Pharmacokinetic analysis driven letermovir dosing in pediatric hematopoietic cell transplantation patients with resistant CMV disease.

BACKGROUND: Reactivation of cytomegalovirus (CMV) in CMV-seropositive patients after haploidentical T-cell receptor αß+ /CD19+ depleted hematopoietic cell transplant (HCT) is common. Due to delayed CMV-specific immune reconstitution, patients may require prolonged antiviral therapy, including secondary prophylaxis (SP). We present our clinical experience with the off-label use of letermovir for SP in a severely immunocompromised 2-year-old toddler with refractory pre-B-cell ALL and bilateral retinitis caused by resistant CMV (A594V UL97 mutation) following a haploidentical TCRαß+ /CD19+ depleted HCT. METHODS: The patient underwent measurement of two separate sets of letermovir serum concentrations, drawn at pre-dose, 1 and 4 h (and 8 h during the second therapeutic drug monitoring) post-dose. Pharmacokinetic parameters, including AUC0-24 were calculated, and dose adjustment was performed based on the drug level. RESULTS: While receiving oral letermovir 240 mg once daily without cyclosporine, the observed AUC0-24 was high (75 815 ng h/mL) with a Cmin of 209 ng/mL. The dose was reduced by 25% to 180 mg once daily. Despite the dose reduction, both AUC0-24 and Cmin values further increased to 119 095 ng h/L and 959 ng/mL, respectively. The patient continued oral letermovir 180 mg once daily for about 3 months, with adequate viral suppression (CMV viral load in plasma <150 IU/mL) and no recurrent CMV end-organ disease or adverse events. CONCLUSIONS: Given limited options for anti-CMV therapy in young children with resistant CMV, letermovir could be considered as an alternative antiviral for SP. Further studies are warranted to evaluate the pharmacokinetics of letermovir in pediatric allogeneic HCT recipients.

Peritoneal and Pleural Drains in Pediatric Hematopoietic Cell Transplant Recipients with Veno-Occlusive Disease are Safe and Do Not Adversely Impact Clinical Outcomes.

There is a lack of data on the safety and efficacy of peritoneal drain (PD) and chest tube (CT) in the management of effusions in stem cell transplant recipients with veno-occlusive disease (VOD). In this retrospective pediatric study, clinical outcomes and health resource utilization (HRU) were compared in 32 patients with VOD who had a PD (PD+) post-HCT versus 27 patients who did not (PD-). Nine patients also had a CT (7 PD+ and 2 PD-). PD + patients were more likely than PD-patients to have received myeloablative conditioning (100% vs. 85.2%; p = 0.04) and have severe or very severe VOD (100% vs. 56% p < 0.01). Mechanical obstruction (38%) and hypotension (38%) were common complications, and 13% developed peritonitis. While the frequencies of cardiac dysfunction and acute kidney injury were comparable between both groups, respiratory support and its median duration were higher in PD + patients. The hospital and intensive care unit length of stay, albumin use, and the duration of defibrotide and albumin therapy was significantly longer in PD + patients. At a median follow-up of 1.04 years (range:0.03-14.6), the 2-year overall survival was similar in both groups (53.8% vs. 51.5%; p = 0.73). Although PD use was similar between 1995 and 2007 vs. 2008-2021; (47% vs. 58%; p = 0.65), day+100 mortality was improved in recent years (53.3% vs. 17.8%; p = 0.01), coinciding with the use of defibrotide (0% vs. 84%; p < 0.01). PD in pediatric patients with VOD post-HCT, although associated with increased HRU, was safe when clinically indicated and did not adversely impact clinical outcomes.

Use of belatacept as alternative graft vs host disease prophylaxis in pediatric allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Immunosuppressive prophylaxis is usually given to decrease the development of acute graft versus host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Belatacept is a Cytotoxic T-lymphocyte-associated protein 4, blocking agent, an immunosuppressive agent used for organ rejection prevention in adult renal transplant recipients. METHODS: We describe two children in whom belatacept was successfully used for GvHD prophylaxis. Case 1 was noncompliant with prior immunosuppressive therapy for aplastic anemia, and Case 2 developed severe thrombotic microangiopathy (TMA) precluding the use of calcineurin inhibitors (CNI) or mTOR inhibitors. RESULTS AND CONCLUSION: Belatacept was found to be a safe alternative in preventing GvHD in 2 patients in whom traditional prophylactic therapies were not possible to use.

Evaluation of medication safety resources in pediatric hospitals.

PURPOSE: As health systems continue to expand pharmacy and clinical services, the ability to evaluate potential medication safety risks and mitigate errors remains a high priority. Workload and productivity monitoring tools for the assessment of operational and clinical pharmacy services exist. However, such tools are not currently available to justify medication safety pharmacy services. The purpose of this study is to determine methods used to assess, allocate, and justify medication safety resources in pediatric hospitals. METHODS: A 32-question survey was designed and distributed utilizing the Research Electronic Data Capture (REDCap) tool. The survey was disseminated to 46 pediatric hospitals affiliated with the Children's Hospital Association (CHA). The survey was distributed in October 2018, and the respondents were given 3 weeks to submit responses. Data analysis includes the use of descriptive statistics. Categorical variables were summarized by frequencies and percentages to distinguish the differences between pediatric health systems. RESULTS: Of 26 respondents, 15.4% utilized metrics to justify medication safety resources. Metrics utilized were based on medication dispenses, projects, and error coding. Twenty-three percent of respondents were dissatisfied with current pharmacy-based medication safety resources within the organization. There was variability of medication safety resources within pediatric hospitals, including the number of dedicated full-time equivalents, time spent on tasks, and task prioritization. CONCLUSION: Assessing medication safety resources at various pediatric hospitals highlights several potential barriers and opportunities. This information will serve as the foundation for the creation of a standardized workload assessment tool to assist pharmacy leaders with additional resource justification.

Refractory Thrombocytopenia Is a Valid Early Diagnostic Criteria for Hepatic Veno-Occlusive Disease in Children.

We compared the incidence of refractory thrombocytopenia (RT) and platelet transfusion requirements (PTR) in 35 children who developed veno-occlusive disease (VOD) with 35 matched control subjects who underwent hematopoietic stem cell transplant but did not develop VOD. RT developed in 100% of the VOD patients, at a median of 8 days before VOD diagnosis, as compared with 71.5% of the control group. VOD patients required more platelet transfusions than control subjects (median PTR, 6.9 mL/kg [range, .57 to 17.59] versus 3.57 mL/kg [range, 0 to 14.63], respectively) with a statistically significant difference (P < .0001). The number of days with platelet requirements was significantly higher for VOD patients as compared with control subjects (median 68% versus 39%, P =< .0001). The PTR peaked at ~12 mL/kg/day, 2 days before VOD diagnosis, whereas the PTR in the control population was 5 mL/kg/day. The positive predictive value of developing VOD was 88.9% (95% confidence interval, 66.5% to 97%) in patients who were given >7 mL/kg/day of platelets during the at-risk period of days +3 to +13 after transplant. For patients who received >8 mL/kg/day of platelets, the positive predictive value of developing VOD was 86.7% (95% confidence interval, 61.2% to 96.4%). There was no difference in the PTR in patients with mild to moderate VOD as compared with severe VOD; however, the PTR was higher in patients whose VOD did not resolve. The median daily PTR after the diagnosis of VOD in 17 patients who got defibrotide as compared with those who did not get defibrotide was 6.04 mL/kg and 5.72 mL/kg, respectively, but the difference was not statistically significant (P = .56). On univariate and multivariate analysis use of intravenous immunoglobulin was significantly associated with VOD (P = .0088) but was not significantly associated with fatal VOD. In conclusion, RT occurs in 100% of patients at a median of 8 days before VOD diagnosis. VOD should be suspected in any patient with RT after the exclusion of other causes of consumptive thrombocytopenia, especially if they require >7 mL/kg/day of platelets.

Outcomes of Unrelated Donor Stem Cell Transplantion with Post-Transplant Cyclophosphamide for Graft-versus-Host Disease Prophylaxis in Patients with Severe Sickle Cell Disease.

Unrelated donor (URD) hematopoietic cell transplantation (HCT) in children with sickle cell disease (SCD) is associated with a high incidence of rejection and graft-versus-host disease (GVHD). We report on the first 4 patients with severe SCD who underwent URD HCT using a novel myeloablative and immunosuppressive regimen composed of busulfan, fludarabine, and antithymocyte globulin with a single dose of post-transplant cyclophosphamide along with tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Three patients engrafted and remain disease-free after a median follow-up period of 2.5 years. One patient had primary graft failure attributed to low stem cell content of the graft. Of interest, none of the engrafted patients developed acute or chronic GVHD. This preparative regimen along with the use of post-transplant cyclophosphamide offers a promising approach for unrelated donor transplants in patients with SCD and needs further corroboration in larger number of patients.

70% Ethanol for Decontamination of Central Venous Lines Exposed to Calcineurin Inhibitors.

BACKGROUND: Tacrolimus, commonly used for graft versus host disease prophylaxis is usually administered via a dedicated central venous line (CVL) and trough levels drawn from the unexposed lumen. Being an oil-based medication, it may be adsorbed to the inner lumen of the CVL and result in falsely high levels drawn from an inadvertently exposed lumen. There is no treatment for decontamination of such CVLs, and natural decay occurs over months before the CVL can be used to draw reliable trough levels. OBJECTIVE: The primary objective of the study was to estimate the effectiveness of 70% ethanol locks for decontaminating CVLs exposed to tacrolimus. METHODS: We studied the efficacy of 70% ethanol lock in decontaminating CVLs exposed to tacrolimus in patients during transplant. Trough tacrolimus levels were drawn from the exposed and unexposed (control) lumens at 8:00 am, followed by a 2-mL 70% ethanol lock instilled for a 2-hour dwell into the exposed (intervention) lumen. Trough tacrolimus levels were again drawn from both lumens at 8:00 pm and levels compared for efficacy. RESULTS: All 20 sets showed a high 8 am trough level in the exposed intervention arm (median = 30 ng/mL), significantly greater ( P < 0.0001) than that in the control arm (median = 9.05 ng/mL), and were contaminated. After the 2-hour ethanol lock, 65% of the lumens were decontaminated. The difference between the control and intervention arms was no longer found to be statistically significant ( P = 0.0826). CONCLUSION: A 2-hour 70% ethanol lock is effective for decontamination of CVLs exposed to tacrolimus.

Consensus Report by the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplant Consortium Joint Working Committees on Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents: Part 2-Focus on Ascites, Fluid and Electrolytes, Renal, and Transfusion Issues.

Even though hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic cell transplantation (HCT), there is paucity of research on the management of associated multiorgan dysfunction. To help provide standardized care for the management of these patients, the HCT Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators and the Supportive Care Committee of the Pediatric Blood and Marrow Transplant Consortium, collaborated to develop evidence-based consensus guidelines. After conducting an extensive literature search, in part 2 of this series we discuss the management of fluids and electrolytes, renal dysfunction; ascites, pleural effusion, and transfusion and coagulopathy issues in patients with VOD. We consider the available evidence using the GRADE criteria.

Nebulized opioids for the palliation of dyspnea in terminally ill patients.

PURPOSE: The use of nebulized opioids for the palliation of dyspnea in terminally ill patients is reviewed. SUMMARY: More than 50% of patients with advanced diseases experience dyspnea during their final stages of life. Systemically administered opioids are recommended for the management of dyspnea in these patients, but adverse effects may limit their use. Nebulization offers an alternative route for administering opioids, providing relief of dyspnea while minimizing adverse events. An extensive literature search was conducted to identify publications evaluating nebulized opioids for the palliation of dyspnea in patients at end-of-life. Ten studies that evaluated nebulized morphine, fentanyl, hydromorphone, and morphine-6-glucuronide were reviewed; 1 of these studies evaluated 4 different opioids. Of these 10 studies, 2 had double-blind, placebo-controlled, randomized crossover designs; 1 was retrospective, and the remaining 7 were prospective studies. A total of 181 patients, all adults, were evaluated. Subjective improvement in dyspnea from baseline was observed in 9 of the 10 studies. Nebulized morphine 20 mg every 4 hours was the most common opioid studied. Other doses of nebulized opioids included fentanyl 25 and 100 µg and hydromorphone 5 mg. Nine studies reported subjective improvement of dyspnea from baseline after administering nebulized opioids. Six studies evaluated objective outcomes and showed decreased respiratory rate (morphine, fentanyl, and hydromorphone) and heart rate (hydromorphone) and increased oxygen saturation (fentanyl). Mild-to-moderate adverse effects such as claustrophobia due to nebulizer mask, drowsiness, cough, and bitter taste were described. CONCLUSION: Nebulized opioids may provide subjective relief of dyspnea in terminally ill patients with mild-to-moderate adverse effects.

Impact of a pharmacy student-driven medication delivery service at hospital discharge.

PURPOSE: A pharmacy student-driven discharge service developed for patients to reduce the number of medication errors on after-visit summaries (AVSs) is discussed. METHODS: An audit of AVS documents was conducted before the implementation period (September 3 to October 23, 2013) to identify medication errors. As part of the audit, a pharmacist review of the discharge medication list was completed to determine the number and types of errors that occurred. A student-driven discharge service with AVS review was developed in collaboration with nursing and medical residents. Students reviewed a patient's AVS, delivered the discharge prescriptions to bedside, and conducted medication reconciliation with the patient and family. The AVS audit was conducted after implementation of these services to assess the impact on medication errors. RESULTS: It was observed that 72% (108 of 150) of AVSs contained at least 1 error before discharge and AVS review. During the 2-month postimplementation period (September 3 to October 23, 2014), this decreased to 27% (34 of 127), resulting in a 52% absolute reduction in the number of AVSs with at least 1 medication error (p < 0.0001). The most common error was as-needed medication with no indication, which decreased from 55% in the preimplementation audit to 16% in the postimplementation audit. Prescribing to Nationwide Children's Hospital's outpatient pharmacy increased from 57% in the preimplementation period to 73% in the postimplementation period for the general pediatrics service. CONCLUSION: A pharmacy student-driven discharge and medication delivery service reduced the number of AVSs and increased access to medications for patients.

Efficacy and safety of using L-cysteine as a catheter-clearing agent for nonthrombotic occlusions of central venous catheters in children.

Critically ill pediatric patients, especially in the intensive care unit, receive multiple medications and have a higher risk of central venous catheter (CVC) occlusion. If an occlusion occurs immediately after the administration of multiple medications or incompatible medications, either an acidic solution such as 0.1 N hydrochloric acid (HCl) or a basic solution of 1 mEq/mL sodium bicarbonate or 0.1 N sodium hydroxide can be used. However, compounding and storing of 0.1 N HCl has become more complex due to USP <797> guidelines for sterile compounding, and an alternative is needed. We report a series of cases in which L-cysteine was used instead of HCl to clear CVCs occluded due to administration of multiple medications. L-cysteine is a commercially available, sterile solution with a pH of 1­2.5. CVC occlusion was resolved in 10 of the 16 episodes in 13 patients. Two of the 16 occlusions were phenytoin related and would not have responded. An L-cysteine dose of 50 mg was used during 10 of the 16 episodes, 100 mg during 5 episodes, and 25 mg during 1 episode. A correlation between catheter clearance and dose was not observed. Occlusion resolution due to L-cysteine was not correlated to the prior use of tissue plasminogen activator. Metabolic acidosis, adverse effects, or damage to the catheters due to L-cysteine were not observed. On the basis of this limited experience, we propose L-cysteine as an effective alternative to 0.1 N HCl for clearing CVC occlusions caused by drugs with an acidic pKa.

Busulfan and melphalan as consolidation therapy with autologous peripheral blood stem cell transplantation following Children's Oncology Group (COG) induction platform for high-risk neuroblastoma: early results from a single institution.

Bu-Mel as preparative therapy prior to autologous stem cell rescue was recently shown to be superior to the conventional CEM regimen for HR NBL in Europe. There are no data available on the feasibility and toxicity of Bu-Mel as consolidation therapy following the COG-type induction regimens used in North America. We report early complications and outcomes of patients with HR NBL who received Bu-Mel for consolidation following COG-based induction. Retrospective analysis of all patients who had received Bu-Mel as preparative regimen prior to stem cell rescue for HR NBL was carried out. Toxicity, outcomes, and any delays to receiving radiation or anti-GD2 antibody therapy were analyzed. Six patients undergoing PBSCT had received Bu-Mel. The treatment was well tolerated. Mucositis was the main toxicity; three patients had developed neutropenia fever and none developed pulmonary toxicity. One patient had developed moderate SOS that responded to conservative management. All patients were able to receive and tolerate post-transplant local radiotherapy and ch.14.18 anti-GD2 antibody therapy without any delays. All patients are alive with no disease recurrence. The Bu-Mel regimen is well tolerated and is feasible post-COG-type induction platform.

Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation.

Anti-seizure prophylaxis is routinely utilized during busulfan administration for HSCT. We evaluated the feasibility and efficacy of levetiracetam in children undergoing HSCT. A total of 28 children and young adults received levetiracetam during HSCT and the outcomes and costs were compared to a historical, but similar cohort of 25 patients who had received fosphenytoin. Levetiracetam was well tolerated and was efficacious in preventing seizures. Cost of drug, administration, and monitoring were also similar among the two groups. Due to non-induction of the hepatic cytochrome P450 enzymes, levetiracetam may lead to better dose assurance of busulfan in targeted dose regimens for HSCT.

Octreotide acetate is efficacious and safe in children for treating diarrhea due to chemotherapy but not acute graft versus host disease.

BACKGROUND: The Common Toxicity Criteria of the National Cancer Institute evaluates diarrhea as an adverse event of chemotherapy administration. Acute graft versus host disease (aGVHD) causes diarrhea in allogeneic hematopoietic stem cell transplant patients. Guidelines for treating grade 3 and 4 chemotherapy induced diarrhea (CID) include octreotide acetate, a somatostatin analogue. These recommendations are based on adult octreotide trials. Data on octreotide use for treatment of CID in pediatric oncology patients are limited. This study evaluated the efficacy and safety of octreotide in the treatment of CID or aGVHD induced diarrhea in pediatric patients. METHODS: This is a retrospective review of 34 patients of average age 6 years who received octreotide between 1994 and 2008 for treatment of CID or aGVHD induced diarrhea. RESULTS: Thirty-eight courses of intravenous octreotide were administered. A complete response was achieved during 25/27 (92%) CID and 5/11 (45%) aGVHD induced diarrhea courses. A partial response was achieved during 4/38 courses, all in the aGVHD induced diarrhea group. No response was observed for 3 of the aGVHD induced diarrhea courses and 1 for the CID course. Octreotide was initiated at 2 mcg/kg/day and increased to a maximum of 9 mcg/kg/day. The mean total duration of treatment was 9 days. Common adverse effects observed were hyperglycemia, hyberbilirubinemia, nausea/vomiting, and abdominal cramping. CONCLUSION: In pediatric patients, octreotide exhibits 92% efficacy in treating CID and 45% efficacy in aGVHD induced diarrhea. Further studies to better characterize the starting dose and dose escalation algorithm for treating CID in children are required.

Delayed administration of filgrastim (G-CSF) following autologous peripheral blood stem cell transplantation (APBSCT) in pediatric patients does not change time to neutrophil engraftment and reduces use of G-CSF.

BACKGROUND: Delayed initiation of granulocyte colony stimulating factor (G-CSF) after high-dose chemotherapy and autologous bone marrow or peripheral blood stem cell (APBSCT) in adult patients does not affect time to neutrophil or platelet engraftment, duration of fever, incidence of bacteremia, duration of non-prophylactic antibiotic therapy, and length of hospitalization when compared to early initiation. This study compares the effect of delayed (day +6) versus early (day +1) administration of G-CSF in pediatric patients on time to neutrophil engraftment (TNE), duration and cost of G-CSF therapy, incidence of blood stream infections, duration of febrile-neutropenia, duration of non-prophylactic antibiotic therapy, and duration of hospitalization due to febrile-neutropenia. METHODS: This is a retrospective review of 65 patients who engrafted after receiving APBSCT and G-CSF between 1993 and 2006. They were divided into the delayed group (day +6) (n = 46) and the early group (day +1) (n = 19). RESULTS: The median ages were 4.7 and 5.3 years in the early and delayed groups, respectively. There was no significant difference in TNE (P = 0.06) between the two groups. The duration of G-CSF administration was significantly less in the delayed group (P = 0.003). No significant differences were observed in the duration of neutropenia, time to platelet engraftment, the incidence of blood stream infections, and duration of fevers. Duration of hospitalization due to febrile-neutropenia was significantly lower in the delayed group (P = 0.01). Significant cost savings were observed by delaying G-CSF administration. CONCLUSION: Delayed administration of G-CSF after APBSCT in children has no adverse effect on TNE or other clinical outcomes when compared to early administration and may incur substantial cost savings.

A technology-enhanced patient case workshop.

OBJECTIVES: To assess the impact of technology-based changes on student learning, skill development, and satisfaction in a patient-case workshop. DESIGN: A new workshop format for a course was adopted over a 3-year period. Students received and completed patient cases and obtained immediate performance feedback in class instead of preparing the case prior to class and waiting for instructors to grade and return their cases. The cases were designed and accessed via an online course management system. ASSESSMENT: Student satisfaction was measured using end-of-course surveys. The impact of the technology-based changes on student learning, problem-solving, and critical-thinking skills was measured and compared between the 2 different course formats by assessing changes in examination responses. Three advantages to the new format were reported: real-life format in terms of time constraint for responses, a team learning environment, and expedient grading and feedback. Students overwhelmingly agreed that the new format should be continued. Students' examination scores improved significantly under the new format. CONCLUSION: The change in delivery of patient-case workshops to an online, real-time system was well accepted and resulted in enhanced learning, critical thinking, and problem-solving skills.

Ibuprofen lysine for the prevention and treatment of patent ductus arteriosus.

Approximately 70-80% of newborns less than 28 weeks' gestational age require pharmacologic and/or surgical intervention to close a hemodynamically significant patent ductus arteriosus (PDA). Indomethacin has been the pharmacologic treatment of choice and has also been used prophylactically in very premature neonates to prevent PDA. The drug, however, is associated with renal and gastrointestinal adverse effects. In July 2006, intravenous ibuprofen lysine became available in the United States for treatment of hemodynamically significant PDA. The mechanism of action for both indomethacin and ibuprofen lysine is through inhibition of prostaglandin synthesis, resulting in ductal constriction. Both drugs appear to be equally efficacious in closing echocardiographically confirmed PDA. Ibuprofen lysine has demonstrated significantly less effects on cerebral, renal, and mesenteric blood flow in premature neonates when compared with indomethacin. A transient but significant increase in serum creatinine concentration, decrease in urine output, and increase in frequency of oliguria were observed with indomethacin when compared with ibuprofen lysine. However, the rate of reopening of the ductus after pharmacologic closure and the need for rescue therapy were not different between the two drugs. In addition, no differences were noted in other outcomes such as frequency of intraventricular hemorrhage, necrotizing enterocolitis, or chronic lung disease, as well as in duration of mechanical ventilation and length of hospital stay. When administered prophylactically, ibuprofen lysine did not prevent intraventricular hemorrhage nor provide any neurodevelopmental benefits. In addition, ibuprofen lysine has not been adequately studied in neonates of 27 weeks' gestational age or younger. Ibuprofen lysine is as efficacious as indomethacin in treating hemodynamically significant PDA in neonates greater than 27 weeks' gestational age.

Use of laser fluorescence and scanning electron microscope to evaluate remineralization of incipient enamel lesions remineralized by topical application of casein phospho peptide amorphous calcium phosphate (CPP-aCP) containing cream.

The aim of this in vitro study was to evaluate the remineralization of incipient enamel lesions by the topical application of Casein PhosphoPeptide-Amorphous Calcium Phosphate (CPP-ACP) using laser fluorescence and scanning electron microscope. Sixty caries free extracted teeth were used in the study. Forty teeth were used as test samples, ten as positive and ten as negative controls. The samples were demineralized and then remineralized by the topical application of CPP-ACP for a period of 14 days. The remineralization was evaluated with the use of laser fluorescence and scanning electron microscope (SEM). The results of this study showed that the laser fluorescent readings of test samples after remineralization were highly significant (p < 0.001). A significant number of test samples observed under SEM showed high scores of remineralization.