Impact of tacrolimus variability on pediatric heart transplant outcomes.

BACKGROUND: Tacrolimus is a narrow therapeutic index drug, requiring consistent levels to maximize transplant success while reducing adverse effects. Elevated tacrolimus level variability (ETLV) is associated with poor outcomes in both pediatric and adult solid organ transplant recipients. We sought to describe the prevalence of ETLV and identify associations with patient-specific factors and poor outcomes. METHODS: Tacrolimus levels were evaluated from 118 patients at our single center. As a marker of variability, standard deviations (SD) were calculated for each patient from their entire tacrolimus level data set (global SD), and 1-2 years and 1-5 years post-HT (prediction window SDs). SD ≥3 denoted ETLV. RESULTS: There was large variability in tacrolimus levels (median global SD 3.1; IQR 2.3, 4; SD ≥3, n = 64, 54%). Patients with elevated SD (≥3) vs lower SD (<3) were more likely to have poor outcomes including rejection (73% vs 46%), cardiac allograft vasculopathy (CAV, 22% vs 9%), and death (20% vs 6%). The prediction window analysis noted ETLV was associated with a 40% greater risk of CAV, re-HT, or death (p = .024) and increasing age at transplantation was associated with a 12% increase in the risk of rejection (p = <.001) and a 19% increase in the risk of a composite event (p = .021). CONCLUSION: ETLV is prevalent in the pediatric HT population with increased frequency of poor outcomes in those with SD ≥3. ETLV is an easily accessible marker with which to risk-stratify patients.

Pharmacokinetic Modeling Using Real-World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement-Clinical Outcomes Relationship.

Unfractionated heparin (UFH) is a commonly used anticoagulant for pediatric patients undergoing extracorporeal membrane oxygenation (ECMO), but evidence is lacking on the ideal dosing. We aimed to (1) develop a population pharmacokinetic (PK) model for UFH, measured through anti-factor Xa assay; (2) optimize UFH starting infusions and dose titrations through simulations; and (3) explore UFH exposure-clinical outcomes relationship. Data from 218 patients admitted to Utah's Primary Children's Hospital were retrospectively collected. A 1-compartment PK model with time-varying clearance (CL) adequately described UFH PK. Weight on CL and volume of distribution and ECMO circuit change on CL were significant covariates. The typical estimates for initial CL and first-order rate constant to reach steady-state CL were 0.57 L/(h·10 kg) and 0.02/h. Comparable to non-ECMO patients, the typical steady-state CL was 0.81 L/(h·10 kg). Simulations showed that a 75 IU/kg UFH bolus dose followed by starting infusions of 25 and 20 IU/h/kg for patients aged younger than 6 years and 6 years or older, respectively, achieved the therapeutic target in 56.6% of all patients, whereas only 3.1% exceeded the target. The proposed UFH titration schemes achieved the target in more than 90% of patients while less than 0.63% were above the target after 24 and 48 hours of treatment. The median intensive care unit survival time in patients within and below the target at 24 hours was 136 and 66 hours, respectively. In conclusion, PK model of UFH was developed for pediatric patients on ECMO. The proposed UFH dosing scheme attained the anti-factor Xa target rapidly and safely.

Outcomes of Prophylactic Enoxaparin Against Venous Thromboembolism in Hospitalized Children.

OBJECTIVES: To assess the biochemical and clinical outcomes of hospitalized children who received prophylactic enoxaparin. METHODS: We conducted a retrospective observational study of hospitalized children aged <18 years who received prophylactic enoxaparin against hospital-acquired venous thromboembolism (HA-VTE). Weight-based enoxaparin dosing was administered using a pharmacy-driven protocol, which later included a low molecular weight, anti-Xa level directed-dose adjustment strategy. Primary biochemical and clinical outcomes were achievement of goal anti-Xa range of 0.2 to 0.5 IU/mL and development of HA-VTE, respectively. Secondary clinical outcome was development of clinically relevant bleed. RESULTS: We analyzed 194 children with 13 (6.7%) infants aged <1 year and 181 (93.3%) older children aged ≥1 year. After the initial dose, only 1 (11.1%) infant, but 62 (57.9%) older children, achieved goal. Median number of anti-Xa levels until goal was 2 (interquartile range: 2-3) in infants and 1 (interquartile range: 1-2) in older children (P = .01). HA-VTE developed in 2 (15.4%) infants and 9 (5.0%) older children. Among children with anti-Xa level, HA-VTE developed less frequently in children who achieved (2.1%) than in those who did not achieve (13.6%) goal (P = .046). A total of 4 (2.1%) older children and no infants developed clinically relevant bleed. Among children with anti-Xa level, frequency of bleeding was comparable between children who did (3.2%) and did not achieve (0%) goal (P >.99). CONCLUSIONS: Our findings suggest the effectiveness and safety of an anti-Xa level directed strategy of prophylactic enoxaparin. However, this strategy should be investigated in prospective controlled studies.

Medication and Fluid Management of Pediatric Sepsis and Septic Shock.

Sepsis is a life-threatening response to infection that contributes significantly to neonatal and pediatric morbidity and mortality worldwide. The key tenets of care include early recognition of potential sepsis, rapid intervention with appropriate fluids to restore adequate tissue perfusion, and empiric antibiotics to cover likely pathogens. Vasoactive/inotropic agents are recommended if tissue perfusion and hemodynamics are inadequate following initial fluid resuscitation. Several adjunctive therapies have been suggested with theoretical benefit, though definitive recommendations are not yet supported by research reports. This review focuses on the recommendations for medication and fluid management of pediatric sepsis and septic shock, highlighting issues related to antibiotic choices and antimicrobial stewardship, selection of intravenous fluids for resuscitation, and selection and use of vasoactive/inotropic medications. Controversy remains regarding resuscitation fluid volume and type, antibiotic choices depending upon infectious risks in the patient's community, and adjunctive therapies such as vitamin C, corticosteroids, intravenous immunoglobulin, and methylene blue. We include best practice recommendations based on international guidelines, a review of primary literature, and a discussion of ongoing clinical trials and the nuances of therapeutic choices.

Time in Therapeutic Range for Bivalirudin Among Pediatric Ventricular Assist Device Recipients.

Given the adverse event rates involving bleeding and thrombosis among children on ventricular assist devices (VADs), anticoagulant management has become a focal point for quality improvement and innovation. There may be advantages to using direct thrombin inhibitors, such as bivalirudin, though this has not been fully explored. As the percent time in therapeutic range (%TTR) for anticoagulants is classically associated with improved clinical outcomes, we evaluated the %TTR for bivalirudin among pediatric VAD recipients. Using a modification of the Rosendaal method, %TTR was calculated using activated partial thromboplastin time measurements for 11 VAD recipients in the early postoperative period (postoperative days 0-14) and for the duration of VAD support. In the initial 2 weeks after VAD implant, mean %TTR was 68.7 (±13.0). During the entire support course, the mean %TTR improved to 79.6 (±11.0). There was an era effect with improving %TTR in the latter half of the study period. We report very good %TTR for bivalirudin both in the first 2 weeks post implant and this improved over the duration of support. Because %TTR reflects the degree of safety and efficacy in chronic anticoagulation, this relatively high %TTR among a diverse, often critically ill cohort suggests that bivalirudin may be a promising agent. Although this study was underpowered to comprehensively evaluate adverse events on bivalirudin, this represents an important next step for larger scale study.

International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients.

Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article.

Rapid identification of pathogens from positive blood cultures by multiplex polymerase chain reaction using the FilmArray system.

Sepsis is a leading cause of death. Rapid and accurate identification of pathogens and antimicrobial resistance directly from blood culture could improve patient outcomes. The FilmArray® (FA; Idaho Technology, Salt Lake City, UT, USA) Blood Culture (BC) panel can identify >25 pathogens and 4 antibiotic resistance genes from positive blood cultures in 1 h. We compared a development version of the panel to conventional culture and susceptibility testing on 102 archived blood cultures from adults and children with bacteremia. Of 109 pathogens identified by culture, 95% were identified by FA. Among 111 prospectively collected blood cultures, the FA identified 84 (91%) of 92 pathogens covered by the panel. Among 25 Staphylococcus aureus and 21 Enterococcus species detected, FA identified all culture-proven methicillin-resistant S. aureus and vancomycin-resistant enterococci. The FA BC panel is an accurate method for the rapid identification of pathogens and resistance genes from blood culture.

Non-invasive sample collection for respiratory virus testing by multiplex PCR.

BACKGROUND: Identifying respiratory pathogens within populations is difficult because invasive sample collection, such as with nasopharyngeal aspirate (NPA), is generally required. PCR technology could allow for non-invasive sampling methods. OBJECTIVE: Evaluate the utility of non-invasive sample collection using anterior nare swabs and facial tissues for respiratory virus detection by multiplex PCR. STUDY DESIGN: Children aged 1 month-17 years evaluated in a pediatric emergency department for respiratory symptoms had a swab, facial tissue, and NPA sample collected. All samples were tested for respiratory viruses by multiplex PCR. Viral detection rates were calculated for each collection method. Sensitivity and specificity of swabs and facial tissues were calculated using NPA as the gold standard. RESULTS: 285 samples from 95 children were evaluated (92 swab-NPA pairs, 91 facial tissue-NPA pairs). 91% of NPA, 82% of swab, and 77% of tissue samples were positive for ≥1 virus. Respiratory syncytial virus (RSV) and human rhinovirus (HRV) were most common. Overall, swabs were positive for 74% of virus infections, and facial tissues were positive for 58%. Sensitivity ranged from 17 to 94% for swabs and 33 to 84% for tissues. Sensitivity was highest for RSV (94% swabs and 84% tissues). Specificity was ≥95% for all viruses except HRV for both collection methods. CONCLUSIONS: Sensitivity of anterior nare swabs and facial tissues in the detection of respiratory viruses by multiplex PCR varied by virus type. Given its simplicity and specificity, non-invasive sampling for PCR testing may be useful for conducting epidemiologic or surveillance studies in settings where invasive testing is impractical or not feasible.

Molecular analysis improves pathogen identification and epidemiologic study of pediatric parapneumonic empyema.

BACKGROUND: Parapneumonic empyema (PPE) is an increasingly common complication of bacterial pneumonia. Epidemiologic study is complicated by the low frequency of positive cultures. We sought to describe the epidemiology of PPE in children using molecular analysis of pleural fluid. METHODS: We performed molecular testing for bacterial pathogens using archived pleural fluid from children hospitalized in 2009 with PPE. Real-time polymerase chain reaction (PCR) to detect Streptococcus pneumoniae, Staphylococcus aureus (including methicillin-resistant), Streptococcus pyogenes, Haemophilus influenzae, and Mycoplasma pneumoniae as well as PCR-based serotyping of S. pneumoniae was performed. Demographic, laboratory, and microbiologic data were abstracted. RESULTS: Pleural fluid specimens from 63 children were available for PCR. By culture, a pathogen was isolated from blood and/or pleural fluid in 22 (35%) patients, with S. pneumoniae in 15 (24%), S. pyogenes in 3 (5%), and methicillin-resistant Staphylococcus aureus in 4 (6%). By PCR, a pathogen was detected in 53 (84%), including S. pneumoniae in 45 (71%). Compared with culture, PCR testing significantly increased detection of any pathogen (35% vs. 84%; P < 0.001) and of S. pneumoniae (24% vs. 71%; P < 0.001). Serotype 7F was the most common pneumococcal serotype detected. Comparison of culture-negative to culture-positive disease showed differences in both the pathogen profile and clinical outcomes. CONCLUSIONS: Molecular analysis of pleural fluid more than doubled the detection of pathogens causing PPE. S. pneumoniae was the most common cause of both culture-positive and culture-negative PPE, although serotype distribution and outcomes differed.

Association of 2009 pandemic influenza A (H1N1) infection and increased hospitalization with parapneumonic empyema in children in Utah.

BACKGROUND: During previous influenza pandemics, many deaths were associated with secondary bacterial infection. In April 2009, a previously unknown 2009 influenza A virus (2009 H1N1) emerged, causing a global influenza pandemic. We examined the relationship between circulating 2009 H1N1 and the occurrence of secondary bacterial parapneumonic empyema in children. METHODS: Children hospitalized with parapneumonic empyema from August 2004 to July 2009, including a period when the 2009 H1N1 circulated in Utah, were identified using International Classification of Diseases, Ninth Revision codes. We compared the average number of children diagnosed with influenza A and the number of admissions for empyema per month for the previous 4 seasons to rates of empyema during the 2009 H1N1 outbreak. We identified causative bacteria using culture and polymerase chain reaction (PCR). RESULTS: We observed an increase in hospitalization of children with pneumonia complicated by empyema during a severe outbreak of 2009 H1N1 during the spring and summer of 2009, compared with historical data for the previous 4 seasons. Streptococcus pneumoniae and Streptococcus pyogenes were the predominant bacteria identified. CONCLUSIONS: Similar to previous pandemics, secondary bacterial infection with S. pneumoniae and S. pyogenes were associated with the 2009 H1N1 outbreak. There is an urgent need to better understand bacterial complications of pandemic influenza. In the interim, influenza vaccines, antiviral agents, and pneumococcal vaccines should be used to prevent cases of secondary bacterial pneumonia whenever possible.