anacsthesiol. 1974;46:133-135. 3. Cattaneo AD, Rivara A, Laund C. Valutazione clinica dell’ acetylsalicilate di lisina nel controllo del dolore postoperatorio [Clinical evaluation of lysine acetylsalycilate in the control of postoperative pain]. M i w v a Arusthesiol. 1975;41:599-606. 4. Papatheodossiou N. Traitement de la doleur post operatoire par I’acetylsalicylate de lysine injectable. Comparison d’eflicacite de I’ASL injectable et de la pentazocine [Parenteral treatment of postoperative pain with cysine acetylsalicylic acid (ASL). Comparison between ASL and pentazocline]. Med Hyg. 1976;1206:1262- 1263. 5. Beutler E. The sickle cell diseases and related disorders. In: Williams WJ, Beutler E, Erslev AJ, et al. eds. Hmtolou, 3rd Ed. New York: McGraw-Hill, 1983;583-609. 6. Pearson HA. Sickle cell hemoglobinopathies. In: Behrman RE, Vaughan VC, Eds. Nelson Zxtbook .f Pediatrics, 13th Ed. Philadelphia: W. B. Saunders, 1987;1049-1051. 7. Pearson H. Sickle cell syndromes and other hemoglobinopathies. In: Miller DR, Baehner RL, McMilIon CW, et al, eds. Blood Diseases of Infan9 and Childhood, 5th Ed. St. Louis: C . V. Mosby, 1984;402438. 8. Cole TB, Sprinkle RH, Smith SJ, Buchanan GR. Intravenous narcotic therapy for children with severe sickle cell pain crisis. AJDC. 1986;140:1255-1259. 9. Serjeant GR. Sickle Cell Disease. Oxford: Oxford Medical Publications, 1989;204. 10. Mallouh AA. Intravenous narcotics in sickle cell crises. AJDC. 1987;141:1039-1040. 11. Mallouh AA. Use of narcotics in sickle cell disease. AJDC. 1988;142:483-484. 12. Vichinsky E, Lubin BH. Suggested guidelines for the treatment of children with sickle cell anemia. HmtoUOncol Clin North Am. 1987;1:483-501. 13. Shapiro BS. The management of pain in sickle cell disease. Pediatr Clin North Am. 1989;36:1029-1045.
376
A. KOREN
14. Josue P. Utilisation de I’Acetylsalicylate de lysine en perfusion continue postoperative. A p r o p s de 42 malades de chirurgie generale. [Postoperative infusion of lysine acetylsalicylic acid. A report in 42 general surgery patients]. 721-Egic. 1973;174:11-13. 15. Stuart MJ, Sills RH. Deficiency of plasma prostacyclin or PGI, regenerating ability in sickle cell anemia. BrJ H m f o l . 1981;48:545-550. 16. Koren A, Halevi R. Decreased prostacyclin levels in sickle cell disease. Pediafr H m f o l Oncol. 1988;6:5 1-54.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB der LMU Muenchen on 07/03/14 For personal use only.
Receiucd November 13, 1991 Accepted January 22, 1992 Address correspondence to A . Koren.
