Faculty Bibliography

OBJECTIVES/OBJECTIVE:We aimed to critically evaluate the effectiveness of a designated ECMO team in our ECMO selection process and patient outcomes in the first 3 years of our low-volume pediatric ECMO program. METHODS:We conducted a retrospective chart review of patients who received an ECMO consultation between the start of our program in March 2015 and May 2018. We gathered clinical and demographic information on patients who did and did not receive ECMO, and described our selection process. We reflected on the processes used to initiate our program and our outcomes in the first 3 years. RESULTS:, lactate, and pH between the patients who went on ECMO and who did not. We improved our outcomes from 0% survival to discharge in 2015, to 60% in 2018, with an average of 63% survival to discharge over the first 3 years of our program. CONCLUSIONS:In a low-volume pediatric ECMO center, having a designated team to assist in the patient selection process and management can help provide safe and efficient care to these patients, and improve patient outcomes. Having a strict management protocol and simulation sessions involving all members of the medical team yields comfort for the providers and optimal care for patients. This study describes our novel structure, processes, and outcomes, which we hope will be helpful to others seeking to develop a new pediatric ECMO program.

INTRODUCTION: Extra-corporeal membrane oxygenation (ECMO) is a treatment modality known to alter drug pharmacokinetics (PK). The PK changes can result from drug binding to the oxygenator, alterations in clearance, and drug adsorption or sequestration. Levels of drug absorption by polymers, silicone rubber and other materials have been linked to the drugs' lipophilicity and the published literature is mostly outdated. Additionally, there is limited data regarding the impact of the oxygenator on drug changes in ECMO circuits in comparison to the other components of the ECMO circuit. The purpose of this study was to determine the impact of the Quadrox-i pediatric and adult oxygenators on the PK of remdesivir (RDV) in contemporary ECMO circuits.
METHOD(S): One 1/4-in. and one 3/8-in. closed loop ECMO circuits were prepared using custom tubing with polyvinylchloride and superTygon (Medtronic Inc., Minneapolis, MN) and a Quadrox-i adult or pediatric oxygenator (Maquet). Additionally, one 1/4-in. and one 3/8- in. closed loop ECMO circuits were assembled without an oxygenator in series. RDV was added to the circuit and levels were obtained pre-and post-oxygenator at the following time intervals; 5 mins, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hrs. RDV was also maintained in a glass vial and samples obtained at the same time periods for control purposes. RDV samples were analyzed by liquid chromatography tandem mass spectrometry.
RESULT(S): For the 3/8-in. circuit with and without an oxygenator, there was a 60-70% RDV loss during the study period. For the 1/4-in. circuits with an oxygenator, there was a 35-60% RDV loss during the study period. For the 1/4-in. circuits without an oxygenator, there was a 5-20% RDV loss during the study period.
CONCLUSION(S): There was RDV loss within the circuit during the study period and the RDV loss was more pronounced with the larger 3/8-in circuit when compared with the 1/4-in. circuit. This preliminary data suggests RDV dosing may need to be adjusted for concern of drug loss via the ECMO circuit. Additional single and multiple dose studies are needed to validate these findings

INTRODUCTION/BACKGROUND:oxygenator. METHODS: RESULTS:For the 1/4-in. circuit with an oxygenator, there was < 15% PRV loss, and for the 1/4-in. circuit without an oxygenator, there was < 3% PRV loss during the study period. For the 3/8-in. circuits with an oxygenator, there was < 15% PRV loss, and for the 3/8-in. circuits without an oxygenator, there was < 3% PRV loss during the study period. CONCLUSION/CONCLUSIONS:the oxygenator. Additional single and multiple dose studies are needed to validate these findings.

INTRODUCTIONS: ECMO is a treatment modality known to alter drug pharmacokinetics (PK). The purpose of this study was to determine the impact of the Quadrox-i pediatric and adult oxygenators on the PK of peramivir (PRV) in contemporary ECMO circuits.
METHOD(S):Two 1/4-in. and two 3/8-in. closed loop ECMO circuits were prepared using custom tubing with polyvinylchloride and superTygon (Medtronic Inc., Minneapolis, MN) and a Quadrox-i adult or pediatric oxygenator (Maquet). Additionally, two 1/4-in. and two 3/8-in. closed loop ECMO circuits wer assembled without an oxygenator in series. The circuits were carbon dioxide primed, evacuated, and then crystalloid primed. After debubbling the circuit, 50 mL of 5% albumin was added and then displaced with the priming solution (whole blood), tromethamine, heparin, and calcium gluconate. The circuit pH was adjusted to a range of 7.35-7.45. The closed-loop design was established by connecting the ends of the arterial and venous cannulae to a reservoir bag, allowing continuous flow of the priming fluid around the circuit. PRV was added to the circuit and levels were obtained pre-and post-oxygenator at the following time intervals; 5 mins, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hrs. PRV was also maintained in a glass vial and samples obtained at the same time periods for control purposes. PRV samples were analyzed by liquid chromatography tandem mass spectrometry.
RESULT(S): For the 3/8-in. circuits with an oxygenator, there was < 15% PRV loss during the study period. For the 3/8-in. circuits without an oxygenator, there was < 3% PRV loss during the study period. For the 1/4-in. circuits with an oxygenator, there was < 15% PRV loss during the study period. For the 1/4-in. circuits without an oxygenator, there was < 3% PRV loss during the study period.
CONCLUSION(S): There was no significant PRV loss over the 24-hour study period in either the 1/4-in. or 3/8-in circuit, regardless of the presence of the oxygenator. The concentrations obtained pre- and post-oxygenator appeared to approximate each other suggesting there may be no drug loss via the oxygenator. This preliminary data suggests PRV dosing may not need to be adjusted for concern of drug loss via the oxygenator. Additional single and multiple dose studies are needed to validate these findings

Extracorporeal membrane oxygenation (ECMO) is known to alter drug pharmacokinetics (PK). The PK changes can result from drug binding to the oxygenator, alterations in clearance, and drug sequestration but the published literature is outdated. There is limited data regarding the impact of the oxygenator on drug changes in ECMO circuits in comparison to the other components of the ECMO circuit. The purpose of this study was to determine the impact of the Quadrox-i pediatric and adult oxygenators on the PK of peramivir (PRV) in contemporary ECMO circuits. Two of both 1/4-in. and 3/8-in. closed loop ECMO circuits were prepared with a Quadrox-i adult or pediatric oxygenator (Getinge) and two of both sizes without an oxygenator in series. The circuits were primed with 20 mL of 5% albumin, packed red blood cells, heparin, sodium bicarbonate and calcium gluconate. Circuits were run at 1L/minute continuously. PRV was added to the circuit and levels were obtained pre-and postoxygenator at the following time intervals; 5 mins,1, 2, 3, 4, 5, 6, 8,12, and 24 hrs. PRV was also maintained in a glass vial and samples obtained at the same time periods. The results were consistent in both circuit sizes with no significant PRV loss over the 24-hour study period (<15% loss with oxygenator and <3% loss without oxygenator). This preliminary data suggests PRV dosing may not need to be adjusted for concern of drug loss via the oxygenator. Additional single and multiple dose studies are needed to validate these findings

Study: Our Pediatric ECMO Program implemented ECMO Safety Rounds (ESR) as a quality improvement (QI) initiative. Objectives were to ensure implementation of protocols, immediately correct quality/safety deficiencies, and provide real-time education to nurses and perfusionists. Our specific aim was to track compliance with this process-improvement bundle and identify areas to target with QI efforts, with a long-term global aim of reducing quality/safety variances and patient harm over time. XXMethod(s): Our team initiated Pediatric ESR in September 2019. Two process- based QI bundles were developed: (1) Circuit Safety - 35 bundle elements, including maintenance and emergency checks; (2) Patient Safety - 13 bundle elements focused on nursing practices specific to minimizing patient harm. Pediatric ESR consisted of these two bundle assessments performed by designated ESR clinicians at the bedside with the patient's nurse and perfusionist. Credit for bundle compliance was awarded only if all elements were properly met. Noncompliant elements were addressed in real-time. All data was recorded in REDCap database. XXResult(s): 36 Pediatric ESRs were completed (Sept. 2019 - Jan. 2021). Monthly bundle compliance was reported using run charts. Median compliance with both bundles appeared to improve over time, with their most recent centerlines both at 67% compliance (Figure 1). Analysis of individual bundle elements revealed that 19/48 (40%) safety items were deficient at least once during the 36 ESRs (Table 1). Any individual bundle element with greater than 2 noncompliance events prompted our team to target interventions addressing these lapses, including new protocols and education, conducting multidisciplinary reviews, and collaborating with ancillary departments. We conclude that Pediatric ESR provides real-time assessment of compliance, immediate corrective and education measures, and actionable data to drive performance improvement around observed vulnerabilities in ECMO protocols

INTRODUCTION/UNASSIGNED:oxygenator. METHODS/UNASSIGNED:1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of MEM/VBR was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, 8, 12, and 24-hour time points. MEM/VBR was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. RESULTS/UNASSIGNED:For the 1/4-inch circuit, there was an approximate mean 55% MEM loss with the oxygenator in series and a mean 33%-40% MEM loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was an approximate mean 70% MEM loss with the oxygenator in series and a mean 30%-38% MEM loss without an oxygenator in series at 24 hours. For both the 1/4-inch circuit and 3/8-inch circuits with and without an oxygenator, there was <10% VBR loss for the duration of the experiment. CONCLUSIONS/UNASSIGNED:This ex-vivo investigation demonstrated substantial MEM loss within an ECMO circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and no significant VBR loss. Further evaluations with multiple dose in-vitro and in-vivo investigations are needed before specific MEM/VBR dosing recommendations can be made for clinical application with ECMO.

BACKGROUND:Outcomes in neonates receiving extracorporeal membrane oxygenation (ECMO) for meconium aspiration syndrome (MAS) and/or persistent pulmonary hypertension (PPHN) are favorable. Infants with preserved perfusion are often offered venovenous (VV) support to spare morbidities of venoarterial (VA) ECMO. Worsening perfusion or circuit complications can prompt conversion from VV-to-VA support. We examined whether outcomes in infants requiring VA ECMO for MAS/PPHN differed if they underwent VA support initially versus converting to VA after a VV trial, and what factors predicted conversion. METHODS:We reviewed the Extracorporeal Life Support Organization registry from 2007 to 2017 for neonates with primary diagnoses of MAS/PPHN. Propensity score analysis matched VA single-runs (controls) 4:1 against VV-to-VA conversions based on age, pre-ECMO pH, and precannulation arrests. Primary outcomes were complications and survival. Data were analyzed using Mann-Whitney U and Fisher's exact testing. Multivariate regression identified independent predictors of conversion for VV patients. RESULTS:3831 neonates underwent ECMO for MAS/PPHN, including 2129 (55%) initially requiring VA support. Of 1702 patients placed on VV ECMO, 98 (5.8%) required VV-to-VA conversion. Compared with 364 propensity-matched isolated VA controls, conversion runs were longer (190 vs. 127 h, P < 0.001), were associated with more complications, and decreased survival to discharge (70% vs. 83%, P = 0.01). On multivariate regression, conversion was more likely if neonates on VV ECMO did not receive surfactant (OR = 1.7;95%CI = 1.1-2.7;P = 0.03) or required high-frequency ventilation (OR = 1.9;95%CI = 1.2-3.3;P = 0.01) before ECMO. CONCLUSION/CONCLUSIONS:Conversion from VV-to-VA ECMO in infants with MAS/PPHN conveys increased morbidity and mortality compared to similar patients placed initially onto VA ECMO. VV patients not receiving surfactant or requiring high-frequency ventilation before cannulation may have increased risk of conversion. While conversions remain rare, decisions to offer VV ECMO for MAS/PPHN must be informed by inferior outcomes observed should conversion be required. LEVEL OF EVIDENCE/METHODS:Level of evidence 3 Retrospective comparative study.

INTRODUCTION: Remdesivir (RDV) is an antiviral agent with in-vitro activity against SARS-CoV-2 that has been used during the COVID-19 pandemic. Dosing strategies for pediatric and adolescent patients have primarily been extrapolated from adult dosing recommendations and, to date, there is a lack of pharmacokinetic (PK) data of RDV in this patient population.
METHOD(S): Electronic medical record review of patients receiving RDV with concurrent therapeutic drug monitoring (TDM). RDV and GS-441524 concentrations were determined by LC-MS/MS methodology.
RESULT(S): 3 patients (2 female:1 male) met inclusion criteria and contributed 74 samples for determination of RDV and the active GS-441524 metabolite. The median age was 16 yrs (IQR 15.5-16 yrs) with a median weight of 76.4 kg (IQR 74.9-94.3kg). Patient #1 received ECMO support for the duration of RDV therapy. Patients #1 and 2 received RDV for 10 days with levels obtained daily. Patient #3 received RDV for 5 days with levels obtained daily. For all patients, mean RDV exposures, range 272-893 ng/mL were below the mean exposures reported in the RDV investigators brochure, 2900-7800 ng/mL. Patient #1 received ECMO and RDV exposures did not appear impacted by ECMO when compared with patients #2 and #3 that did not receive ECMO. For all patients, mean GS-441524 exposures, range 109-258 ng/mL, were similar to the mean exposures reported in the RDV investigators brochure, range 69-184 ng/mL. Similarly, the GS-441524 exposure did not appear to be affected by ECMO. Patients #1 and #2 did not appear to have any observable adverse events as a result of receiving RDV. Patient #3 experienced and increase in ALT >5x ULN which resulted in having RDV discontinued. All 3 patients experienced clinical resolution.
CONCLUSION(S): These are the first PK data of RDV in critically ill adolescent patients. These preliminary data suggest using adult dosing recommendations in adolescent patients result in RDV exposures below mean values demonstrated in adults with similar exposures of GS-441524 which could be a result of rapid conversion of RDV to GS- 441524 with delayed elimination in the setting of critical illness. Additional PK data of RDV in the critically ill pediatric population is warranted