The i-gel® supraglottic airway device compared to endotracheal intubation as the initial prehospital advanced airway device: A natural experiment during the COVID-19 pandemic.

Objective: Unlike randomized controlled trials, practical real-world studies can offer important information about implementation of prehospital interventions, particularly in community settings where there may be reluctance to adopt new practices. We present the results of a natural experiment that was driven by mandated COVID-19 pandemic-driven shift from endotracheal intubation (ETI) to the i-gel® supraglottic airway (SGA) as a primary advanced airway management device in the prehospital setting to reduce emergency medical services (EMS) personnel exposure to potentially infectious secretions. The objective was to compare first-pass success and timing to successful airway placement between ETI and the i-gel® SGA under extenuating circumstances. Methods: This pre/post study compared airway placement metrics in prehospital patients requiring advance airway management for non-trauma-related conditions. Data from EMS records were extracted over 2 years, 12 months pre-pandemic, and 12 months post-pandemic. During the pre-COVID-19 year, the EMS protocols utilized ETI as the primary advanced airway device (ETI group). Post-pandemic paramedics were mandated to utilize i-gel® SGA as the primary advanced airway device to reduce exposure to secretions (SGA group). Results: There were 199 adult patients, 83 (42%) in the ETI group and 116 (58%) in the SGA group. First-pass success was significantly higher with SGA 96% (92%-99%) than ETI 68% (57%-78%) with paramedics citing the inability to visualize the airway in 52% of ETI cases. Time to first-pass success was significantly shorter in the SGA group (5.9 min [5.1-6.7 min]) than in the ETI group (8.3 min [6.9-9.6 min]), as was time to overall successful placement at 6.0 min (5.1-6.8 min) versus 9.6 min (8.2-11.1 min), respectively. Multiple placement attempts were required in 26% of ETI cases and 1% of the SGA cases. There were no statistically significant differences in the number and types of complications between the cohorts. Return of spontaneous circulation (on/before emergency department [ED] arrival), mortality at 28 days, intensive care unit length of stay, or ventilator-free days between the groups were not statistically different between the groups. Conclusion: In this natural experiment, the SGA performed significantly better than ETI in first-pass airway device placement success and was significantly faster in achieving first-pass success, and overall airway placement, thus potentially reducing exposure to respiratory pathogens. Practical real-world studies can offer important information about implementation of prehospital interventions, particularly in community settings and in systems with a low frequency of tracheal intubations.

Elimination of 15N-thymidine after oral administration in human infants.

BACKGROUND: We have developed a new clinical research approach for the quantification of cellular proliferation in human infants to address unanswered questions about tissue renewal and regeneration. The approach consists of oral 15N-thymidine administration to label cells in S-phase, followed by Multi-isotope Imaging Mass Spectrometry for detection of the incorporated label in cell nuclei. To establish the approach, we performed an observational study to examine uptake and elimination of 15N-thymidine. We compared at-home label administration with in-hospital administration in infants with tetralogy of Fallot, a form of congenital heart disease, and infants with heart failure. METHODS: We examined urine samples from 18 infants who received 15N-thymidine (50 mg/kg body weight) by mouth for five consecutive days. We used Isotope Ratio Mass Spectrometry to determine enrichment of 15N relative to 14N (%) in urine. RESULTS/FINDINGS: 15N-thymidine dose administration produced periodic rises of 15N enrichment in urine. Infants with tetralogy of Fallot had a 3.2-fold increase and infants with heart failure had a 4.3-fold increase in mean peak 15N enrichment over baseline. The mean 15N enrichment was not statistically different between the two patient populations (p = 0.103). The time to peak 15N enrichment in tetralogy of Fallot infants was 6.3 ± 1 hr and in infants with heart failure 7.5 ± 2 hr (mean ± SEM). The duration of significant 15N enrichment after a dose was 18.5 ± 1.7 hr in tetralogy of Fallot and in heart failure 18.2 ± 1.8 hr (mean ± SEM). The time to peak enrichment and duration of enrichment were also not statistically different (p = 0.617 and p = 0.887). CONCLUSIONS: The presented results support two conclusions of significance for future applications: (1) Demonstration that 15N-thymidine label administration at home is equivalent to in-hospital administration. (2) Two different types of heart disease show no differences in 15N-thymidine absorption and elimination. This enables the comparative analysis of cellular proliferation between different types of heart disease.

Age and sex differences in blood product transfusions and mortality in trauma patients at a level I trauma center.

Objectives: Hemorrhage is a common complication of trauma. We evaluated age and sex differences in treatment with blood product transfusions and massive transfusions as well as in-hospital mortality following trauma at a Level 1 Trauma Center. Methods: This cross-sectional study evaluated trauma data from a Level 1 trauma center registry from January 2013 to December 2017. The primary outcome was amount of blood products (packed red blood cells (PRBCs), plasma, platelets), and massive transfusion (MT) by biological sex and by age group: 16-24 (youth), 25-59 (middle age), and >=60 (older age) The secondary outcome was in-hospital mortality to hospital discharge. Results: There were 13596 trauma patients in the registry, mean age was 48 years, 4589 (34%) female and 9007 (66%) male, and median ISS of 9. Male patients received significantly more PRBC transfusions than female patients within 4-hours 6.6% vs 4.4%, and 24-hours 6.7% vs 4.5% respectively. Older patients received significantly fewer PRBC transfusions within 4-hours and 24-hours than their younger counterparts, with 6.9% in the youth group, 6.8% in the middle age group, and 3.9% in the older group (p<0.001). When adjusted for injury severity, the odds of receiving a blood transfusion within 4 hours of injury was significantly lower in older females. Using multivariate analysis, predictors of mortality included (in order of significance) injury severity, older age, transfusion within 4 hours of injury, penetrating trauma, and male sex. Conclusion: In this large trauma cohort, older female trauma patients were less likely to receive blood products compared to younger females and to their older male counterparts, even after adjusting for injury severity. Predictors of mortality included injury severity, older age, early transfusion, penetrating trauma, and male sex. Following trauma, older women appear vulnerable to undertreatment. Further study is needed to determine the reasons for these differences and their impact on patient outcomes.

Short-term clinical outcomes and predicted cost savings of dd-cfDNA-led surveillance after pediatric heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB)-led surveillance is common after pediatric heart transplantation (HT), with some centers performing periodic surveillance EMBs indefinitely after HT. Donor derived cell-free DNA (dd-cfDNA)-led surveillance offers an alternative, but knowledge about its clinical and economic outcomes, both key drivers of potential utilization, are lacking. METHODS: Using single-center recipient and center-level data, we describe clinical outcomes prior to and since transition from EMB-led surveillance to dd-cfDNA-led surveillance of pediatric and young adult HT recipients. These data were then used to inform Markov models to compare costs between EMB-led and dd-cfDNA-led surveillance strategies. RESULTS: Over 34.5 months, dd-cfDNA-led surveillance decreased the number of EMBs by 81.8% (95% CI 76.3%-86.5%) among 120 HT recipients (median age 13.3 years). There were no differences in the incidences of graft loss or death among all recipients followed at our center prior to and following implementation of dd-cfDNA-led surveillance (graft loss: 2.9 vs. 1.5 per 100 patient-years; p = .17; mortality: 3.7 vs. 2.2 per 100 patient-years; p = .23). Over 20 years from HT, dd-cfDNA-led surveillance is projected to cost $8545 less than EMB-led surveillance. Model findings were robust in sensitivity and scenario analyses, with cost of EMB, cost of dd-cfDNA testing, and probability of elevated dd-cfDNA most influential on model findings. CONCLUSIONS: dd-cfDNA-led surveillance shows promise as a less invasive and cost saving alternative to EMB-led surveillance among pediatric and young adult HT recipients.

Development of a universal thoracic enhanced recover after surgery protocol for implementation across a diverse multi-hospital health system.

Background: Implementation of enhanced recovery after surgery (ERAS) pathways for patients undergoing anatomic lung resection have been reported at individual institutions. We hypothesized that an ERAS pathway can be successfully implemented across a large healthcare system including different types of hospital settings (academic, academic-affiliated, community). Methods: An expert panel with representation from each hospital within a healthcare system was convened to establish a thoracic ERAS pathway for patients undergoing anatomic lung resection and to develop tools and analytics to ensure consistent application. The protocol was translated into an order set and pathway within the electronic health record (EHR). Iterative implementation was performed with recording of the processes involved. Barriers and facilitators to implementation were recorded. Results: Development and implementation of the protocol took 13 months from conception to rollout. Considerable change management was needed for consensus and incorporation into practice. Facilitators of change included peer accountability, incorporating ERAS care elements into the EHR, and conducting case reviews with timely feedback on protocol deviations. Barriers included institutional cultural differences, agreement in defining mindful deviation from the ERAS protocol, lack of access to specific coded data, and resource scarcity caused by the COVID-19 pandemic. Support from the hospital system's executive leadership and institutional commitment to quality improvement helped overcome barriers and maintain momentum. Conclusions: Development and implementation of a health-system wide thoracic ERAS protocol for anatomic lung resections across a six-hospital health system requires a multidisciplinary team approach. Barriers can be overcome though multidisciplinary team engagement and executive leadership support.

Integrating social determinants into pharmacotherapy courses: A case-based learning approach.

BACKGROUND: The recognition of social determinants as major drivers of health outcomes has important implications for health care providers, including pharmacists. It is therefore imperative that providers have the requisite knowledge, skills, and attitudes to adequately address the contributions of social determinants of health (SDOH) alongside the impact of medical care on health and treatment outcomes. Case-based learning is a common practice in pharmacy education. Patient cases used in pharmacotherapy courses typically highlight clinical parameters and quantitative indices, often to the exclusion of sociocultural contexts. In actual practice, pharmacists (and other health care providers) must consider both clinical information and the context of SDOH in order to deliver responsive and effective patient care. EDUCATIONAL ACTIVITY AND SETTING: The aim of the project was to build patient cases that reflect both aspects. The intent is to use these cases in the core pharmacy curriculum to teach students how to concurrently consider both clinical and social elements in patient care. Eleven pharmacists and educators participated in three work groups to develop 10 cases for pharmacotherapy courses in cardiovascular disease, diabetes management, and mental health. Two of the cases were facilitated with fourth year students on advanced pharmacy practice experiences. SUMMARY: Feedback from case developers and students highlights features of the cases that lend them to utility in the pharmacy curriculum. The integration of SDOH in patient cases provides opportunity for students to build the relevant competencies that will enable them to provide holistic patient care.

Responsiveness to second and third dose of mRNA COVID-19 vaccination in adolescent and young adult heart transplant recipients.

BACKGROUND: Third-dose mRNA COVID-19 vaccine is currently recommended in the United States for SOT recipients based in part on data showing diminished immune response, including Ab production, after a two-dose regimen. Data on vaccine response in adolescent and young adult SOT recipients are limited, including no data reported on third-dose responsiveness. METHODS: Results of serologic testing in a convenience sample of 28 vaccinated adolescent and young adult HT recipients at a single institution were collected from the medical record and summarized. RESULTS: At a median of 98.5 days (IQR 59-150) after second dose, 17 (61%) had an Ab response. Among 12 who had serology before and after third-dose vaccination, four of seven who were negative prior to third dose became positive at a median of 34 days (IQR 31-39.5) following third dose. No myocarditis, acute rejection, graft dysfunction, graft loss, or deaths were observed. CONCLUSIONS: These findings support recommendations for the routine administration of three doses of mRNA vaccines in adolescent and young adult HT recipients and show a potential subpopulation in whom the fourth dose should be contemplated.

Early findings after integration of donor-derived cell-free DNA into clinical care following pediatric heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donor-derived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB). METHODS: We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7 months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed. RESULTS: Over 17 months, 58 recipients [34% female, median age at HT 3.1 years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8 years (8.4-18.3) and time from HT 6.0 years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7 months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1 months (6.9-12.9) with 23 showing no acute rejection (AR): grade 0R/pAMR0 (n = 16); 1R(1A)/pAMR0 (n = 7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19 days (12-32) with AR in 4: grade 1R(1B-2)/pAMR0 (n = 3); 1R(1B)/pAMR2 (n = 1). CONCLUSIONS: dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings.

Implementation of an Innovative Nurse-Driven Resuscitation Protocol.

Creating nurse-driven protocols empower nurses to practice at the top of their scope and provide early interventions. This article describes the development and implementation of an evidence-based, nurse-driven resuscitation protocol for cardiac surgical patients who suffer cardiac arrest using a theoretical framework and leadership-driven process. Readers will gain knowledge of the collaborative process required to develop and implement a complex practice change. Process measures, outcomes, and lessons learned are presented.

Charges and resource utilization for pediatric heart transplantation across a positive virtual and/or cytotoxicity crossmatch.

There is growing acceptance of transplantation across a positive crossmatch for highly allosensitized pediatric HT candidates. While survival may be similar to patients transplanted across a negative crossmatch, costs are unknown. Among 60 HT recipients at our center from 5/07 to 6/12, we analyzed hospital charges and length of stay from the day of HT to discharge and through the first year after transplant. Median age at HT was 6.2 years (15 days-20.5 years). Charges in the first year post-HT were greater for crossmatch-positive patients ($907 678 vs $549 754; P = .017), with a trend toward higher charges for the HT hospitalization ($537 640 vs $407 374; P = .07). Plasmapheresis was more common in crossmatch-positive patients during the HT hospitalization (80% vs 4%, P < .001). In the first year after HT, crossmatch-positive patients had a greater number of endomyocardial biopsies (10 vs 7.5, P = .03) and episodes of treated rejection (2 vs 0, P = .004). Pediatric HT across a positive crossmatch is associated with higher first-year costs, including increased use of plasmapheresis and care around an increased number of rejections. These novel data will help inform decision and policymaking regarding care practices for the growing population of highly sensitized pediatric HT candidates.

Diffuse myocardial fibrosis among healthy pediatric heart transplant recipients: Correlation of histology, cardiovascular magnetic resonance, and clinical phenotype.

Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1±3.0 vs 23.7±2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation.

Utility of C4d immunostaining in the first year after pediatric and young adult heart transplantation.

BACKGROUND: C4d assessment of endomyocardial biopsies (EMBs) after heart transplantation (HTx) has been widely adopted to aid in the diagnosis of antibody-mediated rejection (AMR), yet it remains unclear whether or not to assess all patients routinely and with what frequency/duration. In this study we sought to evaluate the utility of routine C4d immunostaining in the first year after pediatric and young adult HTx. METHODS: We reviewed pre-transplant alloantibody and clinical data, including serial EMB reports, on all 51 patients who received HTx at our center since we instituted routine C4d staining of all first-year EMBs. C4d was considered positive if diffuse capillary staining (≥ 2(+)) was present. Rare/focal capillary staining or absence of staining was considered negative. RESULTS: Twenty-six of 406 first-year EMBs (6%) were C4d(+) in 6 (12%) patients. Sixty-five percent of all C4d(+) EMBs occurred by 30 days post-transplant. Five of 6 patients had pre-transplant donor-specific antibody (DSA) ≥ 4,000 MFI. The sixth patient had neither pre-transplant anti-HLA antibodies nor a positive donor-specific cytotoxicity crossmatch (DSXM), but there was clinical concern for AMR. Among the entire cohort, 5 of 10 patients with pre-transplant DSA ≥ 4,000 MFI and/or a positive DSXM were C4d(+) compared with only 1 of 41 without (50% vs 2%; p = 0.001). CONCLUSIONS: In the first year after HTx, C4d(+) occurred early and only in children and young adults with pre-transplant DSA or with clinical suspicion of AMR. Although our data suggest that assessment limited to the first 90 days post-transplant in patients with pre-transplant DSA ≥ 4,000 MFI may be appropriate in the absence of clinical concern for AMR, further research is needed to determine the optimum strategy for post-transplant surveillance.

Protection detail. Protecting against breach of electronic protected health information.

Covered entities need to conduct risk assessments that cover the requirements of HIPAA, HITECH and Meaningful use, and create a process for steady and consistent mitigation of known gaps and vulnerabilities based on risk. Reducing risk of vulnerabilities of unauthorized access to your ePHI can be done via safeguards and controls, plus audits and monitoring. When reducing risk is outside of a covered entities control, audits and monitoring are required in order to demonstrate due diligence. Know where your ePHI is stored, where it is at risk, and take steps now to reduce or eliminate the risk. Encrypt vulnerable locations. Encrypt sensitive data. By doing so, you will be protecting your organization by reducing risk of breach of ePHI. Finally, don't forget what is sometimes considered to be the hardest part--documenting your compliance activities in order to demonstrate evidence of due diligence in and avoid major $$$$ penalties for negligence under the HITECH Act of 2009.

Survival in allosensitized children after listing for cardiac transplantation.

BACKGROUND: Little is known about the effect of pre-transplant alloantibody in the pediatric cardiac transplant population. METHODS: All cardiac listings (n = 298) at Children's Hospital of Pittsburgh from January 1990 through February 2006 were reviewed to determine the impact of allosensitization on transplantation outcomes. Analysis focused on: (1) wait list outcomes; (2) survival from the time of listing, regardless of subsequent transplantation; (3) post-transplant graft and patient survival; and (4) post-transplant freedom from graft vasculopathy. Institutional policy required a negative, prospective crossmatch for candidates with panel-reactive antibody >20%. RESULTS: Alloantibody data were available for 252 (85%) listings. Median time to transplantation was greater for sensitized vs non-sensitized subjects (2.7 months vs 1.3 months; p = 0.02). At 1 year after listing, sensitized subjects had a higher incidence of death (22% vs 8.4%; p = 0.055). Survival at all time-points after listing (regardless of transplantation) was worse for sensitized subjects (p = 0.04). Although no statistically significant differences in post-transplant graft or patient survival were noted, pre-transplant allosensitization was associated with decreased freedom from graft vasculopathy (hazard ratio [HR] 2.76, 95% confidence interval [CI] 1.18 to 6.45; p = 0.019). CONCLUSIONS: A policy requiring a negative, prospective crossmatch for highly sensitized candidates is associated with longer wait list time and higher mortality after listing. The development of graft vasculopathy appears to be influenced by the presence of pre-transplant alloantibody.

Lipid profiles in pediatric thoracic transplant recipients are determined by their immunosuppressive regimens.

BACKGROUND: Controversy exists over the pattern of lipidemic effects from calcineurin inhibitors and prednisone. We report an extensive longitudinal study of lipid profiles in pediatric thoracic transplant recipients. METHODS: Serial fasting lipids of subjects from a single pediatric center, along with their immunosuppressive regimens, were examined. Groups were analyzed according to cyclosporine- or tacrolimus-based immunosuppression in addition to whether prednisone was used as adjunctive therapy. RESULTS: Of a total of 119 subjects, 85 were and remained on tacrolimus (TAC), 13 remained on cyclosporine (CSA), 4 switched from TAC to CSA, and 17 switched from CSA to TAC. The median age at transplant was 100 months, and the latest follow-up was 48 months. The CSA Group had higher lipid levels than the TAC Group, and levels changed minimally over time. At 1 year, TAC vs CSA total cholesterol was 153 vs 186 mg/dl (p = 0.002), low-density lipoprotein (LDL) cholesterol was 92 vs 117 (p = 0.09), and high-density lipoprotein (HDL) cholesterol was 42 vs 48 (p = NS), respectively. At the latest follow-up, the TAC vs CSA cholesterol was 143 vs 180 mg/dl (p = 0.001), LDL was 84 vs 115 (p = 0.001), and HDL was 42 vs 41 (p = NS). Profiles of subjects that switched agents reflected the agent used (e.g., higher total cholesterol, LDL, and HDL while on cyclosporine). Sub-group analysis showed prednisone augmented the hyperlipidemic effects. CONCLUSION: Hyperlipidemia is common in pediatric thoracic transplant patients and persists over time. It is more pronounced in cyclosporine subjects and is further elevated with prednisone. These findings indicate the need for close monitoring, and consideration for intervention, especially in high-risk sub-groups.

Impact of ELISA-detected anti-HLA antibodies on pediatric cardiac allograft outcome.

In this study, we determine whether the presence of enzyme-linked immunosorbent assay (ELISA) detected anti-human leukocyte antigen (HLA) antibodies correlates with acute and chronic rejection in pediatric heart transplantation (Tx). Forty-five patients, who had serial ELISA pre- and posttransplantation, were studied. Age at Tx was 8.2 +/- 7.2 years. Acute rejection (AR) was defined as International Society for Heart and Lung Transplantation Grade > or =3a. Patients were defined as rejectors (22 cases) if they had recurrent AR or steroid-resistant AR within the first year post-Tx; the other cases (23) were defined as nonrejectors. Overall, 219 samples were analyzed. Twenty-two of the 45 had pre- or post-Tx anti-HLA antibodies: 77% in rejectors (17/22) and only 22% in nonrejectors (5/23), p = 0.0002. Pre-Tx HLA antibodies were present in 12 cases (27%). Presensitization was more frequent in rejectors (11/22, 50%) than in nonrejectors (1/23, 4%, p = 0.0005). Nineteen cases retained (9 cases) or developed (10 cases) anti-HLA antibodies post-Tx: 14 in rejectors (63.6%) and 5 in nonrejectors (21.7%), p = 0.003. Four of eight cases with coronary artery disease (50%) had preformed anti-HLA antibodies compared with 8 of 37 without coronary artery disease (25.6%) (p = 0.09). Preformed, persistent, and de novo ELISA-detected anti-HLA antibodies were correlated with first-year acute rejection profile.

Impact of TGFbeta1 gene polymorphisms on late renal function in pediatric heart transplantation.

Late renal dysfunction may affect long-term outcome of nonrenal transplant recipients. We hypothesized that transforming growth factor beta1 (TGFbeta1) might play a role in the fibrogenic mechanisms leading to renal dysfunction. The aim was to determine whether TGFbeta1 gene polymorphisms are associated with renal outcome in pediatric heart recipients. Eighty-eight patients underwent a first heart transplantation at the age of 7.1 +/- 6.5 years, received tacrolimus-based immunosuppression, and were followed for > or =1 year (6.7 +/- 3.2 years). Creatinine clearance (CrCl; ml/mn/1.73 m2) was calculated (Schwartz) before transplant, then at 1 month, 6 months, and 1 year, and yearly up to 7 years. Impaired function was defined as CrCl <80 ml/mn/1.73 m2. Mean CrCl decreased from 120 +/- 53 ml/mn/1.73 m2 before transplant to 98 +/- 40, 96 +/- 37, 102 +/- 30, and 101 +/- 38 ml/mn/1.73 m2 at, respectively, 6 months and 1, 5 (n = 58), and 7 years (n = 33). The TGFbeta1 high-producer genotype had worse CrCl than intermediate and low producers at every time point, despite similar pretransplant CrCl (pretransplant = 120 +/- 53 vs 118 +/- 55 ml/mn/1.73 m2 [p = 0.8], 1 year = 92 +/- 38 vs 113 +/- 30 ml/mn/1.73 m2 [p = 0.03]) and similar tacrolimus levels. The TGFbeta1 high-producer genotype was associated with CrCl < 80 ml/mn/1.73 m2. The TGFbeta1 high-producer genotype is associated with renal dysfunction in pediatric heart recipients.

Tacrolimus dosage requirements after initiation of azole antifungal therapy in pediatric thoracic organ transplantation.

Azole antifungals inhibit the metabolism of tacrolimus mediated by CYP3A4. Upon initiation of azole therapy, the required dose reduction of tacrolimus is unknown. We reviewed our experience with azole antifungals in our pediatric thoracic transplant population receiving tacrolimus. Tacrolimus levels and dosage requirements were compared before and during azole therapy. Thirty-one patients received both tacrolimus and an azole antifungal (fluconazole = 9, itraconazole = 22). The tacrolimus dose was empirically reduced by approximately one-third when azole therapy was initiated. Mean tacrolimus dose requirements decreased by 68% within the first month of therapy (pre-azole: 0.27 +/- 0.14 mg/kg/day; 30 day post-azole: 0.087 +/- 0.069 mg/kg/day; p < 0.001). Despite a mean decrease in tacrolimus dose from baseline of 33, 42, and 55% on day 1, 2, and 4 of azole therapy, respectively, there was still an unintended 38% increase in tacrolimus levels during the first month of azole therapy. A calculated dose-reduction protocol of 50% on day of azole initiation, 70% on day 3, and 75% on day 14 should result in minimal mean changes in the tacrolimus levels. There was no difference in tacrolimus dose reduction between fluconazole and itraconazole groups. Azole antifungals markedly decrease tacrolimus requirements within the first few days of therapy. An initial reduction in tacrolimus dose by one-third is insufficient, and dose reduction of at least 50% upon azole initiation seems warranted. Once azole antifungal therapy is initiated, frequent therapeutic drug monitoring is required.