Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass.

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.

A normothermic ex vivo organ perfusion delivery method for cardiac transplantation gene therapy.

Clinically, both percutaneous and surgical approaches to deliver viral vectors to the heart either have resulted in therapeutically inadequate levels of transgene expression or have raised safety concerns associated with extra-cardiac delivery. Recent developments in the field of normothermic ex vivo cardiac perfusion storage have now created opportunities to overcome these limitations and safety concerns of cardiac gene therapy. This study examined the feasibility of ex vivo perfusion as an approach to deliver a viral vector to a donor heart during storage and the resulting bio distribution and expression levels of the transgene in the recipient post-transplant. The influence of components (proprietary solution, donor blood, and ex vivo circuitry tubing and oxygenators) of the Organ Care System (OC) (TransMedics, Inc., Andover MA) on viral vector transduction was examined using a cell-based luciferase assay. Our ex vivo perfusion strategy, optimized for efficient Adenoviral vector transduction, was utilized to deliver 5 × 1013 total viral particles of an Adenoviral firefly luciferase vector with a cytomegalovirus (CMV) promotor to porcine donor hearts prior to heterotopic implantation. We have evaluated the overall levels of expression, protein activity, as well as the bio distribution of the firefly luciferase protein in a series of three heart transplants at a five-day post-transplant endpoint. The perfusion solution and the ex vivo circuitry did not influence viral vector transduction, but the serum or plasma fractions of the donor blood significantly inhibited viral vector transduction. Thus, subsequent gene delivery experiments to the explanted porcine heart utilized an autologous blood recovery approach to remove undesired plasma or serum components of the donor blood prior to its placement into the circuit. Enzymatic assessment of luciferase activity in tissues (native heart, allograft, liver etc.) obtained post-transplant day five revealed wide-spread and robust luciferase activity in all regions of the allograft (right and left atria, right and left ventricles, coronary arteries) compared to the native recipient heart. Importantly, luciferase activity in recipient heart, liver, lung, spleen, or psoas muscle was within background levels. Similar to luciferase activity, the luciferase protein expression in the allograft appeared uniform and robust across all areas of the myocardium as well as in the coronary arteries. Importantly, despite high copy number of vector genomic DNA in transplanted heart tissue, there was no evidence of vector DNA in either the recipient's native heart or liver. Overall we demonstrate a simple protocol to achieve substantial, global gene delivery and expression isolated to the cardiac allograft. This introduces a novel method of viral vector delivery that opens the opportunity for biological modification of the allograft prior to implantation that may improve post-transplant outcomes.

Two-Phase Hospital-Associated Outbreak of Mycobacterium abscessus: Investigation and Mitigation.

BACKGROUND: Nontuberculous mycobacteria (NTM) commonly colonize municipal water supplies and cause healthcare-associated outbreaks. We investigated a biphasic outbreak of Mycobacterium abscessus at a tertiary care hospital. METHODS: Case patients had recent hospital exposure and laboratory-confirmed colonization or infection with M. abscessus from January 2013 through December 2015. We conducted a multidisciplinary epidemiologic, field, and laboratory investigation. RESULTS: The incidence rate of M. abscessus increased from 0.7 cases per 10000 patient-days during the baseline period (January 2013-July 2013) to 3.0 cases per 10000 patient-days during phase 1 of the outbreak (August 2013-May 2014) (incidence rate ratio, 4.6 [95% confidence interval, 2.3-8.8]; P < .001). Thirty-six of 71 (51%) phase 1 cases were lung transplant patients with positive respiratory cultures. We eliminated tap water exposure to the aerodigestive tract among high-risk patients, and the incidence rate decreased to baseline. Twelve of 24 (50%) phase 2 (December 2014-June 2015) cases occurred in cardiac surgery patients with invasive infections. Phase 2 resolved after we implemented an intensified disinfection protocol and used sterile water for heater-cooler units of cardiopulmonary bypass machines. Molecular fingerprinting of clinical isolates identified 2 clonal strains of M. abscessus; 1 clone was isolated from water sources at a new hospital addition. We made several water engineering interventions to improve water flow and increase disinfectant levels. CONCLUSIONS: We investigated and mitigated a 2-phase clonal outbreak of M. abscessus linked to hospital tap water. Healthcare facilities with endemic NTM should consider similar tap water avoidance and engineering strategies to decrease risk of NTM infection.

Cardiopulmonary Bypass Strategy for a Cyanotic Child With Hemoglobin SC Disease.

Hemoglobin SC (HbSC) disease is a hemoglobinopathy that may produce sickling under conditions of hypoxemia, dehydration, and acidosis. We present a case of HbSC disease and tricuspid atresia, type IB. We describe management by cardiopulmonary bypass CPB using exchange transfusion at initiation of bypass and fractionation of collected blood, allowing platelet and plasma apheresis, as an option for patients unable to undergo this procedure off pump.

A change in anticoagulation monitoring improves safety, reduces transfusion, and reduces costs in infants on cardiopulmonary bypass.

BACKGROUND: An immature coagulation system coupled with the hypothermia and hemodilution associated with cardiopulmonary bypass (CPB) in infants makes the activated clotting time (ACT) an ineffective monitor for anticoagulation in this population. The Medtronic HMS Plus Hemostasis Management System (HMS; Medtronic, Inc., Minneapolis, MN, USA) is shown to decrease thrombin generation and blood product requirements. AIM: We conducted a quality improvement initiative to test our hypothesis that the use of HMS results in reduced incidence of subtherapeutic ACT values, blood product usage, and operating room time for infants undergoing cardiac surgery. METHODS: Fifty consecutive patients weighing <10 kg having cardiac surgery requiring CPB had anticoagulation managed by the HMS. Data were compared to that of 50 consecutive patients weighing <10 kg having cardiac surgery who had their anticoagulation monitored by the ACT alone. Comparisons between categorical variables were performed with chi-square tests. Comparisons between continuous variables were performed with the Wilcoxon rank-sum test. Statistical significance was defined as two-tailed P value < 0.05. RESULTS: The HMS group had a 61% decrease in incidence of ACT values <480 s and elimination of ACT values < 400 s at any time on bypass. The HMS group received fewer blood products and spent fewer minutes in the operating room after protamine administration, translating to fewer donor exposures and a savings of $403 in transfusion costs and $440 in operating room time costs. CONCLUSION: Our findings highlight the benefits of individualized heparinization for pediatric patients undergoing CPB with a monitored heparinization system.

Bridge to transplant with extracorporeal membrane oxygenation followed by HeartWare ventricular assist device in a child.

A 10-year-old boy was admitted with dilated cardiomyopathy. Before scheduled implantation of a HeartWare ventricular assist device, he experienced a cardiac arrest and required extracorporeal membrane oxygenation for both cardiac and pulmonary support. After 4 days of extracorporeal membrane oxygenation and 126 days of support on the HeartWare ventricular assist device, he underwent successful cardiac transplantation. He is doing well 6 months after transplantation.

Active rehabilitation during extracorporeal membrane oxygenation as a bridge to lung transplantation.

BACKGROUND: Patients with end-stage lung disease often progress to critical illness, which dramatically reduces their chance of survival following lung transplantation. Pre-transplant deconditioning has a significant impact on outcomes for all lung transplant patients, and is likely a major contributor to increased mortality in critically ill lung transplant recipients. The aim of this report is to describe a series of patients bridged to lung transplant with extracorporeal membrane oxygenation (ECMO) and to examine the potential impact of active rehabilitation and ambulation during pre-transplant ECMO. METHODS: This retrospective case series reviews all patients bridged to lung transplantation with ECMO at a single tertiary care lung transplant center. Pre-transplant ECMO patients receiving active rehabilitation and ambulation were compared to those patients who were bridged with ECMO but did not receive pre-transplant rehabilitation. RESULTS: Nine consecutive subjects between April 2007 and May 2012 were identified for inclusion. One-year survival for all subjects was 100%, with one subject alive at 4 months post-transplant. The 5 subjects participating in pre-transplant rehabilitation had shorter mean post-transplant mechanical ventilation (4 d vs 34 d, P = .01), ICU stay (11 d vs 45 d, P = .01), and hospital stay (26 d vs 80 d, P = .01). No subject who participated in active rehabilitation had post-transplant myopathy, compared to 3 of 4 subjects who did not participate in pre-transplant rehabilitation on ECMO. CONCLUSIONS: Bridging selected critically ill patients to transplant with ECMO is a viable treatment option, and active participation in physical therapy, including ambulation, may provide a more rapid post-transplantation recovery. This innovative strategy requires further study to fully evaluate potential benefits and risks.

Improved survival but marginal allograft function in patients treated with extracorporeal membrane oxygenation after lung transplantation.

BACKGROUND: Previous reports demonstrate that 1-year survival is severely compromised in patients with severe primary graft dysfunction (PGD) after lung transplantation. We examined if advances in extracorporeal membrane oxygenation (ECMO) support, including polymethylpentene oxygenators and reliance on venovenous (VV) ECMO have improved outcomes in patients with severe PGD after lung transplantation. METHODS: The analysis included data prospectively collected on all single-lung or double-lung transplants between November 2001 and December 2009. Heart-lung transplants were excluded. Comparisons were made between recipients who did and did not require ECMO for PGD after transplant. RESULTS: Since November 2001, when VV ECMO became the routine treatment for severe PGD after transplant at our center, 28 of 498 patients (6%) have required VV ECMO support. Successful weaning occurred in 27 of 28 (96%). Support was withdrawn for 1 patient with irreversible neurologic injury. Survival was substantially better than in previous reports: 30 days, 82%; 1 year, 64%; and 5 years, 49%. Freedom from bronchiolitis obliterans syndrome was 88% in the ECMO survivors at 3 years, but maximum allograft function was considerably worse than in transplant recipients not requiring ECMO (peak forced expiratory volume in 1 second: 58% in ECMO vs 83% in non-ECMO, p=0.001). CONCLUSIONS: Advances in ECMO technology, particularly VV ECMO, have greatly improved the ability to support patients with severe PGD after lung transplantation. VV ECMO is an important tool in the armamentarium of any lung transplant program to optimize patient outcomes; however, strategies to improve lung allograft function in patients experiencing severe PGD are still needed.

Improved results treating lung allograft failure with venovenous extracorporeal membrane oxygenation.

BACKGROUND: Primary graft failure remains a significant source of mortality after lung transplantation. Extracorporeal membrane oxygenation (ECMO) provides treatment for affected recipients. We hypothesized that venovenous membrane oxygenation provides a safer alternative than venoarterial support for lung recipients suffering from primary graft failure. METHODS: We conducted an analysis of 522 patients who underwent lung transplantation from April 1992 to July 2004. Twenty-three (4.5%) patients required membrane oxygenation secondary to primary graft failure unresponsive to conventional treatment. Of these recipients, 15 (65%) were treated with venoarterial, while 8 (35%) underwent venovenous membrane oxygenation. RESULTS: Median days to initiation and duration of membrane oxygenation did not differ between groups. Eight of 15 patients (53%) from the venoarterial group were successfully weaned from life support, with one surviving greater than 45 days. This lone long-term survivor required retransplantation 4 days after initial transplant. In contrast, all venovenous patients were weaned from support, with 7 of 8 surviving greater than 30 days. The 30-day survival for venovenous recipients (88%) approximates that of all lung recipients at our center (94%, p = 0.42). Noted complications for ECMO patients included renal failure (n = 16), neurologic catastrophes (n = 8), sepsis (n = 5), and hemorrhage (n = 10). The venoarterial recipients suffered 30 of 39 total complications. Most of the complications for venovenous recipients involved renal failure, but by hospital discharge these patients demonstrated a mean creatinine of 0.9 mg/dL. CONCLUSIONS: For lung recipients with primary graft failure, venovenous membrane oxygenation provides better outcomes, with fewer complications, than venoarterial membrane oxygenation.

An isolated limb infusion technique: a guide for the perfusionist.

Isolated limb perfusion with the administration of cytotoxic drugs has been successfully used to treat melanomas of the extremity since it was first introduced in 1958. The use of hyperthermia (40 degrees C) combined with chemotherapy agents, primarily melphalan, has resulted in greater cytotoxicity in laboratory studies, which led to the application of hyperthermia in clinical studies during the 1960s. The effectiveness of this regional technique and the absence of any good systemic therapy made hyperthermic-isolated limb perfusion (HILP) the main treatment for patients with regionally advanced melanoma. HILP involves open surgical dissection and cannulation of the peripheral vessels and is associated with moderate morbidity rates. Blood transfusions, systemic drug leak, infection, and damage to the blood vessels and nerves are all potential hazards associated with this technique. Recently, however, there has been increased interest in an alternative technique termed isolated limb infusion (ILI), which was first reported in 1994 from the Sydney Melanoma Unit in Australia. Based on a few single institution experiences, it was found that there are fewer morbidities associated with HILP than with ILI but no compromise in patient outcomes. ILI is a less invasive procedure involving the use of angiographically placed catheters inserted percutaneously through the femoral vessels that does not require blood donor exposure or use of a heart lung machine. Preliminary data suggest that the resultant local hypoxia and acidosis induced by this procedure potentiates the cytotoxic effects of melphalan. Response rates comparing ILI to HILP seem similar, and both are markedly better than systemic chemotherapy. ILI may be a more desirable option because morbidity is greatly reduced and outcomes appear similar. There is a potential role for the perfusionist in the application of ILI, an evolving area of cancer therapy.