Assessing the Impact of Comprehensive Medication Management on Achievement of the Quadruple Aim.

Nonoptimized medication regimens cost patients and payors in the United States more than $528 billion in additional health care expenses each year. Comprehensive medication management is a patient-centered approach to medication optimization delivered by a clinical pharmacist working with the patient, physicians, and other members of the health care team. Comprehensive medication management ensures medications are assessed for appropriateness, effectiveness, and safety given the patient's clinical status, comorbidities, and other medications, as well as the patient's ability to take the medications as intended and adhere to the regimen. This article reviews the growing body of literature demonstrating the value of comprehensive medication management in achieving the quadruple aim of health care: better care, reduced health care costs, an improved patient experience, and provider well-being.

Management of Hyperactive Delirium in the Pediatric Intensive Care Unit: Case Series of Three Young Children.

Children in the intensive care unit (ICU) are at high risk of developing delirium, given their underlying disease processes, the adverse effects of treatments and medications, and the stressful, abnormal environment. If prevention and nonpharmacologic measures to treat delirium are unsuccessful, atypical antipsychotics are considered, although they are not approved by Food and Drug Administration for the treatment of pediatric delirium and could have significant adverse side effects. This case report presents three pediatric patients with hyperactive ICU delirium that risked life-threating complications who were successfully treated with short courses of atypical antipsychotic medications.

Caffeine Citrate for the Prevention of Apnea Associated With Alprostadil Infusions.

OBJECTIVE: To evaluate the incidence of apnea and requirement for positive pressure ventilation in patients who received caffeine for prevention while receiving alprostadil compared with those who did not receive caffeine. METHODS: This was a single-center, retrospective study of patients who received alprostadil over a 7-year time frame. Patients were divided into 2 groups based on whether they received caffeine for prevention of apnea while receiving alprostadil. The incidence of apnea and requirements for positive pressure ventilation were recorded. RESULTS: A total of 64 patients who received alprostadil were included for review. Thirty-two patients received caffeine for the prevention of apnea, and 32 patients received alprostadil only. Alprostadil doses were similar between the 2 groups (0.04-0.05 mcg/kg/min). Seven patients had a documented apneic event; 3 in the group given caffeine and 4 in the control group. One patient in each group required intubation because of apnea. All patients with documented apnea were on low-dose alprostadil therapy (<0.05 mcg/kg/min). Three patients had apnea after dose reductions had been made. Six out of the seven patients experienced apnea within the first 24 hours after the infusion. Only 1 patient experienced multiple apneic events. CONCLUSIONS: In this small sample, there was no difference in incidence of apnea between patients on low-dose alprostadil who received caffeine for prevention and those who did not. Despite the use of low-dose alprostadil therapy and dose reductions, the incidence of apnea remains low, and most patients did not have repeated apneic events or require intubation.

Stiripentol: A Novel Antiseizure Medication for the Management of Dravet Syndrome.

Objective: To describe the pharmacology, efficacy, and safety of stiripentol in the treatment of refractory seizures in patients with Dravet syndrome. Data Sources: A search of the English language literature was conducted using PubMed and MEDLINE (1978 to April 2019) with the search terms stiripentol, Dravet syndrome, and refractory epilepsy. Other resources included article bibliographies, prescribing information, and relevant trials at https://clinicaltrials.gov/ . Study Selection and Data Extraction: All phase 1, 2, or 3 trials; observational studies; and retrospective studies were analyzed. Data Synthesis: In controlled studies, stiripentol has been shown to reduce seizure frequency by 50% or more in 40% to 70% of patients with Dravet syndrome. Reductions in seizure duration and episodes of status epilepticus have also been documented. Common adverse effects include somnolence and anorexia. Stiripentol inhibits the metabolism of clobazam and valproate, often requiring dose adjustment. Relevance to Patient Care and Clinical Practice: Stiripentol, a direct allosteric modulator of GABAA receptors, offers a novel approach to treatment in patients with Dravet syndrome, both with and without pathogenic variants of the sodium channel α-1 subunit gene, and potentially other refractory seizures. Although available outside the United States for a decade, it was only recently approved by the Food and Drug Administration for patients 2 years of age and older with Dravet syndrome taking clobazam. Conclusions: Stiripentol is an effective adjunctive therapy for reducing the frequency and duration of refractory seizures in patients with Dravet syndrome. Its role in the treatment of other refractory epilepsies requires further study.

Safety and Tolerability of Lidocaine Infusions as a Component of Multimodal Postoperative Analgesia in Children.

OBJECTIVES: Use of lidocaine as part of a multimodal approach to postoperative pain management has increased in adults; however, limited information is available regarding safety and tolerability in pediatrics. This study's primary objective was to evaluate the incidence of adverse effects related to lidocaine infusions in a sample of pediatric patients. METHODS: A retrospective analysis was conducted in pediatric patients receiving lidocaine infusion for the management of postoperative analgesia at the University of Virginia Health System. RESULTS: A total of 50 patients with 51 infusions were included in the final analysis. The median patient age was 14 years (range, 2-17 years). The most frequent surgeries were spinal fusion (30%), Nuss procedure for pectus excavatum (16%), and nephrectomy (6%). The mean ± SD starting rate was 13.6 ± 6.5 mcg/kg/min. The mean infusion rate during administration was 15.2 ± 6.3 mcg/kg/min, with 14.4 ± 6.2 mcg/kg/min at discontinuation. The mean length of therapy was 30.6 ± 22 hours. A total of 12 infusions (24%) were associated with adverse effects, primarily neurologic ones, including paresthesias in the upper extremities (10%) and visual disturbances (4%). The average time to onset was 16.2 ± 15.2 hours. Seven infusions were discontinued, whereas the remaining infusions resulted in either dose reduction or continuation without further incident. No patients experienced toxicity requiring treatment with lipid emulsion. CONCLUSIONS: In this sample, lidocaine was a well-tolerated addition to multimodal postoperative pain management in the pediatric population. Although adverse effects were common, they were mild and resolved with either dose reduction or discontinuation.

Vancomycin Dosing in Pediatric Extracorporeal Membrane Oxygenation: Potential Impacts of New Technologies.

OBJECTIVES: The objective of the current study was to evaluate the doses of vancomycin used to obtain therapeutic drug concentrations in pediatric patients on extracorporeal membrane oxygenation (ECMO), using new ECMO technologies. METHODS: This was a single-center, retrospective study of patients treated with vancomycin while receiving ECMO using low-volume circuit technology. RESULTS: A total of 28 patients were included in the analysis of the primary endpoint. Patients had a median age of 6 weeks (0-11 years) and a median weight of 3.45 kg (2.44-37.2 kg). Ultrafiltration was used in 89.3% of patients at initiation of ECMO regardless of baseline renal function, resulting in a median urine output of 2 mL/kg/hr at the time of the final vancomycin dose. Most patients started vancomycin at the same time as ECMO. The median total daily dose was 30 mg/kg/day. The median total daily dose in a subset of patients less than one year of age was 20 mg/kg/day. Nearly all patients had at least 1 therapeutic trough serum vancomycin concentration. A total of 16 patients completed their vancomycin course using an interval of every 12 hours or shorter. Half-life was calculated in a subset of 11 patients and the mean was found to be 12.3 ± 2.8 hours. CONCLUSIONS: An initial dosing interval of every 12 hours to provide a total daily dose of 30 mg/kg/day is a possible option in pediatric patients on ECMO provided that renal function is normal at baseline. Monitoring of serum vancomycin concentrations for adjustment of dosing is required throughout therapy and is still warranted.

Decreased blood product usage during extracorporeal life support with reduced circuit volumes.

BACKGROUND: Activation and consumption of platelets (PLT) and clotting factors along with hemolysis occurs when blood contacts the extracorporeal life support (ECLS) circuit and its components. STUDY DESIGN AND METHODS: The objective was to examine the effects of reducing ECLS circuit volume by decreasing tubing length and changing components on blood product usage in neonatal and pediatric patients. Blood product administration was analyzed in 40 consecutive patients who required ECLS for respiratory or cardiac failure before (PRE) and after (POST) changes in circuit design and components. RESULTS: The total circuit volume was reduced from 500 mL (PRE) to 275 mL (POST). In the POST group, total blood product volume usage was 58% lower compared to the PRE group (81 mL/kg/day vs. 191 mL/kg/day, p = 0.003), 65% lower for fresh-frozen plasma (FFP; 15 mL/kg/day vs. 43 mL/kg/day, p = 0.001), and PLT volumes trended lower. In the subgroup of infants with respiratory or cardiac failure, there was a 55% reduction of a total blood product replacement (61 mL/kg/day vs. 136 mL/kg/day, p = 0.008), red blood cell (RBC) use was 61% lower (28 mL/kg/day vs. 71 mL/kg/day, p < 0.049), and there was a 73% reduction in FFP use (11 mL/kg/day vs. 41 mL/kg/day, p < 0.001). In the subgroup of postoperative infants, there was a 25% decrease in RBC use (86 mL/kg/day vs. 115 mL/kg/day, p = 0.03). CONCLUSION: Decreasing the ECLS circuit volume by reducing the tubing length and changing the components was associated with a significant reduction in blood product usage.

Bivalirudin as an Alternative to Heparin for Anticoagulation in Infants and Children.

Bivalirudin, a direct thrombin inhibitor, is a useful alternative to heparin for anticoagulation in infants and children. It has been found to be effective in patients requiring treatment of thrombosis, as well as those needing anticoagulation during cardiopulmonary bypass, extracorporeal life support, or with a ventricular assist device. While it has traditionally been used in patients who were unresponsive to heparin or who developed heparin-induced thrombocytopenia, it has recently been studied as a first-line agent. Bivalirudin, unlike heparin, does not require antithrombin to be effective, and as a result, has the potential to provide a more consistent anticoagulation. The case reports and clinical studies currently available suggest that bivalirudin is as effective as heparin at reaching target activated clotting times or activated partial thromboplastin times, with equivalent or the lower rates of bleeding or thromboembolic complications. It is more expensive than heparin, but the cost may be offset by reductions in the costs associated with heparin use, including anti-factor Xa testing and the need for administration of antithrombin. The most significant disadvantage of bivalirudin remains the lack of larger prospective studies demonstrating its efficacy and safety in the pediatric population.

The need for PGY2-trained clinical pharmacy specialists.

The American College of Clinical Pharmacy and other stakeholder organizations seek to advance clinical pharmacist practitioners, educators, and researchers. Unfortunately, there remains an inadequate supply of residency-trained clinical specialists to meet the needs of our health care system, and nonspecialists often are called on to fill open specialist positions. The impact of clinical pharmacy specialists on pharmacotherapy outcomes in both acute care and primary care settings demonstrates the value of these specialists. This commentary articulates the need for postgraduate year two (PGY2)-trained clinical specialists within the health care system by discussing various clinical and policy rationales, interprofessional support, economic justifications, and their impact on quality of care and drug safety. The integrated practice model that has grown out of the American Society of Health-System Pharmacists Pharmacy Practice Model Initiative (PPMI) could threaten the growth and development of future clinical specialists. Therefore, the ways in which PGY2-trained clinical pharmacist specialists are deployed in the PPMI require further consideration. PGY2 residencies provide education and training opportunities that cannot be achieved in traditional professional degree programs or postgraduate year one residencies. These specialists are needed to provide direct patient care to complex patient populations and to educate and train pharmacy students and postgraduate residents. Limitations to training and hiring PGY2-trained clinical pharmacy specialists include site capacity limitations and lack of funding. A gap analysis is needed to define the extent of the mismatch between the demand for specialists by health care systems and educational institutions versus the capacity to train clinical pharmacists at the specialty level.

Evaluation of Off-label Prescribing at a Children's Rehabilitation Center.

OBJECTIVE: This study was developed to evaluate the incidence of off-label prescribing at a pediatric rehabilitation center. Secondary objectives were to describe the medications, patient age groups, and diagnoses most often associated with off-label prescribing. METHODS: This was a prospective observational study conducted at an academic, inpatient children's rehabilitation center from November 11, 2011, to April 1, 2012. Patients younger than 16 years of age who received at least 1 prescription medication were included. Data were collected from the patients' electronic medical records. RESULTS: A total of 240 medications orders were placed during the study, with 57% written off-label. Thirty-five patients (88%) received at least 1 off-label medication. Forty-nine percent of the orders were for patients younger than the approved range, with 48% written for an unapproved indication, 2% for an alternative route of administration, and 1% for an unapproved age and indication. Children 2 to 12 years of age received 40% of the off-label orders, followed by adolescents with 37%. The therapeutic classes most often prescribed off-label were central nervous system agents and anti-infectives. CONCLUSION: Off-label prescribing was found in the majority of children receiving rehabilitative services, a rate as high or higher than that reported in pediatric acute care or clinic settings. The medications prescribed off-label most often were central nervous system agents, reflecting the need to study medications in the chronic rehabilitation population to optimize function in children with brain or spinal cord injury.

Patients with single ventricle anatomy may respond better to octreotide therapy for chylothorax after congenital heart surgery.

BACKGROUND AND AIMS: Chylothorax (CTX) occurs in 3% to 6% of children after surgery for congenital heart disease with significant morbidity and mortality. Octreotide has been proposed as therapy, but there are no predictors of response. The objective of this study was to identify possible predictors of response to octreotide. METHODS: Single-center retrospective review of patients who developed CTX after cardiac surgery. Data collected included demographics, cardiac lesion, surgical data, hospital course, CTX volume and duration, and interventions for CTX. Patients who received octreotide as part of their therapy were compared to those who did not. RESULTS: A total of 1150 patients underwent 1455 cardiac surgeries with 67 (4.6%) episodes of CTX. Patients with CTX were younger, lower weight, more likely to undergo cardiopulmonary bypass, and had higher RACHS-1 scores and mortality. Nineteen patients with CTX received octreotide as part of their treatment and six (32%) had at least 50% reduction in CTX volume. Patients who responded to octreotide had lower CTX volume (18 mL/kg/day vs. 55 mL/kg/day, p=0.023) and a higher proportion of patients with single ventricle anatomy (67% vs. 18%, p=0.046). CONCLUSIONS: There is a subset of patients who seem to respond to octreotide, but they have lower CTX volume and may have already been improving before octreotide therapy. Patients with single ventricle anatomy seemed to respond to octreotide and may benefit from its use.

Recommendations for meeting the pediatric patient's need for a clinical pharmacist: a joint opinion of the Pediatrics Practice and Research Network of the American College of Clinical Pharmacy and the Pediatric Pharmacy Advocacy Group.

Children warrant access to care from clinical pharmacists trained in pediatrics. The American College of Clinical Pharmacy Pediatrics Practice and Research Network (ACCP Pediatrics PRN) released an opinion paper in 2005 with recommendations for improving the quality and quantity of pediatric pharmacy education in colleges of pharmacy, residency programs, and fellowships. Although progress has been made in increasing the availability of pediatric residencies, there is still much to be done to meet the direct care needs of pediatric patients. The purpose of this joint opinion paper is to outline strategies and recommendations for expanding the quality and capacity of pediatric clinical pharmacy practitioners by elevating the minimum expectations for pharmacists entering pediatric practice, standardizing pediatric pharmacy education, expanding the current number of pediatric clinical pharmacists, and creating an infrastructure for development of pediatric clinical pharmacists and clinical scientists. These recommendations may be used to provide both a conceptual framework and action items for schools of pharmacy, health care systems, and policymakers to work together to increase the quality and quantity of pediatric training, practice, and research initiatives.

Neuropsychological recovery and quality-of-life in children and adolescents with growth hormone deficiency following TBI: a preliminary study.

OBJECTIVE: To compare neurocognition and quality-of-life (QoL) in a group of children and adolescents with or without growth hormone deficiency (GHD) following moderate-to-severe traumatic brain injury (TBI). STUDY DESIGNS: Thirty-two children and adolescents were recruited from the TBI clinic at a children's hospital. Growth hormone (GH) was measured by both spontaneous overnight testing and following arginine/glucagon stimulation administration. Twenty-nine subjects participated in extensive neuropsychological assessment. RESULTS: GHD as measured on overnight testing was significantly associated with a variety of neurocognitive and QoL measures. Specifically, subjects with GHD had significantly (p < 0.05) lower scores on measures of visual memory and health-related quality-of-life. These scores were not explained by severity of injury or IQ (p > 0.05). GHD noted in response to provocative testing was not associated with any neurocognitive or QoL measures. CONCLUSIONS: GHD following TBI is common in children and adolescents. Deficits in neurocognition and QoL impact recovery after TBI. It is important to assess potential neurocognitive and QoL changes that may occur as a result of GHD. It is also important to consider the potential added benefit of overnight GH testing as compared to stimulation testing in predicting changes in neurocognition or QoL.

Use of lacosamide in children with refractory epilepsy.

OBJECTIVES: Lacosamide was approved by the US Food and Drug Administration in 2008 for adjunctive therapy for focal onset seizures in patients 17 years of age and older. The efficacy of this agent in adults has led clinicians to consider lacosamide for children with refractory seizures. METHODS: The MEDLINE database (1950-June 2012) was searched for abstracts containing lacosamide as the key term. Additional references were obtained from the manufacturer and the bibliographies of the articles reviewed. All available English-language case reports and clinical trials were included in the evaluation. RESULTS: Several case series studies have been published which support the use of lacosamide in children with refractory seizures. In the papers published to date, 30% to 50% of children experienced at least a 50% reduction in seizure frequency, similar to results obtained in clinical trials in adults. Children with focal onset seizures were most likely to benefit from treatment, while results in children with generalized seizures or multiple seizure types were mixed. Adverse effects in children were similar to those seen in adults, with dizziness, headache, and nausea occurring most frequently. Lack of efficacy has been the most common cause of discontinuation. CONCLUSIONS: Lacosamide appears to be a useful adjunct therapy in children with refractory seizures. Clinical trials are under way that may provide more definitive information on the efficacy and safety of lacosamide in children and allow clinicians to determine the appropriate place of this antiseizure drug in pediatric epilepsy management.

Recommendations for Meeting the Pediatric Patient's Need for a Clinical Pharmacist: A Joint Opinion of the Pediatrics Practice and Research Network of the American College of Clinical Pharmacy and the Pediatric Pharmacy Advocacy Group.

Children warrant access to care from clinical pharmacists trained in pediatrics. The American College of Clinical Pharmacy Pediatrics Practice and Research Network (ACCP Pediatrics PRN) released an opinion paper in 2005 with recommendations for improving the quality and quantity of pediatric pharmacy education in colleges of pharmacy, residency programs, and fellowships. While progress has been made in increasing the availability of pediatric residencies, there is still much to be done to meet the direct care needs of pediatric patients. The purpose of this Joint Opinion paper is to outline strategies and recommendations for expanding the quality and capacity of pediatric clinical pharmacy practitioners by 1) elevating the minimum expectations for pharmacists entering practice to provide pediatric care; 2) standardizing pediatric pharmacy education; 3) expanding the current number of pediatric clinical pharmacists; and 4) creating an infrastructure for development of pediatric clinical pharmacists and clinical scientists. These recommendations may be used to provide both a conceptual framework and action items for schools of pharmacy, health care systems, and policymakers to work together to increase the quality and quantity of pediatric training, practice, or research initiatives.

Hepatotoxicity after continuous amiodarone infusion in a postoperative cardiac infant.

A former 34-week-old female infant with Down syndrome underwent surgical correction of a congenital heart defect at 5 months of age. Her postoperative course was complicated by severe pulmonary hypertension and junctional ectopic tachycardia. Following treatment with amiodarone infusion, she developed laboratory indices of acute liver injury. At their peak, liver transaminase levels were 19 to 35 times greater than the upper limit of normal. Transaminitis was accompanied by coagulopathy, hyperammonemia, and high serum lactate and lipid levels. Hepatic laboratory abnormalities began to resolve within 48 hr of stopping amiodarone infusion. Heart rate control was achieved concurrently with discovery of laboratory test result abnormalities, and no further antiarrhythmic therapy was required. The intravenous formulation of amiodarone contains the diluent polysorbate 80, which may have hepatotoxic effects. Specifically, animal studies suggest that polysorbate 80 may destabilize cell membranes and predispose to fatty change within liver architecture. Polysorbate was implicated in infant fatalities from E-ferol use in the 1980s. This case illustrates a possible adverse event by the Naranjo probability scale. Given the extent of clinically apparent hepatic injury, this patient was not rechallenged with amiodarone during the remainder of her hospitalization. With amiodarone now used as first-line pharmacologic therapy for critical tachyarrhythmia in this population, the number of children exposed to this drug should be expected to increase. Laboratory indices of liver function should be evaluated at initiation of amiodarone therapy, as well as frequently throughout duration of therapy. Consideration should be given to polysorbate-free formulation of intravenous amiodarone for use in the cohort with congenital cardiac disease.

Improving Pediatric Adverse Drug Event Reporting through Clinical Pharmacy Services.

OBJECTIVES: The purpose of this study was to summarize adverse drug event (ADE) reporting and to characterize the type of healthcare practitioners involved in reporting over a 10-year period at a 120-bed university-affiliated children's hospital. METHODS: The University of Virginia Children's Hospital ADE database was analyzed for records involving pediatric patients. Data from patients <18 years of age who were admitted to the University of Virginia Children's Hospital between January 1, 2000, and December 31, 2009, were analyzed. Data collected included drug name and therapeutic class of the suspected causative agent, description of the event, severity, causality, outcome, and the type of healthcare practitioner reporting the event. RESULTS: A total of 863 ADEs were reported over the 10-year period. The 5 most common types reported were extravasation injury (10%), rash (8%), hypotension (5%), pruritus (5%), and renal failure (3%). A total of 196 (21%) cases were categorized as mild, 436 (47%) cases as moderate, and 296 (32%) cases as severe. Further characterization of extravasations was performed to identify trends relating to potential causes. In 45 (57%) reports, parenteral nutrition was identified as the causative agent. Full recovery was documented in 21 (47%) extravasations. Of the total events reported, 83% were reported by pharmacists, 16% by nurses, and <1% by other healthcare practitioners. CONCLUSIONS: Results of this study are consistent with those of previous studies involving ADE reporting in children's hospitals. This consistency is due in part to system design and use of unit-based pharmacists as the primary reporters.

Traumatic brain injury in children and adolescents: surveillance for pituitary dysfunction.

BACKGROUND: Children who sustain traumatic brain injury (TBI) are at risk for developing hypopituitarism, of which growth hormone deficiency (GHD) is the most common manifestation. OBJECTIVE: To determine the prevalence of GHD and associated features following TBI among children and adolescents. STUDY DESIGN: A total of 32 children and adolescents were recruited from a pediatric TBI clinic. Participants were diagnosed with GHD based on insufficient growth hormone release during both spontaneous overnight testing and following arginine/glucagon administration. RESULTS: GHD was diagnosed in 5/32 participants (16%). Those with GHD exhibited more rapid weight gain following injury than those without GHD and had lower levels of free thyroxine and follicle-stimulating hormone. Males with GHD had lower testosterone levels. CONCLUSIONS: GHD following TBI is common in children and adolescents, underscoring the importance of assessing for GHD, including evaluating height and weight velocities after TBI. Children and adolescents with GHD may further exhibit absence or intermediate function for other pituitary hormones.