Vincent Pellegrino’s research while affiliated with Monash University (Australia) and other places

A critical factor in thrombus formation during venoarterial extracorporeal membrane oxygenation (VA ECMO) is prothrombotic flow dynamics generated by the drainage cannula’s design. This study aimed to create and evaluate a novel drainage cannula design which optimized blood flow dynamics to reduce thrombus formation. Computational fluid dynamics (CFD) was used to iteratively vary drainage cannula design parameters such as inner wall shape and side hole shape. The final novel design was then placed in an ex vivo blood circulation loop, and compared against a Bio-Medicus cannula (n = 6, each). Clot volume, hemolysis, and other parameters were measured to assess thrombus formation markers. The novel design consisted of a parabolic inner wall profile with closely spaced side holes angled at 30º to align with flow. When tested in the ex vivo loop, the novel design resulted in lower instances (two vs . four) and volumes of clot in the cannula (360.5 ± 254.8 vs . 1258.0 ± 651.7 µl) when compared to the Bio-Medicus cannula. Results from tests assessing hemolysis, platelet activation, and other thrombotic markers revealed a noninferior relationship between the novel and Bio-Medicus designs. Future work will explore the clinical applicability of these findings.

This study aimed to describe the population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) and to identify dosing regimens with a high likelihood of achieving effective exposures. Serial blood samples were collected over a single-dosing interval during ECMO. Total plasma concentrations were measured by a validated chromatographic assay. A population pharmacokinetic model was built and Monte Carlo dosing simulations were performed using Monolix. The probability of target attainment (PTA) and fractional target attainment (FTA) rates were simulated for various caspofungin dosing regimens against Candida albicans, Candida glabrata, and Candida parapsilosis. In all, 64 plasma concentration-time points were obtained from 8 critically ill patients receiving ECMO. Plasma concentration-time data for caspofungin were best described by a one-compartment model with first-order elimination. Lean body weight was identified as a significant covariate of volume of distribution. The typical volume of distribution and clearance of caspofungin in this cohort were 8.13 L and 0.55 L/h, respectively. The licensed caspofungin dosing regimen (a loading dose of 70 mg on day 1 followed by a maintenance dose of either 50 mg/day or 70 mg/day) demonstrated optimal PTA rates (≥90%) against C. albicans with an MIC of ≤0.064 mg/L, C. glabrata with an MIC of ≤0.125 mg/L, and C. parapsilosis with an MIC of ≤0.064 mg/L. The FTA analysis suggested that the licensed dosing regimen is only optimal (≥95%) against Candida glabrata, regardless of lean body weight. A higher-than-standard empirical dosing regimen (e.g., a loading dose of 100 mg on day 1, followed by a maintenance dose of 100 mg daily) is likely advantageous for critically ill patients receiving ECMO.

Objective Extracorporeal membrane oxygenation (ECMO) is a high-risk procedure with significant morbidity and mortality and there is an uncertain volume-outcome relationship, especially regarding long-term functional outcomes. The aim of this study was to examine the association between ECMO centre volume and long-term death and disability outcomes. Design, setting, and participants This is a registry-embedded observational cohort study. Patients were included if they were enrolled in the binational ECMO registry (EXCEL). The exclusion criteria included patients on ECMO for heart/lung transplants. Data included demographics, clinical information on their first ECMO run, and six-month outcomes obtained by telephone interview. The primary outcome was death or new disability at six months. A multivariable analysis was conducted using hospitals' annual ECMO volume. High-volume centres were defined as having >30 ECMO cases annually, and analyses were run on ECMO subgroups of veno-venous (VV), veno-arterial (VA), and extracorporeal cardiopulmonary resuscitation (ECPR). Results Of 1232 patients, 663 patients were cared for on ECMO at high-volume centres and 569 patients at low-volume centres. There was no difference in six-month death or new disability between high- and low-volume ECMO centres in VV-ECMO [OR: 1.09 (0.65–1.83), p = 0.744], VA-ECMO [OR: 1.10 (0.66–1.84), p = 0.708], and ECPR-ECMO [OR: 1.38 (0.37–5.08), p = 0.629]. This finding was persistent in all sensitivity analyses, including exclusion of patients who were transferred between high- and low-volume centres. Conclusion There was no difference in death or disability at six months between high- and low-volume centres in Australia and New Zealand, possibly due to the current model of coordinated care that includes patient transfers and training between high- and low-volume ECMO centres in our region.

Patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) frequently develop arterial hyperoxaemia, which may be harmful. However, lower oxygen saturation targets may also lead to harmful episodes of hypoxaemia. In this registry-embedded, multicentre trial, we randomly assigned adult patients receiving VA-ECMO in an intensive care unit (ICU) to either a conservative (target SaO2 92–96%) or to a liberal oxygen strategy (target SaO2 97–100%) through controlled oxygen administration via the ventilator and ECMO gas blender. The primary outcome was the number of ICU-free days to day 28. Secondary outcomes included ICU-free days to day 60, mortality, ECMO and ventilation duration, ICU and hospital lengths of stay, and functional outcomes at 6 months. From September 2019 through June 2023, 934 patients who received VA-ECMO were reported to the EXCEL registry, of whom 300 (192 cardiogenic shock, 108 refractory cardiac arrest) were recruited. We randomised 149 to a conservative and 151 to a liberal oxygen strategy. The median number of ICU-free days to day 28 was similar in both groups (conservative: 0 days [interquartile range (IQR) 0–13.7] versus liberal: 0 days [IQR 0–13.7], median treatment effect: 0 days [95% confidence interval (CI) – 3.1 to 3.1]). Mortality at day 28 (59/159 [39.6%] vs 59/151 [39.1%]) and at day 60 (64/149 [43%] vs 62/151 [41.1%] were similar in conservative and liberal groups, as were all other secondary outcomes and adverse events. The conservative group experienced 44 (29.5%) major protocol deviations compared to 2 (1.3%) in the liberal oxygen group (P < 0.001). In adults receiving VA-ECMO in ICU, a conservative compared to a liberal oxygen strategy, did not affect the number of ICU-free days to day 28.

OBJECTIVES To determine the actual cost and drivers of the cost of an extracorporeal cardiopulmonary resuscitation (E-CPR) care cycle. PERSPECTIVE A time-driven activity-based costing study conducted from a healthcare provider perspective. SETTING A quaternary care ICU providing around-the-clock E-CPR service for out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) in Australia. METHODS The E-CPR care cycle was defined as the time from initiating E-CPR to hospital discharge or death of the patient. Detailed process maps with discrete steps and probabilistic decision nodes accounting for the complex trajectories of E-CPR patients were developed. Data about clinical and nonclinical resources and timing of activities was collected multiple times for each process . Total direct costs were calculated using the time estimates and unit costs per resource for all clinical and nonclinical resources. The total direct costs were combined with indirect costs to obtain the total cost of E-CPR. RESULTS From 10 E-CPR care cycles observed during the study period, a minimum of 3 observations were obtained per process. The E-CPR care cycle’s mean (95% CI) cost was $75,014 ($66,209–83,222). Initiation of extracorporeal membrane oxygenation (ECMO) and ECMO management constituted 18% of costs. The ICU management (35%) and surgical costs (20%) were the primary cost determinants. IHCA had a higher mean (95% CI) cost than OHCA ($87,940 [75,372–100,570] vs. 62,595 [53,994–71,890], p < 0.01), mainly because of the increased survival and ICU length of stay of patients with IHCA. The mean cost for each E-CPR survivor was$129,503 ($112,422–147,224). CONCLUSIONS Significant costs are associated with E-CPR for refractory cardiac arrest. The cost of E-CPR for IHCA was higher compared with the cost of E-CPR for OHCA. The major determinants of the E-CPR costs were ICU and surgical costs. These data can inform the cost-effectiveness analysis of E-CPR in the future.

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.

OBJECTIVES: This review aims to: 1) identify the key circuit and patient factors affecting systemic oxygenation, 2) summarize the literature reporting the association between hyperoxia and patient outcomes, and 3) provide a pragmatic approach to oxygen titration, in patients undergoing peripheral venoarterial extra-corporeal membrane oxygenation (ECMO). DATA SOURCES: Searches were performed using PubMed, SCOPUS, Medline, and Google Scholar. STUDY SELECTION: All observational and interventional studies investigating the association between hyperoxia, and clinical outcomes were included, as well as guidelines from the Extracorporeal Life Support Organization. DATA EXTRACTION: Data from relevant literature was extracted, summarized, and integrated into a concise narrative review. For ease of reference a summary of relevant studies was also produced. DATA SYNTHESIS: The extracorporeal circuit and the native cardiorespiratory circuit both contribute to systemic oxygenation during venoarterial ECMO. The ECMO circuit's contribution to systemic oxygenation is, in practice, largely determined by the ECMO blood flow, whereas the native component of systemic oxygenation derives from native cardiac output and residual respiratory function. Interactions between ECMO outflow and native cardiac output (as in differential hypoxia), the presence of respiratory support, and physiologic parameters affecting blood oxygen carriage also modulate overall oxygen exposure during veno-arterial ECMO. Physiologically those requiring venoarterial ECMO are prone to hyperoxia. Hyperoxia has a variety of definitions, most commonly Pao 2 greater than 150 mm Hg. Severe hypoxia (Pao 2 > 300 mm Hg) is common, seen in 20%. Early severe hyperoxia, as well as cumulative hyperoxia exposure was associated with in-hospital mortality, even after adjustment for disease severity in both venoarterial ECMO and extracorporeal cardiopulmonary resuscitation. A pragmatic approach to oxygenation during peripheral venoarterial ECMO involves targeting a right radial oxygen saturation target of 94-98%, and in selected patients, titration of the fraction of oxygen in the mixture via the air-oxygen blender to target postoxygen-ator Pao 2 of 150-300 mm Hg. CONCLUSIONS: Hyperoxia results from a range of ECMO circuit and patient-related factors. It is common during peripheral venoarterial ECMO, and its presence is associated with poor outcome. A pragmatic approach that avoids hyperoxia, while also preventing hypoxia has been described for patients receiving peripheral venoarterial ECMO.

OBJECTIVES To determine the concordance between activated partial thromboplastin time (aPTT) and anti-factor-Xa (anti-Xa) in adults undergoing extracorporeal membrane oxygenation (ECMO) and to identify the factors associated with discordant paired aPTT/anti-Xa. DESIGN Pre-planned secondary analysis of the Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation pilot randomized unblinded, parallel-group controlled trial. SETTING Two ICUs in two university hospitals. PATIENTS Thirty-two critically ill patients who underwent ECMO and who had at least one paired aPTT and anti-Xa assay performed at the same time. INTERVENTIONS We analyzed the concordance between aPTT and anti-Xa and identified factors associated with discordant paired aPTT/anti-Xa based on their respective therapeutic ranges. We also compared biological parameters between heparin resistance episode and no heparin resistance. MEASUREMENTS AND MAIN RESULTS Of the 32 patients who were included in this study, 24 (75%) had at least one discordant paired aPTT/anti-Xa. Of the 581 paired aPTT/anti-Xa that were analyzed, 202 were discordant. The aPTT was relatively lower than anti-Xa in 66 cases (32.7%) or relatively higher than anti-Xa in 136 cases (67.3%). Thirty-three heparin resistance episodes were identified in six patients (19%). CONCLUSIONS In these critically ill patients undergoing ECMO, one third of paired aPTT/anti-Xa measures was discordant. Coagulopathy and heparin resistance might be the reasons for discordance. Our results support the potential importance of routinely monitoring both tests in this setting.

Background and Aims While endomyocardial biopsy (EMB) is recommended in adult patients with fulminant myocarditis, the clinical impact of its timing is still unclear. Methods Data were collected from 419 adult patients with clinically suspected fulminant myocarditis admitted to intensive care units across 36 tertiary centres in 15 countries worldwide. The diagnosis of myocarditis was histologically proven in 210 (50%) patients, either by EMB (n = 183, 44%) or by autopsy/explanted heart examination (n = 27, 6%), and clinically suspected cardiac magnetic resonance imaging confirmed in 96 (23%) patients. The primary outcome of survival free of heart transplantation (HTx) or left ventricular assist device (LVAD) at 1 year was specifically compared between patients with early EMB (within 2 days after intensive care unit admission, n = 103) and delayed EMB (n = 80). A propensity score-weighted analysis was done to control for confounders. Results Median age on admission was 40 (29–52) years, and 322 (77%) patients received temporary mechanical circulatory support. A total of 273 (65%) patients survived without HTx/LVAD. The primary outcome was significantly different between patients with early and delayed EMB (70% vs. 49%, P = .004). After propensity score weighting, the early EMB group still significantly differed from the delayed EMB group in terms of survival free of HTx/LVAD (63% vs. 40%, P = .021). Moreover, early EMB was independently associated with a lower rate of death or HTx/LVAD at 1 year (odds ratio of 0.44; 95% confidence interval: 0.22–0.86; P = .016). Conclusions Endomyocardial biopsy should be broadly and promptly used in patients admitted to the intensive care unit for clinically suspected fulminant myocarditis.