Randomized, double-blind, crossover, placebo-controlled trial of intravenous ondansetron for the prevention of intrathecal chemotherapy-induced vomiting in children.

BACKGROUND: The purpose of this study was to determine the effectiveness of intravenous ondansetron in preventing vomiting after the administration of intrathecal chemotherapy in children. PATIENTS AND METHODS: Twenty-six children (ages 18 mo to 15 y) receiving intrathecal chemotherapy with either methotrexate or the combination of methotrexate, hydrocortisone, and Ara-C for the prophylactic treatment of central nervous system leukemia were randomly assigned to receive an infusion of normal saline or ondansetron at one of two doses (0.15 or 0.45 mg/kg) 30 minutes before undergoing the procedure. One hundred forty-six infusions were administered (51 placebo, 47 at the lower ondansetron dose, and 48 at the higher dose). Each patient acted as his or her own control, and each patient was studied at least three times. RESULTS: Twenty-three of 26 patients (88.5%) had postprocedural vomiting on at least one occasion. At least one episode of vomiting occurred during the 24 hours after the procedure in fifty-two of the procedures (35.6%). The incidence of vomiting was significantly greater after infusion of placebo than after either low-dose or high-dose ondansetron. The likelihood of severe vomiting was even more significantly reduced by the preadministration of ondansetron. Almost all of the intrathecal treatments associated with severe vomiting occurred after the infusion of placebo. CONCLUSIONS: Vomiting induced by intrathecal chemotherapy can be greatly reduced by the intravenous administration of ondansetron before the procedure, and severe vomiting can be virtually eliminated.

Metastatic congenital adrenocortical carcinoma: a case report with tumor remission at 3 1/2 years.

We describe a case of metastasizing congenital adrenocortical carcinoma and a follow-up of 3 1/2 yr. Treatment with surgery and mitotane was associated with multiple complications. The patient was in remission at 3 1/2 yr. Because of the rarity of this condition, we discuss step-by-step problems encountered during management.

Hematologic aspects of systemic mastocytosis.

Systemic mast cell disease is characterized by bone marrow involvement by mast cells and frequently by peripheral blood cytopenias. The coexistence of hematologic disorders, such as myeloproliferative or myelodysplastic syndromes, or of lymphoreticular malignancies with SMCD is common. Overt mast cell leukemia is rare. In general, patients who coexhibit a severe hematologic disorder tend to have a more compressed clinical course and a worse prognosis. Hemorrhage can be a result of heparin release from stimulated mast cells.

MLL genomic breakpoint distribution within the breakpoint cluster region in de novo leukemia in children.

PURPOSE: To assess translocation breakpoint distribution within the MLL genomic breakpoint cluster region (bcr), 40 cases of de novo leukemia in children were examined by karyotype and Southern blot analysis. PATIENTS AND METHODS: Criteria for inclusion were karyotypic or molecular rearrangement of chromosome band 11q23. Of the 40 cases, 31 occurred in infants. Twenty cases were acute lymphoblastic leukemia (ALL), 17 were acute myeloid leukemia (AML), and 3 were biphenotypic. RESULTS: Karyotype identified 27 cases with translocation of chromosome band 11q23 and 2 with abnormalities of band 11q13 but not 11q23. Southern blot analysis showed rearrangement within the MLL genomic bcr in 38 of the 40 cases. In these 38, additional probe-restriction digest combinations localized MLL genomic breakpoints to the 5' portion of the bcr in 14 cases and to the 3' portion in 18; material was insufficient for further localization to 5' or 3' within the bcr in 6 cases. In the two remaining cases, both with t(4;11)(q21;q23), one breakpoint mapped 5' of the bcr between intron 3 and exon 5, whereas the other breakpoint was neither within nor 5' of the MLL genomic bcr. CONCLUSIONS: Suggested trends warranting investigation in more patients were breakpoint sites in the 3' bcr in AML and in patients older than 12 months. The distribution of MLL genomic breakpoints within the bcr in de novo leukemia in children is distinct from that in adults, where the breakpoints cluster in the 5' portion of the bcr.

Deficient in vitro megakaryocytopoiesis and decreased in vivo platelet turnover in children and young adults with chronic thrombocytopenia.

PURPOSE: Chronic thrombocytopenia is uncommon in children and frequently thought to be secondary to chronic idiopathic thrombocytopenic purpura (ITP), which is considered an immune disorder. However, not all children with chronic ITP respond to immunosuppressive therapy. Platelet survival and megakaryocyte growth were studied to determine if there is a failure of platelet production in children with chronic thrombocytopenia who carry a presumptive diagnosis of chronic ITP. PATIENTS AND METHODS: In vitro megakaryocyte growth using a plasma clot system and in vivo survival of 111In-labeled autologous platelets were studied in seven patients (aged 2 days to 17 years at diagnosis; aged 2 to 28 years at time of megakaryocyte study) with chronic isolated thrombocytopenia (range 1,000 to 130,000/microl). RESULTS: All seven patients exhibited elevated platelet-associated immunoglobulin G early in the course of their disease and showed normal marrow morphology with normal numbers of morphologically typical megakaryocytes on initial marrow biopsy. Occasional dysplastic-appearing megakaryocytes were noted in three of the seven patients at diagnosis and all patients were noted to have dysplastic megakaryocytes, reduced megakaryocytes, or both during follow-up (range 5 to 16 years). Either morphologic or karyotypic abnormalities indicative of myelodysplasia subsequently developed in three patients. No patient exhibited any significant megakaryocyte colony growth under basal conditions. In one patient, megakaryocytic colonies significantly increased when grown in the presence of serum from aplastic patients and growth factors (granulocyte-macrophage colony-simulating factor, interleukin-3, and interleukin-6). Erythroid colony growth was markedly deficient in four of five patients studied and myeloid colonies were normal in two of three patients studied. Five of the seven patients underwent platelet survival studies. Platelet survival was < 6 days in the 4 patients with platelet counts < 100,000/microl (range 2 to 60,000/microl; survival range 92 to 137 hours) and was normal in the patient whose platelet count was > 100,000/microl (platelets 132,000/microl; survival 253 hours). All five patients had either overtly low or inappropriately low platelet turnovers (range 100 to 1423 platelets/microl per hour; normal range 1200 to 1600 platelets/microl per hour). The patient with the lowest platelet count and platelet turnover had previously undergone a splenectomy without benefit. CONCLUSIONS: Megakaryocyte dysfunction resulting in subnormal production of platelets may play a significant role in the thrombocytopenia noted in some patients who have an isolated thrombocytopenia and a clinical picture that suggests ITP. Determination of platelet turnover may help to identify these patients. These data suggest the presence of a stem cell defect which may progress to myelodysplasia or overt marrow failure in these patients.

RAS mutations in pediatric leukemias with MLL gene rearrangements.

Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors. Experiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-strand conformation polymorphism analysis and an allele-specific restriction enzyme assay to investigate the frequency of KRAS and NRAS mutations in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia (ALL), 10 were acute myeloid leukemia (AML), and 2 were biphenotypic. Three secondary leukemias were AML, 1 was biphenotypic, 1 was ALL, and 2 were diagnosed as myelodysplasia. The frequency of RAS mutations was 2 of 10 in de novo AML. Both mutations occurred in infant monoblastic variants. RAS mutations were otherwise absent in this series. This is the first report of congenital leukemias where translocation of the MLL gene and RAS mutation coexist. The frequency of RAS mutations in de novo AMLs with MLL gene translocations is similar to that in other forms of AML, but RAS mutations play a limited role in lymphoid and treatment-related leukemias with similar translocations.

Energy-dependent expression of platelet-von Willebrand factor on the surface of unstimulated and stimulated platelets.

We have studied the energy requirements (adenosine triphosphate) for the expression of platelet-von Willbrand factor on platelets under conditions in which glycolysis and/or oxidative phosphorylation were inhibited. We found that platelet-vWf expression on the surfaces of both unstimulated and stimulated platelets required energy and was maximally decreased when metabolic ATP was maximally depleted. Platelet-vWf expression correlated directly with estimates of adenylate energy charge in both unstimulated and stimulated platelets. In addition, platelet shape change and agonist-induced intracellular Ca2+ flux were maintained at lower AECs than were either platelet aggregation or alpha-granule secretion. Our results indicate that the surface expression of platelet-vWf on unstimulated platelets is a dynamic process, and that energy is required to maintain basal amounts of platelet-vWf on the platelet surface. Our data also suggest that the metabolic ATP required to effect changes in platelet shape is less than that necessary to maintain basal platelet-vWf surface expression or to produce full alpha-granule secretion. We show that platelet-shape change in the absence of alpha-granule secretion can result in an increase in platelet-vWf surface expression.

Etiology and treatment of acquired coagulopathies in the critically ill adult and child.

Excessive bleeding frequently complicates the care of critically ill patients. Except in the case of trauma or inpatients with known coagulopathies, the bleeding is generally not directly related to the illness that results in admission to the intensive care unit. In general, the causes of the bleeding can be divided into three categories: consumptive coagulopathies, bleeding related to "hepatic issues," and iatrogenic causes. In most circumstances, the pathogenesis and management of these acquired coagulopathies do not differ between the adult and child patient. However, some differences do exist in regards to the clinical manifestations and management of some consumptive coagulopathies. This article reviews the more common causes of bleeding in the critically ill patient and outlines diagnostic and treatment approaches for these patients. Particular emphasis will be placed on the differences in presentation and management where differences exist.

Efficacy and safety of intravenous midazolam and ketamine as sedation for therapeutic and diagnostic procedures in children.

OBJECTIVE: We have used the combination of midazolam, a short-acting benzodiazepine, and ketamine, a "dissociative anesthetic," to provide conscious sedation for invasive or lengthy procedures. METHODS: A total of 350 procedures (74 lumbar punctures, 97 bone marrow aspirations or biopsies, 84 radiotherapy sessions, and 95 imaging studies) were performed on 68 children, 4 months to 17 years of age, in both inpatient and ambulatory settings. All patients had an intravenous line in place and were monitored for heart rate and O2 saturation by pulse oximetry for the duration of the procedure and recovery time. Blood pressure was monitored periodically (every 5 to 30 minutes). Oxygen and suction equipment was available during the procedure. In addition to the individual performing the procedure, a second staff member trained in airway management (eg, physician, nurse practitioner, or registered nurse) was present to monitor vital signs and respiratory status. Patients were sedated initially with midazolam (0.05 to 0.1 mg/kg intravenously; maximum single dose of 2 mg, maximum total dose of 4 mg), followed by ketamine (1 to 2 mg/kg intravenously). During lengthy procedures, additional doses of ketamine (0.5 to 1 mg/kg) were given as necessary. Effectiveness of the sedation, recovery time, and adverse events associated with the sedative regimen were documented. RESULTS: All patients were effectively sedated with this regimen. Four patients experienced transient decrease in O2 saturation (<85%) requiring temporary interruption of the procedure and oxygen by blow-by; the procedure was subsequently completed without incident in each case. Two patients experienced significant agitation during recovery from sedation. This side effect resolved spontaneously after 5 to 10 minutes in one patient and was effectively treated with diphenhydramine hydrochloride in the other. Twenty-four lumbar punctures were associated with transient decrease in O2 saturation (88% to 92%), which improved by relief of neck flexion and/or blow-by oxygen. No hypotension, bradycardia, or respiratory depression requiring respiratory support or reversal of sedation was noted. Anesthesia recovery time ranged from <15 minutes to 120 minutes with >70% of patients recovering within 30 minutes. Most patients demonstrated an increase in oral secretions requiring occasional suctioning. Transient sleep disturbances were reported in only two patients. CONCLUSIONS: This sedative regimen of intravenous midazolam and ketamine was found to be safe and effective. Its use has greatly reduced patient and parent anxiety for diagnostic and therapeutic procedures.

Liver biopsies in patients with lysosomal storage disease: experience with effective sedation.

We prospectively applied a protocol used to sedate children who required a liver biopsy. Sixty liver biopsies were performed on thirty pediatric patients to assess the effects of treatment. Sixteen patients had Type 1 Gaucher's disease of which seven had a platelet count between 50-100,000/mm3. All seven had bleeding time performed and when indicated, intravenous DDAVP (1-deamino-8-D-arginine vasopressin) was used to improve hemostasis. Fourteen patients had Niemann-Pick disease type C of which eight were significantly demented and uncooperative. Before liver biopsy, all patients were sedated with the following regimen: oral chlorpromazine (1 mg/kg) followed one hour later by intravenous meperidine (1 mg/kg) and pentobarbital (maximum dosage 6 mg/kg) administered by slow intravenous injection. Liver biopsies were obtained safely on all patients. Only 1 patient (2%) developed a potentially serious complication: an obstructed airway which was readily corrected by simple repositioning. Transient less serious complications occurred in another 7 patients (12%). There was no long term sequalae of the biopsy procedures. Our study indicates that with appropriate patient selection, this sedation protocol may be useful in pediatric patients requiring a liver biopsy.

Failure to mobilize intracellular calcium in response to thrombin in a patient with familial thrombocytopathy characterized by macrothrombocytopenia and abnormal platelet membrane complexes.

We report a mother and son who were found to have macrothrombocytopenia, prolonged bleeding time, and abnormal platelet responses to thrombin. Transmission electron microscopy performed on the son's platelets demonstrated an unusual arrangement of membrane complexes formed by association of the open canalicular and dense tubular systems. Number and appearance of platelet alpha-granules, dense bodies, and mitochondria were normal. These platelets demonstrated normal agonist-induced Ca2+ flux in response to collagen and supranormal responses to arachidonic acid but displayed no increase in intracellular free Ca2+ in response to thrombin. Platelet surface glycoproteins IIb-IIIa, Ib, and granular membrane protein-140 measured by fluorescence-activated flow cytometry, along with platelet content of von Willebrand factor and fibrinogen, were normal. The von Willebrand factor binding function of GP-Ib on these platelets was also normal. We believe that this family demonstrates a unique macrothrombocytopenia syndrome characterized by deficient Ca2+ mobilization in response to thrombin that is not related to a defect in GP-Ib.

A human chimera for von Willebrand disease following bone marrow transplantation.

PURPOSE: von Willebrand disease (vWD) is a common bleeding disorder characterized by quantitative or qualitative defects in von Willebrand factor (vWF), a protein important for coagulation and platelet adhesion. There are two forms of vWF currently recognized: plasma vWF synthesized by endothelial cells and platelet vWF produced within megakaryocytes. Although both plasma and platelet vWF play important roles in overall hemostasis, the relative contribution of each form is not clear. PATIENTS AND METHODS: We report the results of bone marrow transplantation from a donor with Type I vWD into a hemostatically normal recipient. RESULTS: Following engraftment, the recipient appears to be a human chimera for vWD, with normal amounts of plasma vWF from endogenous endothelial cells, but low levels of platelet vWF derived from donor megakaryocytes. CONCLUSIONS: Although the vWD chimerism has not been associated with any clinical manifestations, the bleeding time has become prolonged, suggesting that platelet vWF is important for normalization of the bleeding time.

Introducing total quality management in an area health board.

It is essential for the health care industry to demonstrate a quality service. The Canterbury Area Health Board (CAHB), New Zealand is in the process of establishing the principles of Total Quality Management (TQM) and this paper addresses the key issues of committing to TQM. Highlighted are the Board's implemented programmes, business plan and role of the health care industry.

Absence of the largest platelet-von Willebrand multimers in a patient with lactoferrin deficiency and a bleeding tendency.

We have studied a young male with lactoferrin deficiency and a bleeding tendency responsive to cryoprecipitate. This child has had increased bleeding following surgical procedures and a variably prolonged template bleeding time. The patient has a normal platelet count, normal in vitro platelet ATP secretion and aggregation in response to a variety of agonists, and normal concentration of plasma-von Willebrand factor ristocetin cofactor activity and antigen. Analysis of plasma-vWf multimers by agarose gel electrophoresis consistently demonstrated a subtle decrease in the largest vWf multimers. In contrast, analysis of the patient's platelet-vWf revealed normal vWf:Ag, decreased vWf ristocetin cofactor activity, and a striking absence of the high and intermediate size molecular weight vWf multimers. Analysis of surface bound platelet-vWf demonstrated normal amounts on the surface of unstimulated platelets, but after thrombin stimulation the platelet-vWf surface expression did not increase. This lack of increased platelet-vWf surface expression resulted from decreased binding of secreted platelet-vWf to be surface of stimulated platelets. These data suggest that the patient's bleeding tendency may be related to a defect in his platelet-vWf structure and/or mobilization. This case represents a unique demonstration of an abnormality of platelet-vWf in the presence of normal plasma-vWf, and supports the data indicating an important role for platelet-vWf in primary hemostasis.

Dose-dependent responses to macrophage-targeted glucocerebrosidase in a child with Gaucher disease.

Long-term studies of a child with Gaucher disease indicated that the response to treatment with macrophage-targeted glucocerebrosidase (glucosylceramidase) is dose dependent, and that the hematologic response precedes the skeletal response.