Management of Calcium Channel Blocker Toxicity in the Pediatric Patient.

Calcium channel blockers (CCBs) are commonly prescribed cardiovascular medications used in several disease states including hypertension, coronary artery disease, and atrial fibrillation. Inadvertent exposure or intentional overdose of CCBs may result in hypotension, bradycardia, dysrhythmias, conduction disturbances, and hyperglycemia. In the most severe cases, CCB toxicity can lead to rapid cardiovascular collapse. Given the risk of significant morbidity and mortality associated with CCB toxicity, it is important that health care professionals are able to recognize and treat patients who present with a potentially toxic ingestion. Due to the paucity of literature in managing pediatric patients with severe CCB toxicity, treatment strategies for pediatric patients are mostly limited to case reports and extrapolation from expert consensus recommendations for adults. All pediatric patients with a potentially toxic CCB ingestion should be evaluated in the emergency department. Activated charcoal may be considered for asymptomatic patients presenting within an hour of ingestion. Symptomatic patients should be placed under cardiac monitoring and treatments to stabilize the patient's hemodynamics should not be delayed. Traditional first-line IV therapies include small boluses of fluids, calcium, and vasopressors. High-dose insulin has been proposed to independently increase inotropy and improve CCB-induced hypoinsulinemia and insulin resistance that results from CCB inhibition of insulin release from pancreatic ß-islet cells. High-dose insulin is recommended as first-line therapy for adults and shows promising efficacy and safety in several pediatric case reports. Intravenous lipid emulsion may be considered in patients who are refractory to first-line therapies, although the data for pediatric patients are extremely limited.

Controversies surrounding the use of etomidate for rapid sequence intubation in patients with suspected sepsis.

OBJECTIVE: To evaluate the risk of adrenal insufficiency following a single dose of etomidate in patients with suspected sepsis requiring rapid sequence intubation. DATA SOURCES: A literature search was conducted using PubMed, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from the dates of database inception until April 2010, utilizing the terms adrenal insufficiency, etomidate, and sepsis. STUDY SELECTION AND DATA EXTRACTION: Data were synthesized in a qualitative manner, as variable study designs were identified. All studies that evaluated the clinical association between etomidate-induced adrenal insufficiency and sepsis in adults were reviewed and included. DATA SYNTHESIS: A search of the literature revealed 7 studies that specifically evaluated clinical endpoints in septic adults receiving etomidate for induction prior to intubation. Three of the studies evaluated risk factors associated with adrenal insufficiency in critically ill patients. Each of these studies determined that etomidate exposure was independently associated with an inappropriate response to cosyntropin stimulation testing (CST). Two studies found no significant difference in hospital mortality rates when evaluating patients receiving induction with etomidate compared with alternative regimens. Three studies found an increased risk of adrenal insufficiency in patients exposed to etomidate. The majority of studies that evaluated the use of etomidate in sepsis were underpowered, leading to difficulty in establishing a causal relationship between drug-related adrenal insufficiency, morbidity, and mortality. CONCLUSIONS: Until further studies are available, etomidate should be reserved for hemodynamically unstable patients who cannot tolerate an alternative induction agent despite the administration of fluids or vasoactive agents.

Overview, prevention, and treatment of rabies.

Each year, approximately 55,000 individuals worldwide die from an infection due to the rabies virus. Rabies is a life-threatening disease caused by an RNA virus that is usually transmitted to humans through bites from rabid animals. More recently, reports of transmission by means of organ transplantation have been reported. Since human rabies is nearly 100% fatal if prophylactic measures are not followed, an increased awareness of who should receive prophylaxis and when prophylaxis should be administered is necessary. Preexposure prophylaxis entails the administration of the rabies vaccine to individuals at high risk for exposure to rabies viruses (e.g., laboratory workers who handle infected specimens, diagnosticians, veterinarians, animal control workers, rabies researchers, cave explorers). Preexposure prophylaxis involves a three-dose series of the rabies vaccine that may confer some protection from the virus while simplifying postexposure prophylaxis regimens. Postexposure prophylaxis consists of a multimodal approach to decrease an individual's likelihood of developing clinical rabies after a possible exposure to the virus. Regimens depend on the vaccination status of the victim and involve a combination of wound cleansing, administration of the rabies vaccine, and administration of human rabies immune globulin. If used in a timely and accurate fashion, postexposure prophylaxis is nearly 100% effective. Once clinical manifestations of rabies have developed, however, treatment options for rabies are limited, and to date, only seven individuals have survived rabies virus infection. Treatment of clinical rabies consists of medical support in an intensive care unit, using a multifaceted approach that includes supportive care, heavy sedation, analgesics, anticonvulsants, and antivirals. The recently developed Milwaukee Protocol added induction of therapeutic coma to supportive care measures and antivirals; however, its use has shown inconsistent outcomes.

Phase II trial of the combination of denileukin diftitox and rituximab for relapsed/refractory B-cell non-Hodgkin lymphoma.

Denileukin diftitox plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma patients. Of the 38 evaluable patients, 30 (80%) were rituximab-refractory. The overall response rate (ORR) was 32%, with six complete responses (CR) and six partial responses (PR). The median time to progression for responders was 8 months (range: 2-36+); two patients with rituximab-refractory follicular lymphoma were in CR at 25 and 36+ months. The ORR was 55% (4 CRs, 2 PRs) in 11/14 patients with rituximab-refractory follicular lymphoma, and 100% in the three patients with rituximab-sensitive tumour. Most toxicities were low grade and transient, and myelotoxicity was uncommon.

Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma.

This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2-diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL), excluding cutaneous T-cell lymphoma. Eligible patients received denileukin diftitox 18 microg/kg/d x 5 d every 3 weeks for up to eight cycles. Tumour staging was performed every two cycles and the primary endpoint was the objective response rate [complete response (CR) + partial response (PR)]. For 27 patients enrolled, median age: 55 years (range 26-80 years), 70.4% male, and mean prior therapies: 2.5 (range 1-6). Objective responses (six CRs, seven PRs) were achieved in 13 patients (48.1%), stable disease in eight (29.6%) and six (22.2%) had progressive disease. An objective response was achieved in eight of 13 patients (61.5%) with CD25(+) tumours (four CR/four PR) and five of 11 patients (45.5%) with CD25(-) tumours (two CR/three PR). Median progression-free survival was 6 months (range, 1-38+ months). Most adverse reactions were grade 1/2 and transient. No grade 4-5 toxicities were reported. Denileukin diftitox had significant activity and was well tolerated in relapsed/refractory T-NHL, with responses observed in both CD25(+) and CD25(-) tumours. Further studies of denileukin diftitox in combination with other agents are warranted in previously untreated and relapsed/refractory T-NHL.

Toxic epidermal necrolysis associated with denileukin diftitox (DAB389IL-2) administration in a patient with follicular large cell lymphoma.

Denileukin diftitox (DAB(389)IL-2 or Ontak) is a synthetic fusion protein with demonstrated efficacy in a number of lymphoproliferative disorders, including non-Hodgkin's lymphoma. We report the case of a 45-year-old man with progressive follicular large cell lymphoma following an autologous stem cell transplant treated with denileukin diftitox who developed a fatal skin rash associated with extensive erythema, edema and large bullae involving his entire body. The clinical features and pathology were compatible with toxic epidermal necrolysis. This is the first reported case of toxic epidermal necrolysis in the literature associated with denileukin diftitox.

Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience.

BACKGROUND: T-cell non-Hodgkin lymphomas (T-NHL) are more aggressive and patients have a poorer prognosis compared with patients with the corresponding B-cell lymphomas. Although intensive treatments have been developed, it is unknown whether they are more effective than CHOP chemotherapy (cyclophosphamide, doxorubicin, oncovorin, and prednisone). METHODS: The authors' retrospective study evaluated the clinical outcome of 135 previously untreated patients with T-NHL who were treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between 1996 and 2002. Lymphomas with T-cell histologies with the exception of mycosis fungoides were included. RESULTS: The estimated median overall survival was 46 months. Thirty-seven percent of the patients received CHOP therapy, 48% received intensive therapy, and 15% received other therapy. The estimated 3-year overall survival rates were 62% for the patients treated with CHOP therapy and 56% for the patients who received intensive therapy. After the exclusion of patients with anaplastic large cell lymphoma (ALCL), who are known to have a better prognosis than patients with other T-NHLs, the estimated 3-year overall survival rates were 43% for the patients treated with CHOP therapy and 49% for the patients who received intensive therapy. Parameters that may be independent prognostic factors for survival in T-NHL, excluding ALCL, included ECOG performance status > or = 2, beta-2-microglobulin level > 2 mg/L, lactate dehydrogenase level higher than normal, bulky disease > or = 7 cm, and a higher international prognostic index and tumor score. CONCLUSIONS: The current study data suggested that patients treated with intensive therapies did not fare better than those treated with CHOP therapy. New treatment regimens need to be developed for patients with T-NHL.

Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.

PURPOSE: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles. RESULTS: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. CONCLUSION: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.

Denileukin diftitox as novel targeted therapy in non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) is a complex group of hematologic malignancies. The majority are B-cell lineage, with 10%-20% arising from T-cell lineage. Detailed knowledge of the subtypes and staging of NHL is essential to plan treatment and provide effective management of treatment-related side effects. Although numerous regimens have demonstrated efficacy in the treatment of NHL, some subtypes of lymphomas generally are not curable. The recent development of targeted therapies such as denileukin diftitox (Ontak, Ligand Pharmaceuticals, Inc., San Diego, CA) has resulted in potentially significant advances in the treatment of NHL. Oncology nurses must gain a better understanding of the unique mechanism of action of this agent and its side effects to successfully manage patients being treated with this novel therapy.

Pentostatin in T-non-Hodgkin's lymphomas: efficacy and effect on CD26+ T lymphocytes.

Pentostatin is an adenosine deaminase (ADA) inhibitor with antineoplastic activity. CD26 is a surface glycoprotein with a key role in T cell function as the ADA binding protein. We conducted a phase II study to evaluate pentostatin efficacy in relapsed T-non-Hodgkin's lymphoma (T-NHL) and to correlate response with tumor CD26 expression. We also examined the lymphopenic effect of pentostatin on CD26+ T lymphocytes. Eighteen patients were registered for the study. Pentostatin was administered as intravenous bolus daily over 3 days at an initial dose of 5 mg/m(2)/day, repeated every 4 weeks. CD26 surface expression on tumor cells and T lymphocytes was determined by flow cytometry. Out of 14 patients evaluable for response, there was 1 (7%) complete response (CR) and 6 (43%) partial responses (PR). Median progression-free survival for responders was 6 months (range: 2-15 months); median number of courses was 4 (range: 1-6). Responders included 1 of 2 CD26+ and 5 of 9 CD26- cases. Pentostatin also specifically depleted CD26+ rather than CD26- T lymphocytes, potentially associated with immunosuppression. We therefore conclude that while pentostatin is a safe and active agent for T-NHL regardless of CD26 expression, it may selectively deplete CD26+ T lymphocytes, with potentially significant clinical implications.